VOLUME 53 NUMBER 1 MARCH 2021
معيةالطبَّيةال َجل َّ كو ا َ يت َّ ي ة
KUWAIT MEDICAL JOURNAL
The Official Journal of The Kuwait Medical Association
REVIEW ARTICLES
Overview of PCSK9 inhibitor use: Local and regional implications for the treatment of dyslipidemia 1 Taha Hasson Taha, Wasl Al-Adsani, Hany Younan
ORIGINAL ARTICLES
The pattern of skin diseases in a multidisciplinary medical unit 8 Shaima Al-Bader, Kamel El-Reshaid The relationship between different types of nutritional supportive treatment and infection in patients with diagnosis of Chronic Obstructive Pulmonary Disease 13 Unal Kantekin Cigdem, Talih Gamze The role of ultrasonographic measurement of bladder and detrusor wall thickness in diagnosis of urinary incontinence 18 Ozge Sehirli Kinci, Mehmet Ferdi Kinci, Mahmut Kuntay Kokanali, Yasemin Tasci Serotonin transporter gene polymorphism (5- HTTLPR and VNTR) among Sudanese patients with Irritable Bowel Syndrome (IBS) 25 Entsar Elamin, Nasma Elshaikh, Sara Abdelghani, Mohammed Madani, Hisham Ali Waggiallah, Lienda Bashier Eltayeb Retrospective evaluation of cancer patients in Intensive Care Unit 31 Arslan Gulten, Cevik E Banu Does bipolar transuretral resection of prostate increase the incidence of urethral stricture? 38 Eray Hasirci, Enis Kervancioglu, Hakan Ozkardes Ten years clinical and epidemiological picture of cutaneous Leishmaniasis in the Dasht-e-Azadegan County, Southwestern Iran 44 Hamid Kassiri, Ahmad Jalali, Masoumeh Mardani Kataki, Masoud Lotfi Considering the effect of Stapes Footplate’s macroscopic vision on surgical complication rate 51 Serkan Cayir, Mehmet Ali Cetin, Hacer Baran, Serdar Ensari, Haci Huseyin Dere Preliminary findings: Functionality in patients with migraine 56 Fatos Kirteke, Nilufer Cetisli-Korkmaz, Taskin Duman Molecular epidemiology of Mycobacterium tuberculosis and rifampicin resistance among pulmonary tuberculosis patients in Erbil city, Kurdistan region, Iraq 63 Fairuz H Abdullah Tawgozy, Bushra K Qarasnji Gamma-glutamyltransferase and lactic acid as markers of oxidative stress in carbon monoxide poisoning 69 Ibrahim Caltekin, Emre Gokcen, Atakan Savrun, Hilal Korkmaz, Levent Albayrak, Bilgehan Demir The relationship between nutritional status and Fetuin-A in Inflammatory Bowel Disease patients 74 Burcu Barutcuoglu, Nalan Gulsen Unal, Gunes Ak, Zuhal Parildar, Nevin Oruc, Ahmet Omer Ozutemiz
CASE REPORTS
Fusariosis as a cause of subcutaneous infection in immune-compromised patient 81 Khaled Alobaid, Deepthi Nair, Socrates Mathew Parayil Robotic radical prostatectomy in patients with cerebrovascular disease history: safe but epilepsy 84 Bahri Gok, Abdullah Erdem Canda, Erem Asil
KU ISSN 0023-5776 Continued inside Open access for articles at http: www.kmj.org.kw
Indexed and abstracted in:
SCOPUS
EMBASE (The Excerpta Medica Database)
Science Citation Index Expanded (also known as SciSearch®)
Journal Citation Reports/Science Edition
IMEMR Current Contents (Index Medicus for the Eastern Mediterranean Region) available online at: www.emro.who.int/EMRJorList/online.aspx Vol.March 53 No. 2021 1 KUWAIT MEDICAL JOURNAL MARCH 20213 KUWAIT MEDICAL JOURNAL CONTENTS
Continued from cover
A total hip arthroplasty practice in a coxarthrosis case with hereditary multiple exostoses 87 Koray Basdelioglu, Aziz Atik, Serdar Sargin Patellar tendon ganglion cyst with Osgood Schlatter disease: A rare coexistence 90 Nilufer Aylanc, Nebil Eker, Mustafa Resorlu Unusual location of the hydatid cyst: Coexistence of serratus anterior muscle and lung 93 Ibrahim Ethem Ozsoy, Mehmet Akif Tezcan Invasive fungal rhinosinusitis in a chronic kidney disease patient 97 Lubna A Khreesha, Suhaib M Eid, Mohammad Y Ghunaim
SELECTED ABSTRACTS OF ARTICLES PUBLISHED ELSEWHERE BY AUTHORS IN KUWAIT 101
FORTHCOMING CONFERENCES AND MEETINGS 104
WHO-FACTS SHEET 109
1. E.coli 2. Guillain-Barré syndrome 3. Immunization coverage 4. Newborns: improving survival and well being 5. Scabies
***
THE PUBLICATION OF ADVERTISEMENTS IN THE KUWAIT MEDICAL JOURNAL DOES NOT CONSTITUTE ANY GUARANTEE OR ENDORSEMENT BY THE KUWAIT MEDICAL ASSOCIATION OR THE EDITORIAL BOARD OF THIS JOURNAL, OF THE ADVERTISED PRODUCTS, SERVICES, OR CLAIMS MADE BY THE ADVERTISERS. THE PUBLICATION OF ARTICLES AND OTHER EDITORIAL MATERIAL IN THE JOURNAL DOES NOT NECESSARILY REPRESENT POLICY RECOMMENDATIONS OR ENDORSEMENT BY THE ASSOCIATION.
PUBLISHER: The Kuwait Medical Journal (KU ISSN-0023-5776) is a quarterly publication of THE KUWAIT MEDICAL ASSOCIATION. Address: P.O. Box 1202, 13013 Safat, State of Kuwait; Telephone: 1881181 Fax: 25317972, 25333276. E-mail : [email protected] COPYRIGHT: The Kuwait Medical Journal. All rights reserved. No part of this publication may be reproduced without written permission from the publisher. Printed in Kuwait. INSTRUCTIONS FOR AUTHORS: Authors may submit manuscripts prepared in accordance with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals. These Requirements are published in each issue of the Kuwait Medical Journal. CHANGE OF ADDRESS: Notice should be sent to the Publisher six weeks in advance of the effective date. Include old and new addresses with mail codes. KUWAIT MEDICAL JOURNAL (previously The Journal of the Kuwait Medical Association) is added to the list of journals adhering to the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals”, American College of Physicians, Independence Mall West, Sixth Street at Race, Philadelphia, PA 19106-1572, USA, and can be located at http://www.icmje.org/jrnlist.html Kuwait Medical Journal
Published by the Kuwait Medical Association Previously known as The Journal of the Kuwait Medical Association (Est. 1967)
Honorary President: Abdulaziz Al-Babtain
EDITORIAL BOARD Editor-in-Chief:Fuad Abdulla M Hasan, Kuwait Editor:Adel Khader Ayed, Kuwait International Editor:Pawan K Singal, Canada Associate Editors:Adel A Alzayed, Kuwait Ignacio Rodriguez, USA Michael Redmond, USA Mousa Khoursheed, Kuwait Mustafa M Ridha, Kuwait Nasser Behbehani, Kuwait Noura Al-Sweih, Kuwait INTERNATIONAL ADVISORY BOARD Ananda S Prasad, USA Giuseppe Botta, Italy Peter RF Bell, UK Anders Lindstrand, Sweden James W Roach, USA Philip M Moody, USA Andrew J Rees, UK Jan T Christenson, Switzerland Raymond M Kirk, UK Belle M Hegde, India John V Forester, UK Samuel Dagogo-Jack, USA Bengt Jeppsson, Sweden Julian Little, Canada S Muralidharan, India Charles A Dinarello, USA Kostadin L Karagiozov, Japan Stig Bengmark, Sweden Christian Imielinski, Poland Lewis D Ritchie, UK Tulsi D Chugh, India Elizabeth Dean, Canada Mechael M Meguid, USA William A Tweed, Canada Fiona J Gilbert, UK Mohammed Zayer, Sweden William B Greenough, USA Frank D Johnston, UK Neva E Haites, UK Zoheir Bshouty, Canada George Russell, UK Nirmal K Ganguli, India Graeme RD Catto, UK Oleg Eremin, UK
REGIONAL ADVISORY BOARD Abdulla Behbehani Habib Abul Nawaf Al-Mutairi Abeer K Al-Baho Joseph C Longenecker Nebojsa Rajacic Alexander E Omu Kefaya AM Abdulmalek Sami Asfar Ali Al-Mukaimi Khalid Al-Jarallah Soad Al-Bahar Ali Al-Sayegh Mazen Al Essa Sukhbir Singh Uppal Asmahan Al-Shubaili Mohamed AA Moussa Waleed Alazmi Chacko Mathew Mousa Khadadah Waleed A Aldhahi Eiman M Mokaddas Mustafa Al-Mousawi Faisal A Al-Kandari Nasser J Hayat EDITORIAL OFFICE
Editorial Manager : Vineetha Elizabeth Mammen EDITORIAL ADDRESS
P.O. Box: 1202, 13013-Safat, Kuwait Telephone: (00-965) 1881181(Ext. 114, 115) - Fax: (00-965) 25317972, 25333276 E-mail: [email protected] Website: www.kmj.org.kw Guidelines for Authors
Formerly known as ‘The Journal of the Kuwait Medical the editors. If there is no conflict of interest, please state: “The Association’, the Kuwait Medical Journal (KMJ) was established authors declare no conflicts of interest.” in the year 1967. It is the official publication of the Kuwait Medical Association and is published quarterly and regularly Peer Review every March, June, September and December. All submitted manuscripts are reviewed by the editorial KMJ aims to publish peer-reviewed manuscripts of staff to ensure adherence to the guidelines of the Journal. international interest. Submissions on clinical, scientific or Manuscripts that are considered suitable for review are sent to laboratory investigations of relevance to medicine and health a peer in the relevant field of study as part of a double- blinded science come within the scope of its publication. Original peer review. The reviewer may recommend the manuscript be articles, case reports, brief communications, book reviews, accepted as is, undergo revision, or be rejected. If a reviewer insights and letters to the editor are all considered. Review recommends revision of a manuscript, the revised version must articles are solicited. Basic medical science articles are published be re-submitted to the Journal within 3 months from the date under the section ‘Experimental Medicine’. when the review report is sent to the corresponding author. The Kuwait Medical Journal follows the guidelines set down in “Recommendations for the Conduct, Reporting, Authors Editing, and Publication of Scholarly Work in Medical Journals” To be named as an author on a submission, the following 4 developed by the International Committee of Medical Journal criteria are followed: Editors (ICMJE). The official and most recent version of the 1. Substantial contributions to the conception or design of the recommendations are available at www.icmje.org. work; or the acquisition, analysis, or interpretation of data for the work; AND Journal Policies 2. Drafting the work or revising it critically for important intellectual content; AND Ethics in Publishing 3. Final approval of the version to be published; AND Where human investigations are part of the study, the 4. Agreement to be accountable for all aspects of the work in research must be conducted ethically in accordance with the ensuring that questions related to the accuracy or integrity Declaration of Helsinki, and the design of the work has to be of any part of the work are appropriately investigated and approved by a local ethics committee and informed written resolved. consent must be obtained from all subjects. Documented In addition to being accountable for the parts of the work review and approval from the Institutional Review Board or he/she has done, an author should be able to identify which Ethics Committee must be submitted along with any studies co-authors are responsible for specific other parts of the work. involving people, medical records and human tissues. A Authors should also have confidence in the integrity of the relevant statement of approval should be added in the ‘Subjects contributions of their co-authors. Specific contributions made and Methods’ section of the manuscript. by each author to the article must be clearly stated at the end Authors should also consult guidelines for the reporting of the document. Those who do not meet all four criteria of specific study types (e.g., the CONSORT guidelines for the should be mentioned in the Acknowledgment section of the reporting of randomized trials); see http://equator-network.org. submission. Once a paper has been accepted, the Journal does not Copyright consider requests to add, delete or rearrange the sequence of the The publisher reserves copyright on the Journal’s contents. authors. If the corresponding author requests to add, remove or No part may be reproduced, translated or transmitted in rearrange the authors’ names after manuscript submission, the any form by any means, electronic or mechanical, including journal will seek justification for the requested change. Written scanning, photocopying, recording or any other information confirmation signed by all authors, attesting that they agree to storage and retrieval system without prior permission from the the addition, removal, or rearrangement of names is required. publisher. The publisher shall not be held responsible for any In the case of the addition or removal of authors, the author inaccuracy of the information contained therein. being added or removed must confirm assent. Requests that are not sent by the corresponding author will not be considered. Conflict of Interest The corresponding author is responsible for communication Potential conflicts of interest for all authors must be with the journal during the manuscript submission, peer review, identified in a ‘Conflict of interest’ statement at the end of the and publication process, and must ensure that all the journal’s manuscript. An electronic cover letter from the corresponding administrative requirements are properly completed. He/ author is acceptable. Authors of research articles should she should also be available throught out the submission and disclose any affiliation with any organization with a financial peer review process to respond to editorial queries in a timely interest, direct or indirect, in the subject matter or materials manner. It is also the corresponding authors responsibility to discussed in the manuscript (e.g., consultancies, employment, ensure all the co-authors are made aware of the most recent expert testimony, honoraria, retainers, stock) that may affect status of their submission. the conduct or reporting of the work submitted. If uncertain as to what might be considered a potential conflict of interest, Fees authors should err on the side of full disclosure. Because reviews Publication in the Kuwait Medical Journal is free of charge. and editorials are based on selection and interpretation of the literature, the Journal expects that authors of such articles will Plagiarism not have any financial interest in a company (or its competitor) The Journal defines plagiarism as the use of others’ that makes a product discussed in the article. Information about published and unpublished ideas or words without prior potential conflict of interest will be made available to reviewers consent, and presenting them as new and original, whether and will be published with the manuscript at the discretion of intentional or not. If an accepted or published paper is found to Guidelines for Authors be plagiarised, the manuscript will be retracted and the author Outcome Measure(s), Result(s), and Conclusion(s). (See: Haynes will be blacklisted from submitting to the journal. RB, Mulrow CD, Huth AJ, Altman DG, Gardner MJ. More informative abstracts revisited. Annals of Internal Medicine Preparing your manuscript 1990; 113:69-76). Abstracts for all other category of submissions shall be a short summary followed by Key words and the report Article types or review. Original Articles: Original Articles include laboratory and clinical investigations as well as research not previously Preparation of the manuscript published or being considered for publication elsewhere. The The manuscript should be typed as ‘normal text’ with text should contain a Title page, Abstract (in structured format) no hyphenation and no hard-returns within paragraphs (use of not more than 250 words, Key Words (no more than five), automatic wordwrap) on A4 size (29.7 x 21 cm) paper in single Introduction, Subjects (or Materials) and Methods, Results, column format, preferably in font size 12. Cell format for Discussion, Conclusion, Acknowledgment/s (if any) and paragraphs, artwork and/or special effects for the text and/or References, Figure Legends, Tables, and Figures in this order. table(s) are not acceptable. Italics shall be used only for foreign/ Details of the section contents are explained below for further Latin expressions and/or special terminologies such as names of adherence. micro-organisms. Maintain a minimum of 2 cm margin on both Review Articles (solicited only): Review articles should contain sides of the text and a 3 cm margin at the top and bottom of each separate sections such as Title Page, Abstract (preferably in page. No part of the manuscript other than abbreviations and/or structured format) of no more than 250 words, Key Words (no subtitles should be written in upper case. Header/foot notes, end more than five), Introduction, Methods/History (if applicable), notes, lines drawn to separate the paragraphs or pages etc. are Literature Review, Conclusion, Acknowledgment/s (if any) and not acceptable. Do not submit articles written/saved in ‘Track- References followed by (if relevant), Legends to figures, Tables, change’ mode. and Figures. More than six authors are not appreciated for a research Case Reports: These should contain separate sections such article and if listed, the authors may be asked to justify the as Title page, Abstract (a short summary of not more than 200 contribution of each individual author. For case reports, not words), Key Words (no more than five), Introduction, Case more than three authors are acceptable. Regarding contributions history/report, Discussion, Conclusion, Acknowledgment/s of authors over the limit mentioned above, please read the (if any) and References followed by (if relevant), Legends to ‘Acknowledgment’ section. figures, Tables, and Figures. Short Communications: Short communications are concise Key words articles that aim to report new ideas, significant improvements Key Words (maximum five) should be preferably MeSH to existing methods, a new practical application, or a new terms, and shall not duplicate words already in the manuscript tool or resource. Short communications do not cover in detail title. MeSH terms can be checked at: http://www.nlm.nih.gov/ background information about the problems treated, rather they mesh/. provide key pointers to the reader. The work reported needs to be technically sound, innovative and significantly unique, Tables advancing the state of the art. Short communication is not Tables typed on separate pages using table format (MS Word intended to publish preliminary results. Short communications or Excel) should follow the list of references. Tables must be should be similar to a research article, but with briefer Materials numbered consecutively using Arabic numerals and provided and Methods and Discussion. with appropriate titles. Contents of the table should be simple, Letters to the Editor: Letters may comment on recently and information therein not duplicated, but duly referred to, published KMJ articles, novel cases or topics of current interest in the main text. Tables recording only a few values are not to the public. They should be concise and to the point, with a appreciated, since such information can be more accurately, maximum of 1000 words and 2 authors. Letters commenting on usefully and concisely presented in a sentence or two in the previously published articles must be received within 6 months manuscript. of publication of the relevant article. Design of the work Title Page This should be stated clearly. The rationale behind the choice The title page of the submitted manuscript should provide of sample size should be given. Those about to begin randomized a clear title of the study followed by full names of all authors, controlled studies may wish to study the CONSORT statement the highest academic degree and affiliations if any, the name (JAMA 1996; 276:637-639). and address of the institution(s) where the work was done including the department, the name and complete address of Illustrations the corresponding author to whom proofs and correspondences All illustrations including figures should be numbered as shall be sent, duly supported with contacts such as telephone, Fig 1, Fig 2, etc in running sequence and submitted as separate mobile and the e-mail address. This page must also contain attachments along with the manuscript. Photographs should any disclaimers, sources of support and a conflict of interest fit within a print area of 164 x 235 mm. In the case of figures declaration. where patient’s identity is not concealed, authors need to submit a written consent of the patient or of the patient’s guardian, in Structured abstract case of minors. Figure legends should be listed separately after A structured abstract (no more than 250 words) is required the ‘References’ section. If any of the tables, illustrations or for studies under the section “Original Articles”. It must photomicrographs have been published elsewhere previously, a provide an overview of the entire paper, and should contain written consent for re-production is required from the copyright succinct statements on the following, where appropriate: holder along with the manuscript. When charts are submitted, Objective(s), Design, Setting, Subjects, Intervention(s), Main the numerical data on which they were based should be supplied. KUWAIT MEDICAL JOURNAL
Abbreviations Medical microbiology. 4th ed. St. Louis: Mosby; 2002. Except for units of measurement, abbreviations should be Book chapter: Meltzer PS, Kallioniemi A, Trent JM. Chromosome defined on their first use in the abstract and in the text and then alterations in human solid tumors. In: Vogelstein B, Kinzler applied consistently throughout the article. Non-standard KW, editors. The genetic basis of human cancer. New York: abbreviations or those appearing fewer than three times are McGraw-Hill; 2002. p. 93-113. not accepted. Use abbreviated units of measure, only when used with numbers. Abbreviations used as legends in Tables Weblinks: eatright.org [Internet]. Chicago: Academy of and/or figures should be duly defined below the respective Nutrition and Dietetics; c2016 [cited 2016 Dec 27]. Available item. from: http://www.eatright.org/.
Numbers and units Manuscript submission Measurements of length, height, weight and volume To present your original work for consideration, one must be reported in metric units (meter, kilogram, liter etc.) complete set of the manuscript written in English, accompanied or their decimal multiples. Temperature should be given in by tables and one set of figures (if applicable) should be degrees Celsius, Blood pressure in mmHg, and hematological submitted to the Editor by e-mail to “[email protected]” as and biochemical measurements in Système International (SI) attachment files. units. For decimal values, use a point, and not a comma, e.g., The manuscript submitted by e-mail should be in MS 5.7. Use a comma for numbers > 10,000 (i.e., 103) and do not Word document (.doc) format, together with a scanned copy use a comma for numbers < 9999, (e.g., 6542). or PDF version of the signed consent letter of the author(s) (see the section ‘Authorship and Consent Form’ for details). Drug names Figures or photographs, if any, need to be presented as separate Non-proprietary (generic) names of product should be attachments in JPG or BMP format with a resolution of 300 employed. If a brand name for a drug is used, the British or dpi and illustrations such as graphs, charts etc., as Excel international non-proprietary (approved) name should be format files. Incomplete/improper submissions will not be given in parentheses. The source of any new or experimental processed, and will be returned. Author(s) will receive a formal preparation should also be given. acknowledgment letter with a permanent reference number towards each successful submission. Acknowledgment Following a peer review process, the corresponding author Contributors who meet fewer than all 4 of the afore- will be advised of the status; acceptance or recommendation for mentioned criteria for authorship should only be listed in revision or rejection of the paper, in a formal letter sent through this section. Contributions of others who have involved in e-mail. A galley proof will be forwarded to the corresponding the study, such as statisticians, radiologists etc. and/or those author by e-mail at the time of publication of the accepted paper, who have assisted in the preparation of the manuscript which must be returned to the journal office within 48 hours being submitted could also be included in this section. The with specific comments or corrections, if any. Such corrections corresponding author must obtain written permission to be in the galley proof must be limited to typographical errors or acknowledged from all acknowledged individuals. missing contents from the finally accepted version.
References Authorship and consent form Indicate references in the text in sequence using Arabic All authors must give their signed consent for publication in numerals within square brackets and as superscripts (e.g.,[1, 3-5] a letter of submission, which should accompany the manuscript. etc). Do not quote additional data (like part of the title, year of This letter should contain the following statement: publication etc.) from the references, with citations in the text, “This manuscript (write the title) is an unpublished work which unless very important. In the References section, list them in is not under consideration elsewhere and the results contained in this the same sequence as they appeared in the text. Include the paper have not been published previously in whole or part, except names and initials of all authors if not more than six (< 6). in abstract form. In consideration of the KMJ accepting my/our Write the last name of authors followed by the initials with submission for publication, the author(s) undersigned hereby assign all no punctuation other than a comma to separate the names. copyrights ownership to the KMJ and shall have no right to withdraw In references where authorship exceeds six, use et al after its publication. It is expressly certified that I/we, have done/actively six author names. Do not use automatic numbering, end participated in this study and agree to the accuracy of contents of notes or footnotes for references. References to manuscripts this manuscript. It was conducted in accordance with current ethical either in preparation or submitted for publication, personal considerations and meets with the committee’s approval. I/all of us communications, unpublished data, etc. are not acceptable. agree to its publication in KMJ and to the authorship as expressed in References should be limited to those relating directly to this declaration and in the title page of our manuscript”. the contents of the paper and should be set out in the style The consent form must also contain the names of all authors, outlined by the International Committee of Medical Journal along with their signatures. Editors (ICMJE), as shown in the examples below. Additional examples are in the ICMJE sample references. https://www. Manuscripts should be submitted to: nlm.nih.gov/bsd/uniform_requirements.html The Editor, Kuwait Medical Journal Examples P.O. Box: 1202 Article: Rose ME, Huerbin MB, Melick J, Marion DW, Code-13013-Safat Palmer AM, Schiding JK, et al. Regulation of interstitial Kuwait. excitatory amino acid concentrations after cortical contusion Telephone: (965) 1881181, 25333920 extn. 114 injury. Brain Res. 2002;935(1-2):40-6. E-mail: [email protected] Book: Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Website: www.kma.org.kw/KMJ 1 KUWAIT MEDICAL JOURNAL March 2021
Review Article Overview of PCSK9 inhibitor use: Local and regional implications for the treatment of dyslipidemia
Taha Hasson Taha1, Wasl Al-Adsani2, Hany Younan3 1Department of Internal Medicine, Dar Alshifa Hospital, Kuwait 2Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Kuwait 3Department of Cardiology, Dar Alshifa Hospital, Kuwait
Kuwait Medical Journal 2021; 53 (1): 1 - 7
ABSTRACT
Objectives: To provide an overview for the use of is substantial and hence requires a cost/benefit analysis proprotein convertase subtilisin-kexin type 9 (PCSK9) for use in actual practice. Such analysis can take into inhibitors with local and regional implications for the account recommendations from the 2019 European Society treatment of dyslipidemia of Cardiology and European Atherosclerosis Society Design: Literature review guidelines for the management of dyslipidemias, as well Setting: Dar Alshifa Hospital, Kuwait as guidelines on the primary prevention of cardiovascular Conclusions: A new class of medications that inhibit disease from the 2019 American College of Cardiology / PCSK9 has been developed to treat dyslipidemia. PCSK9 American Heart Association Task Force. Greater awareness inhibitors are injectable medications that may be used in of these recommendations for the use of PCSK9 inhibitors lipid lowering therapy and cholesterol control, especially is needed given the critical magnitude of local and regional for patients at high risk with high levels of low-density implications, which necessitates reducing the risks related lipoprotein cholesterol. Major clinical trials have shown to cardiovascular diseases. Local studies are also required to benefits in decreasing the rate of acute atherosclerotic overcome barriers in research involvement and to address cardiovascular disease events and mortality with the the uncovered knowledge gaps in existing research and use of these agents. However, the cost of these agents trials for PCSK9 inhibitors and emerging treatment options.
KEY WORDS: cardiovascular diseases, dyslipidemia, PCSK9 inhibitors, statins
INTRODUCTION One of the major risk factors associated with CVD is Cardiovascular diseases (CVDs) are a group of dyslipidemia, which has become an important risk disorders of the heart and blood vessels and they factor to target in both the primary and secondary include coronary heart disease, cerebrovascular disease prevention of CVD[2]. Dyslipidemia is an abnormal and peripheral arterial disease. Heart attacks and amount of lipids (e.g. triglycerides, cholesterol and/ strokes are usually acute events as a result of CVD. The or fat phospholipids) in the blood. Since 1960, the most common etiology is a build-up of fatty deposits or fundamental discovery of the relationship between plaque on the inner walls of the blood vessels, causing a lipids, cholesterol and atherosclerosis allowed the blockage due to the process of atherosclerosis, leading development of lipid lowering drugs (LLDs). Further to atherosclerotic cardiovascular disease (ASCVD). in 1985, the role of low-density lipoprotein (LDL) According to the World Health Organization, CVDs receptors in lipid clearance was first discovered by are the leading cause of death globally; more people Goldstein and Brown, which earned them the Nobel die annually from CVDs than from any other cause[1]. Prize. Then in 2003, Dr. Nabil Seidah, born in Cairo
Address correspondence to: Dr. Taha Hasson Taha, Consultant Internist & Cardiologist, MB chB, MRCP(I&UK), DCC, FRCP(UK), Department of Internal Medicine, Dar Alshifa hospital, Hawally, Kuwait. Mob: (965) 99838575; E-mail: [email protected] March 2021 KUWAIT MEDICAL JOURNAL 2 and working in Montreal, Canada, discovered the and Yemen)[11]. The prevalence of dyslipidemia in role of proprotein convertase subtilisin-kexin type 9 this study was 32%, and dyslipidemia was defined (PCSK9) as a specific protein in the liver that regulates when patients were known to have the risk factor LDL receptors responsible for uptake of cholesterol and were already on LLDs. Also, the Gulf RACE- from the blood[3]. This discovery paved the way for a 2 was a prospective study conducted from 2008 to new type of medication, PCSK9 inhibitors, as a new 2009 in 65 hospitals from six Arabian Gulf countries form of medication used in lipid lowering therapy and (Bahrain, Saudi Arabia, Qatar, Oman, UAE and cholesterol control, especially for patients at very high Yemen), that enrolled 7930 acute coronary syndrome risk. patients with 30-day and one-year mortality follow- up. In this study, the prevalence of dyslipidemia LITERATURE REVIEW was 32.7%[12]. The Africa Middle East Cardiovascular This review provides an overview of PCSK9 Epidemiological study conducted between 2011 and inhibitors as a new treatment option. We conducted 2012 surveyed 4378 outpatients (2337 from eight a literature review on the use of PCSK9 inhibitors, countries in Africa and 2041 from six countries focusing on the major clinical trials that evaluated in the Middle East, including Saudi Arabia, UAE efficacy. We also reviewed international and regional and Kuwait) with intermediate and high-risk CVD articles related to CVDs, with a focus on dyslipidemia, status[13]. The overall prevalence of dyslipidemia in the to clarify risks and underscore the significance Africa Middle East Cardiovascular Epidemiological of required therapies for effective treatment and study was 70%. management. We also present the local and regional The presence of high LDL-C levels is a strong implications for the management of dyslipidemia. independent risk factor for CVD in several Our objective is to raise awareness among clinicians, populations worldwide[14]. Major guidelines have to promote research, and to develop or update local targeted the LDL-C level to be the primary target of clinical practice guidelines (CPG) on the treatment cholesterol-lowering therapy[15,16]. In the Arabian Gulf, of dyslipidemia to reduce the risks of CVD, with a significant proportion of patients on LLDs, mainly emphasis on patient safety. those considered to be in the high and very high- risk groups for CVD, are not at their recommended Dyslipidemia in the Gulf area therapeutic LDL-C targets. This was evident from CVD is considered the most common cause of the Centralized Pan-Middle East Survey on the death in the Arabian Gulf, accounting for up to 45% undertreatment of hypercholesterolemia, which was of all mortalities[4,5]. Studies such as the Gulf Registry conducted with 5276 patients on LLDs in six Arabian of Acute Coronary Events (Gulf RACE) and the Gulf countries. The LDL-C goal was attained in 91.1% International Case-Control Analysis of Risk Factors of low-risk, 52.7% of high-risk, and 32% of very high- for a First Myocardial Infarction have found that risk category patients[17]. Al-Hashmi et al evaluated patients in the Middle East and Gulf present with non high density lipoprotein cholesterol (HDL-C) heart attacks at an age 10-12 years younger than their target attainment according to the National Lipid counterparts in Europe and North America[6,7]. Association in patients on lipid lowering therapy Limited data exist on the epidemiology of stratified by serum triglycerides level [(<150mg/dL dyslipidemia in the Gulf area. A cross-sectional or 1.69mmol/L); (150–200mg/dL or 1.69–2.26mmol/L) study performed in Saudi Arabia in 2017 estimated and (>200mg/dL or 2.26 mmol/L)] in 4383 patients the prevalence of dyslipidemia in 75.5% of the study on lipid lowering therapy from six Middle Eastern group[8]. Systematic review conducted by Aljefree countries participating in the Centralized Pan- et al on the CVD risk factors in adult population in Middle East Survey and found that the overall non– the Gulf countries from 1990 to 2014 found that the HDL-C goal attainment was 41% of the subjects, and overall prevalence of hypercholesterolemia (defined hence there remains a substantial residual risk[18]. In as total cholesterol >5.1 mmol/L (200 mg/dL)) ranged a study conducted in 160 dyslipidemia patients in from 17% to 54.9% in males and 9% to 53.2% in Oman, the LDL-C goal was achieved in only 43% of females[9]. Alhyas et al conducted another systematic high-risk patients[19]. review of risk factors for diabetes mellitus in studies The suboptimal management of dyslipidemia from the Gulf countries between 1987 and 2010. In across the Arabian Gulf countries necessitates this review, reported rates of dyslipidemia ranged intensive management strategies which would between 2.7-51.9%[10]. The Gulf RACE-1 prospective include widespread lifestyle modifications, study was conducted in 2007 with 6704 acute coronary adherence to international guidelines for lipid syndrome patients from 64 hospitals in six Middle management, and the use of optimal lipid lowering East countries (Bahrain, Kuwait, Qatar, Oman, UAE therapies[14]. 3 Overview of PCSK9 inhibitor use: Local and regional implications for the treatment of dyslipidemia March 2021
Cardiovascular risk estimation recommends risk stratification among patients with The European Society of Cardiology and European ASCVD to identify “very high-risk ASCVD patients”[20]. Atherosclerosis Society recommends use of the These patients have characteristics associated with a Systematic Coronary Risk Estimate methodology higher risk of recurrent ASCVD events; consequently, to calculate risk[20,21], which considers age, gender, they derive a higher net absolute benefit from addition smoking and cholesterol level based on lipid profile of PCSK9 inhibitors to statin therapy. Further, the assessment, as well as blood pressure readings. 2019 European Society of Cardiology Guidelines Also, there are other factors that increase the risk, for the management of dyslipidemias recommends including social deprivation and psychosocial stress; a combination of a statin with a PCSK9 inhibitor for obesity as measured by the body mass index and primary prevention in patients at very-high risk, but waist circumference; physical inactivity; family without familial hypercholesterolemia[21]. For patients history of CVD; autoimmune and other inflammatory with high-risk familial hypercholesterolemia, PCSK9 disorders; treatment for human immunodeficiency inhibitors are also recommended in combination virus infection; atrial fibrillation; left ventricular with statins if the LDL-C target is not reached after hypertrophy; obstructive sleep apnea syndrome treatment with the maximum tolerated dose of statins and major psychiatric disorders. To facilitate risk and ezetimibe as a cholesterol absorption inhibitor. estimations, smart applications are also available for The international guidelines are extensive and ASCVD risk calculations from the American College provide recommendations on lipid-lowering therapies of Cardiology[22]. as per the risk categories, patient conditions and treatment options among many factors. As such, it Management of dyslipidemia may be necessary to develop more specific CPGs for Once the risk is calculated, the intensity of local use depending on the type of practice, scope treatment and preventive actions should be tailored to of services and availability of medications. The CPG the patient’s total CV risk as per the recognized risk needs to ensure that updates to international guidelines category following the European Society of Cardiology are evaluated and considered in actual practice with and European Atherosclerosis Society guidelines on greater awareness among physicians. dyslipidemia. These guidelines recommend LDL-C targets based on CV risk with LDL-C goal of <1.4 PCSK9 inhibitors mmol/L (<55 mg/dL) for patients at very high risk[21]. The two currently available antibodies Not only should those at high risk be identified and (alirocumab, evolocumab) against PCSK9 are fully managed, but those at moderate risk should also receive human IgG subtypes that bind with an approximate professional advice regarding lifestyle changes; and if 1:1 stoichiometry to circulating PCSK9 and prohibit its needed, lipid-lowering therapy to control cholesterol binding to the LDL-R, thus creating a PCSK9-deficiency levels. Such efforts will aim to prevent further increase state that results in tremendous accumulation of LDL-R in total CV risk, increase awareness of the danger of on the membrane of hepatocytes, accelerated clearance CV risk, improve risk communication and promote of LDL particles, and large decreases in plasma LDL-C primary prevention efforts. Also, low-risk patients levels. PCSK9 inhibitors were initially approved by the need to be advised to maintain a firm commitment United States Food and Drug Administration “as an to implementing lifestyle measures such as smoking adjunct to diet and maximally tolerated statin therapy cessation and regular exercise. for treatment of adults with heterozygous familial Statins have been approved for the treatment of hypercholesterolemia or clinical ASCVD who require dyslipidemia for 25 years[23]. This class of medications additional lowering of LDL-C”[25,26]. Evolocumab has demonstrated significant reduction of LDL-C and also has an indication for use in homozygous familial cardiovascular events with an acceptable safety profile. hypercholesterolemia. The United States Food However, statins increase the expression of PCSK9, and Drug Administration added an indication for which promotes hepatic LDL receptor degradation, evolocumab based on the results of the FOURIER trial reducing LDL receptor density and clearance of LDL to reduce the risk of myocardial infarction, stroke and particles, and hence patients continue to experience coronary revascularization in adults with established residual risk. This negative feedback response may cardiovascular disease”[26]. attenuate the statins’ lipid effects. Blocking PCSK9 The FOURIER trial for evolocumab was a increases the clearance of atherogenic lipoproteins and randomized, double-blind, placebo-controlled, augments the efficacy of statins. Thus, PCSK9 inhibitors multinational clinical trial involving 27,564 patients at offer a novel approach to lipid management[24]. The 1242 centers in 49 countries[26]. However, no country 2018 American College of Cardiology / American from the Gulf area was listed as being involved in this Heart Association Multisociety Cholesterol Guidelines study. For alirocumab, the ODYSSEY OUTCOMES trial March 2021 KUWAIT MEDICAL JOURNAL 4 was designed as a multicenter, randomized, double- that can assist in behavior and lifestyle modifications blind, placebo-controlled trial that was sponsored by needed to help patients recover from dyslipidemia pharmaceutical companies as specifically mentioned or ASCVD. Also, specific health-related expertise in the trial. The trial involved 18,924 patients from and services, including community health awareness 58 countries[25]. Despite involving patients from more campaigns that are readily available in other countries, countries, most of the countries were the same as those may not be readily available locally or be restricted listed in the FOURIER Trial. Again, no country from by certain limiting constraints. Patient profiles may the Gulf region was listed as being involved in the also differ in terms of other underlying conditions or clinical trial. co-morbidities, as well as their tolerance to LLDs or Barriers in conducting clinical trials contribute to level of adherence to treatment. These limiting factors sustained health inequity among countries, leading necessitate careful monitoring of patients treated to gross under-representation in global clinical trial with PCSK9 inhibitors. Further, patients need to be platforms[27]. Local investigator-initiated trials are well informed of what treatment may entail in terms recommended to overcome the absence of suitable of ongoing lipid profile investigations and instructed research infrastructure, which is a recognized to report any adverse reactions during treatment barrier[27]. Given the magnitude of regional monitoring. implications, it is critical for there to be representation In terms of patient monitoring, the dosage of PCSK9 from regional research centers in international trials, inhibitors plays an integral part in setting a timeline without which the study results may be inherently to meet the LDL-C target. Alirocumab is available limited by ethnical and environmental factors. These in two injectable doses: 75 and 150 mg administered limitations may also extend to treating patients from subcutaneously every two weeks or 300 mg monthly[25]. many other countries not included in the trials. The The lower dose is the recommended starting dose, but lack of regional representation at the early stages of the higher dose can be initiated directly. Monitoring new treatment development raises several concerns, of the effect of this class on LDL-C is recommended, and further initiatives are required to improve local with measurement at the trough level of the dosing research capabilities as well as collaboration with interval (i.e., 14 days after the previous dose). With international efforts. the 75 mg dose, LDL-C levels fall by 45-48%, and they It is essential to note that both cardiovascular fall by approximately 60% with the 150 mg dose[30]. If outcome trials used to evaluate PCSK9 inhibitors the desired level of LDL-C lowering is not achieved provide evidence taken as the basis for international after four to eight weeks, the dose can be titrated guideline recommendations, yet they mostly only to 150 mg[30]. In the largest randomized controlled involved patients from participating research sites interventional trial to date on homozygous familial in certain countries. To truly apply to the global hypercholesterolemia patients, alirocumab resulted community, medical treatments need to reflect in significant and clinically meaningful reductions in biological and non-biological variations that exist LDL-C at week 12[31]. Therefore, patient monitoring across the world[27]. In fact, it has been found in some may need to continue for up to three months or more, as studies that patients from different ethnic groups necessary, to ensure achievement of the LDL-C target have different risks for adverse drug reactions to depending on the patient condition. Evolocumab is cardiovascular drugs[28]. Ethnic groups may therefore also available in two dosing schedules that achieve a be one determinant of harms, either due to genetic similar level of LDL-C reduction (approximately up to differences or because cultural factors alter the risk[28]. 60%): 140 mg subcutaneously every 2 weeks or 420 mg For advanced future research, it has been suggested subcutaneously monthly[32]. that ‘precision medicine’ be used to utilize patient- Both PCSK9 inhibitors lower triglycerides by specific information, including environmental and 10-15%, raise HDL cholesterol by 5-10%, and lower genetic factors, to guide therapy decisions[29]. lipoprotein (a) by 25-30%[30,32]. High sensitivity The safety of PCSK9 inhibitors remains to be C-reactive protein levels remain unchanged with validated in many countries that were not involved PCSK9 inhibition, but a reduction in proinflammatory in the trials, including all Gulf and Arabic countries, cytokines was reported in human monocyte-derived as well as many African countries. To date, there is no macrophages[33]. mention of any large-scale trial locally or in the Gulf Currently, the cost of the PCSK9 inhibitors region for PCSK9 inhibitor use. Hence, there is likely to precludes the widespread use of these drugs in patients be numerous environmental and ethnic differences that who might benefit. The wholesale acquisition price of may affect clinical guidelines as well as factors related both alirocumab and evolocumab exceeds $14,000/year to healthcare structure, such as access to nutritional in the United States, although discounting may occur counseling, cardiac rehabilitation or other services for some payers and in other countries[34,35]. The 2018 5 Overview of PCSK9 inhibitor use: Local and regional implications for the treatment of dyslipidemia March 2021
American College of Cardiology / American Heart myocardial infarction in the developed world and Association Multisociety Guideline includes a cost- the change in the pathophysiology of acute coronary effectiveness evaluation in the shared decision-making syndrome in the statin era (with plaque erosions being algorithm for clinicians placing PCSK9 inhibitors as the more frequent than plaque rupture), such studies third choice after statins and ezetimibe, unless ongoing would need to be larger and longer than previous development leads to further cost reductions[36]. studies in the field[40]. The safety profile of both PCSK9 inhibitors Considering that atherosclerosis is a long-standing indicate that they are well tolerated as far as the disease whose consequences take years to ensue, trials showed, with no major safety concerns in then mortality benefits of lipid-lowering therapy either trial[36]. The most common adverse reactions might be anticipated after several years have elapsed. are nasopharyngitis and mild injection-site reactions. Cardiovascular death has not been consistently There is no increase in myalgia, and importantly, no reduced in newer lipid-lowering trials comparing increase in neurocognitive adverse effects, even at high-intensity with lower-intensity lipid-lowering very low LDL-C level[37]. However, both evolocumab therapies[36]. Moreover, the safety profile remains in and alirocumab demonstrated a possible signal for question when it comes to prolonged use of these new higher rates of adverse events related to cognitive medications, given that no trial to date has considered impairment. Within the FOURIER trial, a dedicated long-term use. Further, the impact of PCSK9 inhibitors study known as EBBINGHAUS, with a shorter follow- in patients with other underlying conditions is not up than that of the main trial (median 19 months), fully studied, given the inclusion or exclusion criteria demonstrated no signal of harm on cognitive function of the evaluating cardiovascular outcome trials. Several based on evaluation by a structured standard battery knowledge gaps remain, including long-term efficacy of cognitive tests or in the pre-specified patient self- and safety of PCSK9 inhibitors in actual clinical use, survey of everyday cognition[36]. An assessment is as well as long-term safety of very low LDL-C levels still ongoing in a trial of alirocumab in patients with on overall patient health, particularly given the LDL-C established CVD or familial hypercholesterolemia clearance mechanism of PCSK9 inhibitors and related using formal cognitive testing[36]. effects. A potential problem of long-term antibody treatment is the occurrence of auto antibodies. To CONCLUSION date, only very few cases of antidrug antibodies with PCSK9 inhibitors have emerged as a new treatment use of PCSK9 inhibitors have been reported, and no option for patients at high risk of CVD to lower levels reduction of LDL-C lowering has been observed, of LDL-C, allowing patients with dyslipidemia to meet however the implications of long-term use remain to their recommended LDL-C targets as per international be considered[21]. guidelines. The prevalence of CVD globally and high Despite extensive investigation into the role of risk of cardiovascular death dictates the necessity PCSK9, significant gaps in understanding remain, of fast adoption of such potentially beneficial new including intriguing areas of investigation as to PCSK9 treatments that can achieve a reduction in LDL-C inhibitor modulation of lipoprotein (a), and the biologic levels. This is also the case in the Arabian Gulf region, causes of drug hypo-responsiveness that has shown to where research has shown despite limited data, that sporadically lead to PCSK9 inhibitor resistance in some the risks of CVD are severe and require more optimal cases[38]. Theoretical mechanisms underlying PCSK9 management strategies. Given the relatively new inhibitor hypo-responsiveness are thought to occur emergence of PCSK9 inhibitors use, further research by either impaired monoclonal antibody entry into is required considering the identified knowledge gaps, the systemic circulation or physiological impairment especially regarding the impact of long-term effects. once the monoclonal antibody is absorbed[38]. Poor The main cardiovascular outcome trials for evaluation adherence to treatment or improper administration of PCSK9 inhibitors did not include countries from are both potential impediments that require careful the Arabian Gulf or many African countries, and as patient monitoring. Several investigations suggest that such, there remains possible ethnic and environmental PCSK9 function extends beyond regulation of LDL-C implications as well as risks of adverse events. Regional levels. One area of interest is its ability to modulate studies on dyslipidemia are required to provide a triglycerides; however, the available data remains framework for the evaluation of PCSK9 inhibitors contradictory and inconclusive[39]. Finally, the question and other advances in treatment management for the of when mortality reduction can be achieved with region. PCSK9 inhibitors is challenging and would be more Furthermore, specific CPGs need to be developed easily answered with long term longitudinal studies of for local use with continuous review and evaluation high-risk patients. Given the declining mortality from of the international guidelines and research updates. March 2021 KUWAIT MEDICAL JOURNAL 6
These CPGs need to specify that patients who are diseases, diabetes mellitus, and cancer in the occupied prescribed PCSK9 inhibitors will require close Palestinian territory. Lancet 2009; 373(9668):1041- treatment monitoring over time, which is advised for 1049. patient safety. 6. Zubaid M, Rashed WA, Almahmeed W, Al-Lawati J, Sulaiman K, Al-Motarreb A, et al. Management and outcomes of Middle Eastern patients admitted ACKNOWLEDGMENT with acute coronary syndromes in the Gulf registry We thank Dr. Osama Alaradi, Head of Internal of acute coronary events (Gulf RACE). Acta Cardiol Medicine at Dar Alshifa Hospital for his continuous 2009; 64(4):439-446. support in developing the hospital-based clinical 7. Gehani AA, Al-Hinai AT, Zubaid M, Almahmeed W, practice guidelines for PCSK9 inhibitors, as well as Hasani MRM, Yusufali AH, et al. Association of risk other esteemed colleagues. Further, we thank the factors with acute myocardial infarction in Middle previous efforts of Dr. Ali Ahmad and Dr. Yousif Al Eastern countries: the INTERHEART Middle East Rodhan. Also, Dr. Taha wishes to thank the support of study. Eur J Prev Cardiol 2014; 21(4):400-410. 8. Ahmed AM, Hersi A, Mashhoud W, Arafah MR, his family, especially Nora Taha, for research support. Abreu PC, Al Rowaily MA, et al. Cardiovascular risk factors burden in Saudi Arabia: The Africa Middle Conflict of interest declaration: Our study has not East Cardiovascular Epidemiological (ACE) study. J received any financial support. Further, the authors Saudi Heart Assoc 2017; 29(4):235-243. declare that no conflict of interest exists. 9. Aljefree N, Ahmed F. Prevalence of cardiovascular disease and associated risk factors among adult Authors contribution: Dr. Taha Hasson Taha is the population in the Gulf region: A systematic review. main author of this article and has worked extensively Advances in Public Health 2015; Article ID 235101. on developing guidelines for PCSK9 inhibitor use 10. Alhyas L, McKay A, Balasanthiran A, Majeed A. Prevalence of overweight, obesity, hyperglycemia, at Dar Alshifa Hospital. Further, he is currently hypertension and dyslipidemia in the Gulf: working on a number of case studies involving Systematic review. JRSM Short Rep 2011; 2(7):55. actual use of PCSK9 inhibitors. Dr. Wasl Al-Adsani 11. El-Menyar A, Zubaid M, Shehab A, Bulbanat B, is a former colleague of Dr. Taha Hasson Taha at Dar Albustani N, Alenezi F, et al. Prevalence and impact Alshifa Hospital and contributed substantially in of cardiovascular risk factors among patients developing the abstract of the article and preparing it presenting with acute coronary syndrome in the for submission. Dr. Hany Younan contributed greatly Middle East. Clin Cardiol 2011; 34(1):51-58. in adding the local and regional implications, as well 12. Alhabib KF, Sulaiman K, Al-Motarreb A, Almahmeed as adding further treatment details and specifics with W, Asaad N, Amin H, et al. Baseline characteristics, management practices, and long-term outcomes of updates to the references. Middle Eastern patients in the second Gulf Registry of Acute Coronary Events (Gulf RACE-2). Ann Saudi REFERENCES Med 2012; 32(1):9-18. 13. Alsheikh-Ali AA, Omar MI, Raal FJ, Rashed W, 1. World Health Organization (WHO). “The Top 10 Hamoui O, Kane A, et al. Cardiovascular risk factor Causes of Death.” www.who.int/news-room/fact- burden in Africa and the Middle East: the Africa sheets/detail/the-top-10-causes-of-death, accessed Middle East Cardiovascular Epidemiological (ACE) 21/3/2019. Study. PLoS One 2014; 9(8):e102830. 2. Arnett DK, Blumenthal RS, Albert MA, Buroker 14. Al-Rasadi K, Al-Sabti H. Dyslipidemia in the Arabian AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/ Gulf and its impact on cardiovascular risk outcome. AHA Guideline on the Primary Prevention of Oman Med J 2015; 30(6):403-405. Cardiovascular Disease: Executive Summary. A 15. Grundy SM. Low-density lipoprotein, non-high- Report of the American College of Cardiology/ density lipoprotein, and apolipoprotein B as American Heart Association Task Force on targets of lipid-lowering therapy. Circulation 2002; Clinical Practice Guidelines. Circulation 2019; 106(20):2526-2529. 140(11):e596-e646. 16. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays 3. Elguindy A, Yacoub MH. The discovery of PCSK9 HE, Jones PH, et al. National Lipid Association inhibitors: A tale of creativity and multifaceted recommendations for patient-centered management translational research. Glob Cardiol Sci Pract 2013; of dyslipidemia: part 1 - executive summary. J Clin 2013(4):343-347. Lipidol 2014; 8(5):473-488. 4. Al Rasadi K, Almahmeed W, AlHabib KF, Abifadel 17. Arafah M, Al-Hinai AT, Al Mahmeed W, Al-Rasadi M, Farhan HA, Al Sifri S, et al. Dyslipidemia in the K, Al Tamimi O, Al Herz S, et al. Centralized pan- Middle East: Current status and a call for action. Middle East Survey on the under treatment of Atherosclerosis 2016; 252:182-187. hypercholesterolemia: results from the CEPHEUS 5. Husseini A, Abu-Rmeileh NME, Mikki N, Ramahi study in Arabian Gulf countries. Angiology 2014; TM, Ghosh HA, Barghuthi N, et al. Cardiovascular 65(10):919-926. 7 Overview of PCSK9 inhibitor use: Local and regional implications for the treatment of dyslipidemia March 2021
18. Al-Hashmi K, Al-Zakwani A, Al Mahmeed W, 29. Ferdinand KC, Igari M. The role of racial/ethnic Arafah M, Al-Hinawi AT, Shehab A, et al. Non–high- factors in global clinical trials. Expert Rev Clin density lipoprotein cholesterol target achievement Pharmacol 2018; 11(9):829-832. in patients on lipid-lowering drugs and stratified by 30. Cannon CP, Cariou B, Blom D, McKenney JM, triglyceride levels in the Arabian Gulf. J Clin Lipidol Lorenzato C, Pordy R, et al. ODYSSEY COMBO II 2016; 10:368-377. Investigators. Efficacy and safety of alirocumab in 19. Al-Siyabi K, Farhan H, Al-Rasadi K, Al-Salhi A, high cardiovascular risk patients with inadequately Al-Hinai AT, Al-Zakwani I. Safety of simvastatin controlled hypercholesterolemia on maximally and goal attainment for low-density lipoprotein tolerated doses of statins: the ODYSSEY COMBO cholesterol in Sultan Qaboos University Hospital. II randomized controlled trial. Eur Heart J 2015; Oman Med J 2010; 25(4):264-268. 36(19):1186-1194. 20. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher 31. Blom DJ, Harada-Shiba M, Rubba P, Gaudet D, KK, Blumenthal RS, et al. AHA/ACC/AACVPR/ Kastelein JP, Charng M, et al. Efficacy and safety of AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/ Alirocumab in Adults with homozygous familial PCNA guideline on the management of blood hypercholesterolemia the ODYSSEY HoFH Trial. J cholesterol: a report of the American College of Am Coll Cardiol 2020; 76(2):131-142. Cardiology/American Heart Association Task Force 32. Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, on Clinical Practice Guidelines. JACC 2019; 79:e285- Burgess L, et al. A 52-week placebo-controlled trial of 350. evolocumab in hyperlipidemia. N Engl J Med 2014; 21. Mach F, Baigent C, Catapano AL, Koskinas 370(19):1809-1819. KC, Casula M, Badimon L, et al. 2019 ESC/EAS 33. Moens SJB, Neele AE, Kroon J, van der Valk FM, Guidelines for the management of dyslipidemias: van den Bossche J, Hoeksema MA, et al. PCSK9 lipid modification to reduce cardiovascular risk: The monoclonal antibodies reverse the proinflammatory Task Force for the management of dyslipidemias profile of monocytes in familial hypercholesterolemia. of the European Society of Cardiology (ESC) and Eur Heart J 2017; 38(20):1584-1593. European Atherosclerosis Society (EAS). Eur Heart J 34. Tice JA, Kazi DS, Pearson SD. Proprotein convertase 2020; 41(1):111-188. subtilisin/kexin type 9 (PCSK9) inhibitors for 22. American College of Cardiology. ASCVD Risk treatment of high cholesterol levels: effectiveness Estimator Plus. http://tools.acc.org/ascvd-risk- and value. JAMA Intern Med 2016; 176(1):107-108. estimator-plus/#!/calculate/estimate/ accessed 35. Schulman KA, Balu S, Reed SD. Specialty 21/3/2019. pharmaceuticals for hyperlipidemia-impact on 23. Gotto Jr AM, Moon JE. Twenty-five years of statins: insurance premiums. N Engl J Med 2015; 373:1591- where do we go from here? J Clin Lipidol 2015; 1593. 10(1):33-45. 36. Furtado RHM, Giugliano RP. What lessons have we 24. Vogel RA. PCSK9 Inhibition: The Next Statin? J Am learned and what remains to be clarified for PCSK9 Coll Cardiol 2012; 59(25):2354-2355. inhibitors? A review of FOURIER and ODYSSEY 25. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner Outcomes Trials. Cardiol Ther 2020; 9:59-73. VA, Diaz R, et al. Alirocumab and cardiovascular 37. Rosenson RS, Hegele RA, Fazio S, Cannon CP. The outcomes after Acute Coronary Syndrome. N Engl J evolving future of PCSK9 inhibitors. J Am Coll Med 2018; 379(22):2097-2107. Cardiol 2018; 72(3):314-329. 26. Sabatine MS, Giugliano RP, Keech AC, Honarpour 38. Warden BA, Fazio S, Shapiro MD. The PCSK9 N, Wiviott SD, Murphy SA, et al. For the FOURIER revolution: Current status, controversies, and future Steering Committee and Investigators. Evolocumab directions. Trends in Cardiovascular Medicine 2000; and clinical outcomes in patients with cardiovascular 30(3):179-185. disease. N Engl J Med 2017; 376:1713-1722. 39. Shapiro MD, Minnier J, Tavori H, Kassahun H, Flower 27. Alemayehu C, Mitchell G, Nikles J. Barriers for A, Somaratne R, et al. Relationship between low- conducting clinical trials in developing countries- a density lipoprotein cholesterol and lipoprotein(a) systematic review. Int J Equity Health 2018; 17(1):37. lowering in response to PCSK9 inhibition with 28. McDowell SE, Coleman JJ, Ferner RE. Systematic evolocumab. J Am Heart Assoc 2019; 8(4):e010932. review and meta-analysis of ethnic differences 40. Libby P. Mechanisms of acute coronary syndromes in risks of adverse reactions to drugs used in and their implications for therapy. N Engl J Med cardiovascular medicine. BMJ 2006; 332(7551):1177- 2013; 368(21):2004-2013. 1181. March 2021 KUWAIT MEDICAL JOURNAL 8
Original Article
The pattern of skin diseases in a multidisciplinary medical unit
Shaima Al-Bader1, Kamel El-Reshaid2 1Asaad Al-Hamad Dermatology Center, Kuwait 2Department of Medicine, Faculty of Medicine, Kuwait University
Kuwait Medical Journal 2021; 53 (1): 8 - 12
ABSTRACT
Objective: Data on skin disorders in medical units is rare. and maintenance dialysis as well as immunosuppressive We aimed to report on its epidemiological profile using the treatment for idiopathic glomerulopathy and autoimmune data of a multidisciplinary medical clinic and compare it systemic diseases were common practice. with those of dermatological units. Results: A total of 2931 lesions were diagnosed in 4834 Design: Retrospective analysis patients (66%). Most patients were adults and had median Setting: El-Reshaid kidney clinic follow-up of 38 months. Nearly half of the cases were drug Subjects: Patients were included in the study if they had induced. Immunosuppressive treatment, and corticosteroids a skin disorder which was evaluated by a consultant in particular, had increased the percentage of patients with dermatologist during the study period. acne and infections (pyogenic, viral and fungal) as compared Interventions: Medical records of patients were reviewed to dermatitis and eczema in the specialized dermatological retrospectively for such phenomenon in the past six years. centers. Main outcome measures: The unit is responsible for a large Conclusion: Skin diseases are common in medical units. proportion of patients with acute and chronic kidney diseases Since nearly half are drug-induced, prevention and early of diverse etiologies and multiple co-morbid conditions. Acute diagnosis are essential for diligent management.
KEY WORDS: allergy, drugs, infection, medicine, skin disorders
INTRODUCTION epidemiological profile of such skin disorders, and The skin is one of the most important organs of the from our area in particular, is rarely reported. Hence, body because it protects the internal organs from the we conducted the present study to shed some light on deleterious effects of the environment. The latter can these disorders. be categorized into: (a) physical agents viz. trauma, extremes of heat and cold, and sunlight; (b) external SUBJECTS AND METHODS allergic or corrosive agents; (c) infections/infestations; Study design (d) genetic defects; (e) nutritional deficiencies; and (f) Medical records of patients attending El-Reshaid drug side effects[1]. Moreover, it can provide valuable kidney clinic from 1st July 2012 to 31st June 2018 were information about certain disorders of the body viz. analyzed retrospectively for skin diseases. The clinic autoimmune diseases, cardiovascular and metabolic was established in 1997 in the center of Kuwait City. insufficiency[2]. Hence, data on skin diseases in It is a referral center with adequate diagnostic and medical units can aid in health management with therapeutic facilities to care for both in- and out- regards to planning and direct patient care. The patients with all medical and renal diseases.
Address correspondence to: Dr. Kamel El-Reshaid, Professor, Department of Medicine, Faculty of Medicine, Kuwait University, P O Box 24923, 13110 Safat, Kuwait. Fax: (965) 25318454; E-mail: [email protected] 9 The pattern of skin diseases in a multidisciplinary medical unit March 2021
Inclusion criteria Patients were included in the study if they had a Table 1: Epidemiological profile of the patients screened skin disorder which has been evaluated by a consultant dermatologist during the study period. Diagnosis, in Category No. each case, was established based on clinical findings, Demographical data and histopathological examination of skin biopsies Age (years) 39 ± 14 Sex (Male/Female) 0.9 were used if indicated. Duration of follow up (months) 38(18) Initial cause of screening Definitions and classification Renal-related For the sake of comparison with other studies, the Acute renal failure 538 Chronic renal failure 827 skin disorders were further classified into the nine Nephrotic syndrome 432 major groups of the 9th revision of the International Electrolytes abnormalities 159 Classification of Diseases. Active autoimmune state 276 Co-morbid conditions Coronary artery disease 557 Statistical analysis Infection 340 The mean and + standard deviation were used to Uncontrolled diabetes mellitus 458 describe the normally distributed variables viz. age. Uncontrolled hypertension 206 However, since the duration of follow-up was not GI-related 437 Autoimmune disease (without renal involvement) 97 normally distributed, they were expressed as a median Peripheral vascular disease 68 and interquartile range. Miscellaneous 43 Grand total 4438 RESULTS In-patient activity Admissions 283 Over the past six years, a total of 4438 patients Observation room 395 were screened. The demographic data of the patients Access placement 420 are summarized in Table 1. Patients with different Access complications 366 age groups were included (range: 6-78 years), Kidney biopsy 136 Skin biopsy 16 yet mostly were adults (mean ± SD: 39±14 years). Gender distribution was almost equal (male/female: Miscellaneous conditions included fractures, malignancy, 0.9). Patients were followed up for 38(18) months. psychiatric disorders, deep vein thrombosis / pulmonary embolism * Age expressed in mean±SD and duration of follow up in median A total of 2232 patients (50%) have been evaluated (interquartile range) for kidney ailments and the rest were for medical diseases. The unit’s in-patient activity included 283 hospital admissions and 395 day-case managements. and lymphedema) were common (n=16). Six cases Histopathological examination was done in 16 patients had deep-seated infection that had required surgical to confirm diagnosis of skin disorder. drainage. Lesions of impetigo were few (n=3) since children were few, and folliculitis were only in four Common skin categories since most patients had high socio-economic status. Data on skin disorders are summarized in Table 2, c. Mycobacterial skin disease was seen as of which, some had the following associations: nodular leprosy in one patient. Skin tuberculosis was a. Diseases due to physical agents were rare and the main concern was the allergic side effects common, especially bed (pressure) sores in the of anti-mycobacterial dugs. elderly and bed ridden patients (n=93). They were a d. Other infections: Candidiasis was common, major concern with regards to mortality, and all had especially in diabetics and those treated with to be treated in hospital. Burns associated with poor corticosteroids. Viral infections were common sensation due to diabetic peripheral neuropathy due to immunosuppressive drugs. Warts were (n=5). Frost bite was not seen. Erythema, papules and common in patients treated with azathioprine, while lichenoid lesions due to solar photodermatitis were cytomegalovirus was common in those treated with reported in 18 patients. cellcept. Herpes zoster was common due to wide- b. Bacterial infections (pyoderma), especially spread use of immunosuppressive drugs in treatment erysipelas and cellulitis were common. They were of glomerular, lupus nephritis and systemic vasculitis. associated with dialysis catheters (hemo- and Skin infestations with scabies and pediculosis were peritoneal) as well as exit sites (n=36). Moreover, rare, yet a major concern in diagnosis of pruritis. infected AV fistulae and Gortex catheters were few e. Allergic dermatoses were common. (n=19). Infected venous ulcers with/without deep However, toxic epidermal necrosis was rare. Drug- venous thrombosis were common (n=48). Cellulitis in allergy was the most common cause of acute urticaria. edematous states (post-phlebetic, nephrotic syndrome Atopy was the cause in chronic idiopathic one. March 2021 KUWAIT MEDICAL JOURNAL 10
Table 2: Skin disorders encountered in the study Percentage Skin category Disorder * No of total Hereditary Albinism (3), X-linked Icthyosis vulgaris (2), Autosomal recessive lamellar icthyosis (1) 6 0.2 Nutritional deficiencies Angular stomatitis (24) 24 0.81 Diseases due to physical agents Pressure sores (93), Burns (5), Photodermatitis (18) 116 3.95 Pyoderma Impetigo contagiosa (3), Erysipelas and cellulites (119), Carbuncles (6), Folliculitis (4) 132 4.5 Mycobacterium Nodular Leprosy (1) 1 0.03 Dermatophytosis Ringworms (capitis 1 & corporis 1) 2 0.07 Candidiasis Thrush (43), Genital-perianal (56), Pedis (138) 237 8.08 Viral infections Warts (52), Herpes zoster (83), Disseminated herpes simplex (5), Cytomegalovirus (12) 152 5.19 Infestations Scabies (5), Pediculosis (3) 8 0.27 Allergic dermatosis Acute urticaria (84), Idiopathic chronic urticaria (7), Physical chronic urticaria (2), 151 5.2 Chronic vasculitic urticaria (6), Exfoliative dermatitis (3) Erythema multiformis (5), Stevens Johnsons (3), Contact dermatitis (33), Insect bites (2), DRESS (4), AGEP (2) Autoimmune disorders Pemphigus vulgaris (2) Bolus pemphigoid (3), Dermatitis herpitiformis (1), Lupus 45 1.54 vulgaris (27), Scleroderma (5), Erythema nodosum (5), Erythema gangrenosum (2) Pigmentary disorders Vitiligo (5), Chloasma (6), Hydroxyurea-hyperpigmentation (2) 13 0.44 Disorders of the hair Immunosuppression-related (268), Alopecia areata (2), Tinea (1), Lupus (9), Lichen 281 9.58 planus (1) Disorders of sebaceous glands Steroid-induced acne (836), Persistent idiopathic Acne (11) Seborrhic dermatitis (13), 862 29.41 Hidradenitis suppurativa (2) Skin cancers Basal cell carcinoma (13) Squamous cell carcinoma (1) Seizery (1) 15 0.5 Skin necrosis Heparin-induce thrombocytopenia (4), Calciphylaxis (1), Warfarin-induced (1) 7 0.23 Antiphospholipid (1) Miscellaneous disorders Pityriasis capitus (dandruff) (58) Milaria rubra (prickly heat) (3), Lichen plannus 879 30 chronicus (7), Pompholyx (2), Eczema (36), Psoriasis (47), Rosacea (3), Rhinophyma (3), Acanthosis nigricans (26), Prurigo nodules (2), Stria atrophica (692), Necrobiosis lipoidica (n=67), Immune-mediated purpura (n=2), EBV-induced purpura, (n=2), Immunosuppressive-induced purpura (n=3) Total 2931 100
* Disorder (number of cases)
Chronic vasculitis was idiopathic in five cases and generalized and vasculitic. Scleroderma skin changes due to adalimumb in one patient. Contact eczema were the most common manifestation of disease was common and mainly due to elastic dressing and (n=5). Erythema nodosum was seen with patients antiseptics around dialysis access and surgical gloves with interstitial lung disease (n=5) and erythema (n=2). No case of epidermal necrolysis was reported. gangrenosum with patients with inflammatory bowel Exfoliative dermatitis was due to drugs in two patients disease (n=2). Isolated leucocytoclastic vasculitis was (Sulphonamide and Epanutin). Erythema multiformis seen in one patient, while most had systemic disease was seen in five patients and Stevens Johnson in three. (n=46). The culprit drugs were rifampicin (n=2), azithromycin g. Hair disorders were common due to (n=1), clarithromycin (n=1) and levofloxacin (n=1). inhibition of hair growth by immunosuppressive Fixed drug reactions were noted in 12 patients. agents viz. steroids, azathioprine, cyclophosphamide Insect bites were encountered, yet rarely a cause of and mycophenolate used for treatment of idiopathic systemic pruritis (n=2). Drug rash with eosinophilia glomerulopathy and autoimmune diseases (n=268). and systemic symptoms was seen in four patients who Once the course of chemotherapy ends, new hair had received epanutin (n=2), carbamazipime (n=1) and growth begins 3-10 weeks later. However, alopecia allopuronol (n=1). Acute generalized exanthematous areata which is an autoimmune disease that shortens pustulosis was seen in two patients who had received the anagen phase and stops hair growth were also seen sulphonamide and levofloxacin. sporadically in few patients (n=2). Other secondary f. Autoimmune diseases included pemphigus causes were taenia (n=1), lupus (n=9) and lichen planus vulgaris (n=2) and bolus pemphigoid (n=3). The former (n=1). one is idiopathic while the latter is usually secondary h. Disorders of sebaceous glands were also to drugs. Dermatitis herpitiformis, which is associated common due to steroid-use (n=836). The latter with celiac disease, has been seen rarely (n=1) and improve within 3-10 weeks after discontinuation of improved with gluten-free diet. Skin lupus (lupus the drug. Persistent idiopathic acne was seen in 11 vulgaris) has been seen in few cases of systemic disease patients. Sebaceous dermatitis was seen in 13 patients. (n=27). Most were referred with lupus nephritis. Hidradenitis suppurativa was seen in two obese Lesions were not limited to the face; nearly ½ were patients. 11 The pattern of skin diseases in a multidisciplinary medical unit March 2021
Table 3: Comparison of percentage of common dermatosis in different countries
Multidisciplinary Dermatology clinics Dermatosis medical clinic Canada Kenya India UAE Saudi Arabia Kuwait Dermatitis/eczema 39.2 28.1 15-20 20.98 18.6 6.4 Pyoderma 5.7 6.4 30-40 2.55 7.65 4.5 Acne 7.3 3.9 3.5 9.07 9.48 29 Superficial mycosis 4.3 9.5 15-20 8.5 6.35 8.2 Psoriasis 4.7 3.2 0.5-1.5 4.49 3.01 1.6 Vitiligo NR 2.9 4 3.18 3.12 0.2 Viral warts 6.8 2 2 5.47 6.78 1.8 Lichen planus NR 1.6 0.5-1.5 0.95 0.64 0.2 Total >68 57.6 81.5 55.19 55.63 51.9
DISCUSSION drugs, except for two due to insect bites. Serious skin The current study is the first to describe the lesions were mainly due to genetically-determined pattern of skin diseases in a multidisciplinary clinic T-cell activation i.e. idiosyncratic reactions[7]. Those in Kuwait. Although the study was limited to a single manifested as pemphigus vulgaris (n=2), erythema medical unit, we believe that the results represent multiformis (n=5), Steven-Johnson reaction (n=3), a rough estimate of the percentage of skin diseases drug rash with eosinophilia and systemic symptoms in active wards. With a total of 2931 skin disorders (n=4), acute generalized exanthematous pustulosis reported during the study period in 4438 patients, (n=2), pustular (generalized) erythroderma due to the study has generated adequate data base from psoriasis (n=2) and vasculitis (n=1). Skin necrosis was a large patient population. The design of the study a distressing phenomenon in the past year, with a total using a single center with proper data collection and of seven cases reported. Four of those cases were due to recording as well as adequate follow up on diagnostic heparin-induced thrombocytopenia and thrombosis[8]. and out/in-patient admissions has improved the The rest were isolated cases of calciphylaxis as well accuracy of results. In our study, the accuracy of data as warfarin- and antiphospholipid-induced[9-11]. collection was verified by referring all patients with Interestingly, skin lesions induced by drugs viz. skin diseases to dermatology consultants as out- and/ erysipelas, cellulitis, viral infections, hydroxyurea- or in-patients. Moreover, the last two months of the induced, hair immunosuppression-induced disorders, study has consolidated prospectively the internal steroid-induced acne, heparin and warfarin skin auditing of the patient’s data. In our study, the necrosis and immunosuppressive-induced purpura prevalence of skin diseases was different from that constituted 56% of the overall skin disorders in the seen in dermatology units in Canada, Kenya, UAE medical unit, which is a matter of concern. and Saudi Arabia (Table 3)[3]. Our study showed (a) similar total percentage of major dermatomes in CONCLUSION Kenya, UAE and Saudi Arabia but not to India and In conclusion, skin diseases are common in the Canada; (b) a higher percentage of patients with acne medical units. Since nearly half are drug-induced, in our study compared to dermatitis/eczema in the prevention and early diagnosis are essential for specialized dermatology clinics; and (c) superficial diligent management. mycoses were the second disorder in our study similar to that seen with others. REFERENCES The difference is due to the high proportion of patients in our study who had received dialysis with 1. Lippens S, Hoste E, Vandenabeele P, Agostinis P, inherent access complications and those who had Declercq W. Cell death in the skin. Apoptosis 2009; received immunosuppressive therapy for progressive 14(4):549-569. glomerulopathy and autoimmune diseases[4]. The 2. Robson KJ, Piette WW. Cutaneous manifestations of systemic diseases. Med Clin North Am 1998; 82(6):1359- latter treatment, and corticosteroids in particular, 1380. increased the percentage of patients with acne and 3. Raddadi AA, Abdullah SA, Damanhouri ZB. Pattern of infections (pyogenic, viral and fungal) compared to skin diseases at King Khalid National Guard Hospital: dermatitis and eczema[5]. Moreover, 281 cases of hair- A12-month prospective study. Ann Saudi Med 1999; disorders have been reported, 95% of which were 19(5):453-454. due to immunosuppression[6]. A total of 151 cases of 4. Summary of Recommendation Statements. Kidney Int allergic dermatitis have been reported. All were due to Suppl (2011) 2013; 3:5-14. March 2021 KUWAIT MEDICAL JOURNAL 12
5. AHFS drug information 2005. McEvoy GK, ed. the diagnosis and treatment of heparin-induced Corticosteroids general statement. Bethesda, MD: thrombocytopenia. Ther Adv Hematol 2012; 3(4):237- American Society of Health-System Pharmacists; 251. 2005:2908-2921. 9. Nigwekar SU, Thadhani R, Brandenburg VM. 6. Hsu DC, Katelaris CH. Long-term management of Calciphylaxis. N Engl J Med 2018; 378:1704-1714. patients taking immunosuppressive drugs. Aust 10. Chan YC, Valenti D, Mansfield AO, Stansby G. Prescr 2009; 32:68-71. Warfarin induced skin necrosis. Br J Surg 2000; 7. Davies SJ, Jackson PR, Ramsay LE, Ghahramani P. 87(3):266-272. Drug intolerance due to nonspecific adverse effects 11. Hughes, Graham; Khamashta, Munther A. Hughes related to psychiatric morbidity in hypertensive Syndrome: Highwayss and Byways. Springer Science patients. Arch Intern Med 2003; 163(5):592-600. & Business Media (2017). ISBN 9781447151616. 8. Bakchoul T, Greinacher A. Recent advances in 13 KUWAIT MEDICAL JOURNAL March 2021
Original Article
The relationship between different types of nutritional supportive treatment and infection in patients with diagnosis of Chronic Obstructive Pulmonary Disease
Unal Kantekin Cigdem, Talih Gamze Department of Anesthesiology, School of Medicine, Bozok University, Yozgat, Turkey
Kuwait Medical Journal 2021; 53 (1): 13 - 17
ABSTRACT
Objective: To investigate the effect of enteral (EN), parenteral mortality rates, albumin and procalcitonin values, duration (PN) and enteral-parenteral (EN+PN) nutritional support of mechanical ventilation and duration of stay were treatments on the type and location of micro-organisms evaluated. Microorganism types and production sites were produced causing infection and mortality in chronic examined for microbiological evaluation. obstructive pulmonary disease (COPD) patients treated by Results: Albumin values of the PN group were determined invasive mechanical ventilation in the Intensive Care Unit to be significantly lower than those of the EN and EN+PN (ICU). groups (P <.001). The procalcitonin values of the EN group Design: Retrospective study were significantly lower than EN+PN group (P=.003). The Setting: Bozok University Hospital. rates of production of any micro-organism were determined Subjects: Between January 2014 and January 2018, records as 44.1% in the EN group, 70% in the PN group and 83.3% of 78 COPD patients followed up in the ICU were reviewed in the EN+PN group. The duration of mechanical ventilation retrospectively. and the length of stay in ICU were significantly shorter in Intervention: The type of nutrition, age, gender, mortality the EN group than in the other two groups (z=2.179, P=.029) rates, albumin and procalcitonin values, duration of (z=2.029, P=.042). mechanical ventilation, length of stay in ICU and types of Conclusion: In patients with COPD treated with mechanical microorganisms were evaluated. ventilation for whatever reasons, enteral nutrition could be Main outcome measure: Nutritional methods, age, sex, one of the factors reducing infection rates.
KEY WORDS: chronic obstructive pulmonary disease, enteral nutrition, infection, parenteral nutrition
INTRODUCTION in the termination of mechanical ventilation[1]. By Malnutrition is one of the most important indicators negatively affecting the immune system, malnutrition of mortality in chronic obstructive pulmonary is known to increase the risk of infection[2]. In patients disease (COPD). Malnutrition has negative effects on with community-acquired pneumonia accompanying morbidity and mortality by impairing the function COPD, mechanical ventilation and the incidence of of respiratory muscles, epithelial regeneration and the production of hospital-acquired micro-organisms the pulmonary defence mechanism both in COPD have been reported to increase[3]. patients with spontaneous respiration and those on Nutritional support treatment, which is used mechanical respiration[1]. Several previous studies to meet an increased energy requirement and have shown that insufficient nutrition prolongs the to support other treatments, must be a part of a duration of mechanical ventilation and causes failure rehabilitation program. When it is considered
Address correspondence to: Dr. Cigdem Unal Kantekin, Adnan Menderes Bulvarı, No: 44, 66200 – Yozgat, Turkey. Tel: + 90 3542127060; Fax: + 90 354 2123739; E-mail: drcgdm@ hotmail.com March 2021 KUWAIT MEDICAL JOURNAL 14 that enteral nutrition (EN) is less expensive than intolerance (abdominal distension, diarrhea >1000 ml/ parenteral nutrition (PN) and is associated with fewer day, gastric residual volume >150 ml), central venous complications, EN should be the first approach when catheterisation was applied and a blended emulsion COPD patients need nutritional support. However, in containing both mid and long-chain triglycerides cases where the enteral route cannot be tolerated, PN was started as a 20 ml/hour infusion through the or the two routes together can be used[4]. superior vena cava. In the subsequent days, the The aim of this study was to investigate the effect of amount was progressively increased according to the enteral, parenteral, and enteral-parenteral nutritional daily calorie requirement. In patients where the daily options on the type and location of production of calorie requirement could not be met with EN, the micro-organisms causing infection, hospital stays and combination of EN+PN was applied. mortality in COPD patients on invasive mechanical ventilation (IMV) in the Intensive Care Unit (ICU). Statistical analysis Statistical analysis of the study data were made MATERIALS AND METHODS using SPSS version 22.0 software (Statistical Package Ethics approval for this study (Registration No. for the Social Sciences, IBM Inc., Chicago, IL, USA). 2017-KAEK-189_2018.07.11_06) was provided by Following descriptive statistical analysis (frequency, Bozok University Clinical Research Ethics Committee. percentage, mean ± standard deviation, median, A retrospective evaluation was made of the records minimum and maximum values), conformity of of patients diagnosed with COPD between January the data to normal distribution was assessed with 2014 and January 2018 in the general ICU of a university the Kolmogorov-Smirnov test, and conformity to hospital. The study included a total of 78 patients with homogenous variance assumptions was evaluated a diagnosis of COPD who were followed up with IMV. with the Levene Test statistic. Values not showing Patients were excluded if they had congestive heart normal distribution such as albumin, procalcitonin, failure, liver disease, malignancy, chronic renal failure, ventilator duration and length of stay in ICU were neurological disease or accompanying diseases such evaluated with the Mann Whitney U-test, and as malabsorption. All the patients had a diagnosis of relationships between variables with the Spearman COPD, which had been previously made on the basis correlation test. In the comparison of percentage rates of physical examination, radiographc examination between groups, the Chi-square test was applied. A and respiratory function tests. In addition, the value of P <.05 was accepted as statistically significant. patients had a history of the use of corticosteroids, β-2 agonists, diuretic drugs and home use of non-invasive RESULTS mechanical ventilator or oxygen support. The 78 patients comprised 41 females and 37 From the retrospective scan of the records, males with a mean age of 73.06±9.63 years. The the patients were separated into three groups physical examination and clinical status of the as those receiving EN support, PN support and patients were evaluated with the APACHE II score. enteral+parenteral nutrition (EN+PN) support. There The mean APACHE II score on admission to ICU were 34 patients in group EN, 20 patients in group PN was determined as 25.43±8.20. When the APACHE and 24 patients in EN+PN. Evaluation was made in II scores were evaluated according to mortality, the respect of the type of nutrition, age, gender, mortality mean score was 21.34±7.22 in surviving patients and rates, albumin and procalcitonin values, duration of 29.30±7.38 in non-survivors and the difference was mechanical ventilation and length of stay in ICU. For statistically significant (P <.001). The mean albumin the microbiological evaluation, the types of micro- level of all the patients was 2.70 mg/dl (interquartile organisms and production sites were examined. range (IR)=0.60) and the mean procalcitonin value was Antimicrobial susceptibility tests and evaluation of 1.20 ng/dl (IR=4.85). The mean duration on mechanical responsible microorganisms were performed using ventilation was 192 hours (IR=312) and the mean the bioMerieux Vitek instrument. length of stay in ICU was 264 hours (IR=402) (Table 1). Nutritional support in our clinic was applied as follows. The calorie requirement of all the patients Table 1: Albumin and procalcitonin values, duration on mechanical was calculated using the Harris-Benedict formula. EN ventilator and length of stay in ICU of the patients was started with a 20 ml/hour infusion of protein-rich, hypercaloric, high-fibre, low-carbohydrate nutritional Parameters Median IR product via a nasogastric tube, and the gastric residual Albumin (mg/dl) 2.70 0.60 Procalcitonin (ng/ml) 1.20 4.85 volume was measured from the drainage at four Duration on mechanical ventilator (hours) 192 312 hours. When the process was tolerated, the previous Length of stay in ICU (hours) 264 402 infusion amount was doubled and the full daily calorie intake was reached. In patients who developed gastric ICU: Intensive Care Unit; IR: interquartile range 15 The relationship between different types of nutritional supportive treatment and infection in patients with... March 2021
In the comparison of albumin values, the values significantly lower than that of the survivors (P <.001) of the PN group were determined to be significantly (Table 4). lower than those of the EN group and the EN+PN In the evaluation of the patients in respect of group (P <.001). The procalcitonin values of the EN albumin and procalcitonin values and duration of group were significantly lower than those of the mechanical ventilation and length of stay in ICU, it EN+PN groups (P=.003) (Table 2). was observed that as age increased, the albumin level decreased and procalcitonin values and duration Table 2: Comparison of the albumin and procalcitonin values of the of mechanical ventilation and length of stay in ICU groups increased (Table 5). Group Group Group Parameters EN PN EN+PN P value (n=34) (n=20) (n=24) Table 5: Relationships of the albumin and procalcitonin values of the cases with ICU stay and ventilator duration Albumin (mg/dl) 42.94 20.52 50.44 <.001 Procalcitonin (ng/ml) 31.38 41.60 49.25 .003 Stay in Ventilator Parameters Age ICU duration EN: enteral nutrition; PN: parenteral nutrition; n: number of patients Albumin Mortality was determined as 44.1% in group EN, r -0.291 -0.358 -0.407 P .010 .001 <.001 60% in group PN and 41.7% in group EN+PN. No Procalcitonin statistically significant difference was found between r 0.271 0.616 0.601 the groups in respect of the mortality rates. Mortality P .016 <.001 <.001 was related to sepsis secondary to pneumonia. ICU: Intensive Care Unit
Table 3: Duration of mechanical ventilation and length of stay in Table 6: The rates of micro-organism production in each group ICU of the groups Group EN Group PN Group EN+PN Micro-organism Group EN Group PN Group EN+PN n(%) n(%) n(%) Parameters Median - IR Median - IR Median - IR Acinetobacter 4(26.7) 5(35.7) 3(15) Duration of Staphylococcus 1(6.7) 3(21.4) 5(25) mechanical MRSA 4(26.7) 1(7.1) 2(10) ventilation (hours) 168 - 200 180 - 312 312 - 557 Pseudomonas 1(6.7) 2(14.3) 4(20) Length of stay in Streptococcus 4(26.7) 1(7.1) 4(20) ICU (hours) 218 - 235 240 - 420 384 - 582 Enterococcus 1(6.7) 1(7.1) 2(10) E.Coli - 1(7.1) - ICU: Intensive Care Unit; EN: enteral nutrition; PN: parenteral EN: enteral nutrition; PN: parenteral nutrition nutrition The rates of production of any micro-organisms A statistically significant difference was found were determined as 44.1% in the EN group, 70% in the between the EN group and the EN+PN group in PN group and 83.3% in the EN+PN group. The micro- respect of the length of stay in ICU (z=2.179, P=.029) organisms produced in the patients are shown in Table and the duration of mechanical ventilation (z=2.029, 6. Micro-organisms were seen to be produced in the P=.042) (Table 3). trachea at the rate of 63.3%. Patients who were positive The mean age, procalcitonin value, duration of for tracheal aspirate culture had pneumonia infection. mechanical ventilation and length of stay in ICU were determined to be higher in the patients with mortality DISCUSSION than in the surviving patients (P <.001, P <.001, P=.012, Malnutrition is a frequently seen problem in COPD P=.059). The albumin value of the non-survivors was patients. Evaluation of malnutrition is important as it is an indicator of poor prognosis in these patients. Table 4: The value of albumin, procalcitonin, duration of mechanical Decreased protein intake, reduced protein synthesis ventilation and length of stay in ICU and increased inflammation cause an impaired protein Non- blance in COPD patients. Moreover, in parallel with Parameters Survivors survivors reduced body weight, somatic protein and fat deposits Albumin (mg/dl) 2.40(0.65) 2.80(0.40) are reduced. Hypoxia and excessive medication use Procalcitonin (ng/dl) 3.50(10.40) 0.50(1.60) cause dyspeptic complaints, leading to a reduced Duration of mechanical ventilation (hours) 288(587) 165(169) desire for food intake. As the disease progresses, Length of stay in ICU (hours) 384(702) 200(200) Age (years) 78.43±8.50 68.22±7.92 weight loss increases and respiratory functions are negatively affected[5]. The main goal of nutrition ICU: Intensive Care Unit March 2021 KUWAIT MEDICAL JOURNAL 16 treatment in COPD is to prevent weight loss and meet current study showed that although the target calories the calculated nutritional requirements. were reached in all the patients provided with enteral, COPD patients who do not respond to medical parenteral and both enteral and parenteral nutrition treatment and non-invasive ventilation may require support, the COPD patients who received EN were the application of IMV with endotracheal intubation. taken off the mechanical ventilator significantly earlier Weakness of the respiratory muscles and impaired and the length of stay in hospital was significantly pulmonary mechanics are frequently seen problems in shorter. There was no significant difference between these patients[6]. Therefore, it can be difficult to wean the three groups of the current study in respect of patients off the device once they have started IMV mean age. However, as the mean age of the group with support. As the length of hospital stay is prolonged and a shorter stay in hospital and earlier discharge was there is greater energy expenditure by these patients, lower, this suggests that this result is not only related there is a greater tendency to infection. The start of EN to EN. within 24-48 hours of starting mechanical ventilation Liver-originated protein is used as an indicator is strongly recommended[7]. The most important cause reflecting the protein energy balance. After insufficient of prolonged stay in hospital and increased mortality protein or energy intake, the production and rates is the development of infection[8]. Agarwal et al expression of these proteins from the liver reduces reported mean length of hospital stay as 13 days in and plasma levels fall. With an improvement in intensive care patients who developed ventilator- nutrition, values return to normal. These proteins are related pneumonia and as eight days in those who did albumin, transferrin, transthyretin and retinol-binding not develop pneumonia. protein[11]. Although serum albumin level is usually In a study by Elke et al[9], it was reported that EN evaluated as a protein index of the nutritional status, alone reduced infection-associated complications in it may be reduced as a result of re-distribution. The certain patient groups. Consistent with the results of low albumin that develops associated with acute- Elke et al, in the current study, although the target phase reaction during infection and inflammation is calorie value was reached in all three groups, the interpreted as reflective of protein malnutrition in the procalcitonin value was significantly lower in the patient[12]. group that received EN support. The production rate All conditions progressing with a clinically low of any micro-organisms was 44.1% and this was lower albumin level show that a current or past systemic than that of the other two groups. However, there inflammatory response has developed[12]. In the current was no significant difference between the groups in study, the albumin value of the group applied with PN respect of mortality. In a study by Heidegger et al[10] was significantly lower than the values of the other two of 305 critically ill patients in ICU, one group was groups. Nevertheless, the target calories were reached given EN + PN support and the other group, EN only. in that group, just as in the other two groups. As the No difference was determined between the groups procalcitonin value of the patients given EN support in respect of mortality rates, but it was reported that only was significantly lower than that of the other two fewer nosocomial infections developed in the group groups, this suggests that the albumin levels of the PN provided with EN + PN support and the duration and EN+PN groups were low beause of infection. on mechanical ventilation was shorter. In the current Mortality rates were determined as 44.1% in group study, the rate of production of any micro-organism EN, 60% in group PN and 41.7% in group EN+PN, was highest at 83.3% in the patient group administered with no statistically significance between the groups. with both EN + PN support. Similarly, the duration on The deaths were seen to be related more to the mean mechanical ventilation and the length of hospital stay age, the procalcitonin value and the time spent on were significantly longer in the patients who received mechanical ventlation and in ICU rather than the both EN + PN support. The difference between the nutrition method. These values were significantly results of the current study and those of the above- higher than those of the discharged patients (P <.001, mentioned studies can be attributed to the lower P <.001, P=.012, P=.059). The albumin value of the number of patients in this study. non-survivors was significantly lower than that of the Various studies have reported that as infection rates surviviors (P <.001). are low in patients given sufficient nutritional support There were some limitations to this study. First is by the enteral or parenteral routes, separation from the that it was a single-centre study and the number of mechanical ventilator is more successful and length of patients was low. That the study was retrospective hospital stay is shorter. The most recent findings have could have reduced the power of the study with shown that the earlier EN is started, then length of some data unavailable, thereby preventing the clear stay in ICU will be shorter and the outcome will be determination of some correlations. Finally, this better[7]. Consistent with literature, the results of the study only included COPD patients being treated 17 The relationship between different types of nutritional supportive treatment and infection in patients with... March 2021 and followed up in ICU. A significant ICU patient in patients with chronic obstructive pulmonary disease population was not included, such as trauma, burns requiring admission to the intensive care unit: risk and postoperative patients. Therefore, the study factors for mortality. J Crit Care 2013; 28(6):975-979. results cannot be generalised. 4. Anker SD, John M, Pedersen PU, et al. ESPEN Guidelines on Enteral Nutrition: Cardiology and Pulmonology. In: Valentini L, Schütz T, Allison S, Howard P, Pichard C, CONCLUSION Lochs H, editors. Clin Nutr 2006; 25(2):311-318. The combination of COPD and nosocomial 5. Karadağ F, Karul A, Polatlı M, Türkan H, Pirim C. The infections causes signficant morbidity in ICU patients relation of pulmonary dysfunction and nutritional and prolongs the length of hospital stay. Enteral parameters. Turkiye Klinikleri Archives of Lung 2001; nutrition is associated with fewer infections in patients. 2(2):73-78. Therefore, for COPD patients treated with mechanical 6. Uçgun İ. Mechanical ventilation in COPD. Güncel Göğüs ventilation, it should be kept in mind that the primary Hastalıkları Serisi-KOAH 2013; 1:65-79. option of nutritional supportive treatment is enteral 7. Antonione R. Nutrition in pulmonary and cardiac disease. In: Sobotka L, editor. Basics in Clinical Nutrition. nutrition, as it could be one of the factors reducing Czech Republic:Galen; 2013.p.485-493. infection rates. 8. Agarwal R, Gupta D, Ray P, Aggarwal AN, Jindal SK. Epidemiology, risk factors and outcome of nosocomial ACKNOWLEDGMENT infections in a respiratory intensive care unit in North Conflict of interest: None India. J Infect 2006; 53(2):98-105. Source(s) of support: None 9. Elke G, Kuhnt E, Ragaller M, Schädler D, Frerichs I, Cigdem Unal Kantekin conceived, designed and Brunkhorst F, et al. Enteral nutrition is associated with did statistical analysis & editing of manuscript. Gamze improved outcome in patients with severe sepsis. Talih and Cigdem Unal Kantekin did data collection A secondary analysis of the VISEP trial. Med Klin Intensivmed Notfmed 2013; 108(3):223-233. and manuscript writing. Gamze Talih did review and 10. Heidegger CP, Darmon P, Pichard C. Enteral vs. final approval of manuscript parenteral nutrition for the critically ill patient: a combined support should be preferred. Curr Opin Crit REFERENCES Care 2008; 14(4):408-414. 11. Graves C, Saffle J, Morris S. Comparison of urine urea 1. Huang YC, Yen CE, Cheng CH, Jih KS, Kan MN. nitrogen collection times in critically ill patients. Nutr Nutritional status of mechanically ventilated critically Clin Pract 2005; 20:271-275. Sobotka L. Diagnosis ill patients: comparison of different types of nutritional of malnutrition. In: Allison SP, eds. Basic in clinical support. Clin Nutr 2000; 19(2):101-107. nutrition. 4th ed. Prague: GalenPr. 2011:269-271. 2. Pingleton SK. Enteral nutrition in patients with 12. Grimble RF. Injury and Sepsis. In: Sobotka L, editor. respiratory disease. Eur Respir J 1996; 9(2):364-370. Basics in Clinical Nutrition. Czech Republic:Galen. 3. Cilli A, Erdem H, Karakurt Z, Turkan H, Yazicioglu-Mocin 2013.p.185-197. O, Adiguzel N, et al. Community-acquired pneumonia March 2021 KUWAIT MEDICAL JOURNAL 18
Original Article The role of ultrasonographic measurement of bladder and detrusor wall thickness in diagnosis of urinary incontinence
Ozge Sehirli Kinci1, Mehmet Ferdi Kinci2, Mahmut Kuntay Kokanali3, Yasemin Tasci3 1Department of Obstetrics and Gynecology, Kızılcahamam State Hospital, Ankara, Turkey 2Department of Obstetrics and Gynecology, Gülhane Education and Research Hospital, Ankara, Turkey 3Department of Obstetrics and Gynecology, Zekai Tahir Burak Woman’s Health Education and Research Hospital, Ankara, Turkey
Kuwait Medical Journal 2021; 53 (1): 18 - 24
ABSTRACT
Objective: To evaluate the diagnostic accuracy of bladder considered as the mean BWT and DWT. wall thickness (BWT) and detrusor wall thickness (DWT) Intervention: BWT and DWT at both empty and full bladder measurements by transvaginal ultrasound in diagnosis and were significantly thicker in DOI group than in controls. classification of urinary incontinence DOI group measurements were also thicker than SUI group, Design: Fifty-one women with pure stress urinary except for DWT measurement in full bladder. incontinence (SUI), 53 women with pure detrusor over Main outcome measure: There were no statistical differences activity incontinence (DOI), both of which were diagnosed in DWT and BWT measurements between SUI and control by urodynamic studies, and 50 women without urinary groups. incontinence (as controls) were enrolled in this prospective Results: By using ROC curve analysis, the best cut off values cross-sectional study. for predicting the DOI were calculated as 4.35 mm for full Settings: Using transvaginal probe, BWT was measured in BWT; 1.95 mm for full DWT; 5.95 mm for empty BWT and three sites: at the thickest part of the dome of the bladder, the 2.25 mm for empty DWT. trigone and the anterior wall of the bladder. Measurements Conclusion: Transvaginal ultrasonographic measurement of are taken first at 250-300 ml bladder volume and repeated BWT and DWT in full and empty bladder can be valuable after voiding at <50 ml bladder volume. in diagnosis of DOI with low sensitivity and relatively high Subjects: An average of the three measurements was specificity.
KEY WORDS: transvaginal ultrasonography, urinary incontinence, wall thickness
INTRODUCTION with an increase of intraabdominal pressure such as Urinary incontinence (UI) is a common condition exertion, coughing or sneezing. DOI is incontinence among women defined as the complaint of any that accompanies a strong desire for urinating due to involuntary leakage of urine. It affects sexual, social involuntary detrusor contractions during the bladder and physical activities of a woman. The prevalence of filling phase, appearing spontaneously or after UI has been determined at different values in different provocation. MUI is defined as urine loss that happens studies ranging from 16.1 to 68.8%[1-3]. UI mainly both with exercise, coughing and sneezing and with a presents as either stress UI (SUI), detrusor over activity strong desire to urinate[4]. incontinence (DOI) or mixed UI (MUI). SUI is defined Differentiation of UI subtypes in primary care as a loss of urine that happens during situations based on patient’s complaints, history or physical
Address correspondence to: Ozge Sehirli Kinci, Kızılcahamam State Hospital, Kızılcahamam, Ankara, Turkey. Tel: +90 5056167320; Fax: +90 3123124931; E-mail: drozgesehirlikinci@ gmail.com 19 The role of ultrasonographic measurement of bladder and detrusor wall thickness in diagnosis of urinary... March 2021 examination is not always sufficient. Thus, further For all patients, ultrasonographic measurements methods may be needed to investigate the symptoms. were performed using Aloka ProSound SSD 5500 Urodynamic study tries to find the condition in which UI SV Pure HD (Aloka Co Ltd, Tokyo, Japan) with the occurs and is considered as a gold standard diagnostic vaginal 7 Mhz probe in supine position. Ultrasound tool for evaluating lower urinary tract symptoms. examinations were made by one author who was blind However, it is an expensive, time consuming, invasive to urodynamic study results. For cases, ultrasound and not easily accessible method[5]. Therefore, there is was not performed in combination with urodynamic a growing number of researches to find a noninvasive, test on the same day. Before the measurements of BWT cheap and widely available method for assessing lower and DWT, the amount of urine in the bladder was urinary tract symptoms. Ultrasound is a diagnostic calculated using the formula described by Haylen[9]. tool with widespread use in obstetrics and gynecology Initially, BWT and DWT were measured on the sagittal practice. Although there is no standardization about plan while the bladder was 250-300 cc full. Then, the method, some previous studies have suggested patients were asked to void. Following urination, BWT that measurement of bladder wall thickness (BWT) and DWT were measured as the residual urine volume and detrusor wall thickness (DWT) via ultrasound is was <50 cc. During measurements, the vaginal probe a reliable method for the diagnosis of UI subtypes[6,7]. was careful not to press on the bladder. BWT and DWT In this study, we aimed to determine the diagnostic were measured as described by Oelke and Robinson role of transvaginal ultrasound measurement of BWT et al[5,10]. The bladder was first displayed on the and DWT in determining the UI subtype in the full and sagittal plan. In this position, the hypoechoic urethra, empty bladder. which caused the shadowing of the bladder dome, was displayed. Subsequently, the probe was shifted SUBJECTS AND METHODS laterally 1 cm. When measurements were taken, the This prospective cross-sectional case control bladder was maximally enlarged to cover the entire study was carried out at Zekai Tahir Burak Women’s screen. The bladder wall was ultrasonographically Health Education and Research Hospital between displayed as a 3-layered hypoechoic area between the March 2015 and October 2016. Patients admitted to two hyperechoic areas. In this image, the hypoechoic the urogynaecology outpatient clinic with a complaint area forms detrusor wall when hyperechogenic areas of UI were included. The study was approved by the form adventitia and mucosa. BWT including three ethical research committee of the hospital. Written and layers was measured from the outside to the outside. verbal information was given to all the patients and DWT was also measured in such a way as to measure their signed approvals were taken. Patients with any only the hypoechoic area and to be perpendicular systemic disease, drug use history affecting the urinary to the bladder lumen from outside to outside. Three system, urinary system obstruction, current urinary different measurements were taken from the bladder system infection or recurrent urinary tract infection dome, trigone and bladder anterior wall, and their history, > grade 2 pelvic organ prolapse according average was calculated and accepted as the final to the Baden-Walker classification system, MUI and value. Intra-observer reliability was assessed using pelvic surgery history were excluded from the study. the measurements of the first investigator (T.S.L. who We included 104 incontinent patients as cases and was blind to urodynamic study results and performed 50 continent patients as controls. Continent patients all measurements) with an interval of 7-14 days and were women who were referred to gynecology was blinded to the previous analysis. For interobserver outpatient clinic due to gynecological diseases other reliability test, another author was blinded to first than UI, like fibroids or adnexial cysts. All patients author’s results and urodynamic findings and were subjected to detailed history and general physical repeated the ultrasonographic measurements for the and urogynaecological examination. Of the 104 first 20 cases. Test–retest series for all parameters in incontinent patients, 51 women were diagnosed with the first 20 patients were measured and showed good SUI and 53 women with DOI, based on urodynamic interobserver agreement. Intraobserver intraclass test results. Urinalysis was performed for all patients to correlation coefficient ranged from 0.648-0.886. exclude any pyuria or bacteriuria before urodynamic When the size of the sample was calculated for our test. Urodynamic examinations were performed using study, previous studies[10-12] with BWT measurement MMS Solar Blue multijointed urodynamic system difference of 1 mm were taken as a reference between when the patients were in sitting position, according to female patients with and without UI diagnosis. As a International Continence Society recommendations[8]. result, it was estimated that for detection of a 1 mm The urodynamic findings of the patients were evaluated difference between groups, each group should consist by physicians working in the urogynecology clinic, but of 48 females with a power of 80% and a 5.0% alpha not in the study team. error. March 2021 KUWAIT MEDICAL JOURNAL 20
to be impacted on the full, empty BWT and DWT Table 1: Demographic characteristics of the groups increases. For each independent variable odds ratio, Demographic SUI DOI Control P 95% confidence interval (CI) and significance levels for characteristics (n=51) (n=53) (n=50) were calculated. For P <.05, the results were considered Woman’s age (years) 47.8±7.2 47.9±9.7 46.1±8.8 .527 statistically significant. Gravida 3 (1-10) 4 (1-13) 3 (0-8) .130 Parity 2 (1-5) 2 (0-7) 2 (0-7) .240 BMI (kg/m2) 30.0±6.2 29.1±6.2 28.8±5.1 .591 RESULTS No. of vaginal delivery 2 (0-5) 2 (0-7) 1 (0-7) .201 A total of 154 women were enrolled, 51 of which ≥4000g birth history 8 (15.7) 8 (15.1) 15 (30.0) .106 were SUI, 53 were DOI and 50 were control group. Cesarean section history 7 (13.7) 7 (13.2) 12 (24.0) .262 There were no statistically significant differences Current smoking 11 (21.6) 4 (7.5) 6 (12.0) .105 Menopausal status 15 (29.4) 22 (41.5) 12 (24.0) .147 between the groups in terms of demographic characteristics as shown in Table 1. Data were presented as mean±standard deviation, median According to the ultrasonographic measurements, (minimum-maximum value), number (%). statistically significant difference was found in all of SUI: stress urinary incontinence; DOI: detrusor over activity incontinence; BMI: Body mass index full BWT, full DWT, empty BWT and empty DWT P <.05 was considered statistically significant. values between SUI, DOI and control groups (Table 2). The mean values of full BWT were measured as 3.7±0.8 SPSS (Statistical Package for Social Sciences) for mm in the SUI group, 4.8±1.7 mm in the DOI group Windows 17.0 program was used for statistical analysis. and 4.0±0.8 mm in the control group. The mean values Whether or not the data had normal distribution was of full DWT were measured as 1.5±0.5 mm in the checked by the Kolmogorov-Smirnov test. Those with SUI group, 1.6±0.5 mm in the DOI group and 1.3±0.4 normal distribution of quantitative data are shown as mm in the control group. The mean values of empty mean±standard deviation and those without normal BWT were measured as 4.5±1.2 mm in the SUI group, distribution as median (minimum-maximum value). 6.0±1.9 mm in the DOI group and 4.7±1.0 mm in the The one-way ANOVA test was used to compare the control group. The mean values of empty DWT were differences between groups with normal distribution measured as 1.7±0.7 mm in the SUI group, 2.4±1.0 mm and when the difference was significant, a post-hoc in the DOI group and 1.7±0.6 mm in the control group Tukey test was used to identify the group that caused (P <.001). All wall thickness measurements in DOI the difference. Differences between groups without group were significantly greater than in control group. normal distribution were assessed by Kruskal Wallis Similarly, full BWT, empty BWT and empty DWT test. Qualitative data were presented as number measurements were greater in DOI group than in SUI (%) and Chi-square test was used to investigate the group, but there was no significant difference between differences among the groups consisting of these data. SUI and DOI groups for full DWT. On the other hand, The receiver-operating characteristic curve was created SUI and control groups were statistically similar in to measure the predictive sensitivity and specificity terms of all wall thickness measurements (Table 2). of DOI measurements of different ultrasonographic When we compared four different ultrasonographic full BWT measurements. Multiple logistic regression measurement ratios, there was only a statistically analysis was used to identify those who had the most significant difference between the groups regarding significant effect from the risk factors considered full BWT/full DWT ratio (P=.039) (Table 2). Namely,
Table 2: Ultrasonographic measurements and ratios of full BWT, full DWT, empty BWT and empty DWT by groups
SUI DOI Control P2 Ultrasonographic measurements P -I- -II- -III- 1 I-II I-III II-III Full BWT 3.7±0.8 4.8±1.7 4.0±0.8 <.001 <.001 .408 .003 Full DWT 1.5±0.5 1.6±0.5 1.3±0.4 .025 .485 .258 .019 Empty BWT 4.5±1.2 6.0±1.9 4.7±1.0 <.001 <.001 .713 <.001 Empty DWT 1.7±0.7 2.4±1.0 1.7±0.6 <.001 <.001 .858 <.001 Full BWT/Full DWT 2.8±1.0 3.2±1.1 3.2±0.9 .039 .046 .985 .088 Empty BWT/Empty DWT 2.8±0.9 2.8±0.9 2.9±0.7 .377 ------Full BWT/Empty BWT 0.8±0.2 0.8±0.2 0.8±0.1 .579 ------Full DWT/Empty DWT 0.9±0.4 0.7±0.3 0.8±0.2 .057 ------
Data were presented as mean±standard deviation.
SUI: Stress urinary incontinence; DOI: Detrusor over activity incontinence; BWT: Bladder wall thickness; DWT: Detrussor wall thickness; P1: probability value for one-way ANOVA Test; P2: probability values for post hoc Tukey Test P <.05 was considered statistically significant. 21 The role of ultrasonographic measurement of bladder and detrusor wall thickness in diagnosis of urinary... March 2021
Table 3: Areas under ROC curve for ultrasonographic bladder and detrussor wall thickness measurements in predicting stress urinary incontinence
Ultrasonographic measurements AUC SE P 95% CI in predicting SUI Full BWT 0.41 0.06 .102 0.29-0.52 Full DWT 0.59 0.06 .121 0.48-0.70 Empty BWT 0.44 0.06 .313 0.33-0.55 Empty DWT 0.52 0.06 .674 0.41-0.64 Full BWT/Full DDT 0.33 0.05 .303 0.22-0.44
AUC: Area under curve; SE: Standard error; CI: Confidence interval; BWT: Bladder wall thickness; DWT: Detrussor wall thickness; ROC: receiver operating characteristic P <.05 was considered statistically significant. Figure 1 shows the generated receiver- operating characteristic curve for ultrasonographic measurements of different BWT and DWT in predicting SUI. However, no statistically significant relationship was found between any ultrasonographic measurement and presence of SUI (all P-values >.05) (Table 3). On the other hand, as seen in Figure 2, the curves plotted for full BWT, full DWT, empty BWT and empty DWT are above the 45° line, indicating a significant relationship between each of these values and the presence of DOI [for full BWT, area under curve (AUC)=0.68, standard error (SE)=0.05, 95% CI= 0.58-0.78, P=.002; for full DWT, AUC=0.63, SE=0.06, 95% CI=0.52-0.74, P=.023; for empty BWT, AUC=0.72, Fig 1: Receiver-operating characteristic curve of transvaginal SE=0.05, 95% CI=0.62-0.82, P<.001; for empty DWT, ultrasonographic bladder and detrussor wall thickness AUC=0.74, SE=0.05, 95% CI=0.64-0.83, P<.001]. measurements and stress urinary incontinence However, for full BWT / full DWT ratio, there was no relationship with the presence of DOI (P=.345) (Table full BWT/full DWT ratio was statistically greater in 4). DOI group (3.2±1.1 mm) than in SUI group (2.8±1.0 The best cut off values for predicting the DOI are mm) (P=.046). 4.35 mm with 59% sensitivity and 76% specificity for full BWT; 1.95 mm with 36% sensitivity and
Table 4: Areas under ROC curve for ultrasonographic bladder and detrussor wall thickness measurements in predicting detrusor over activity incontinence and cut-off values
Areas under ROC curve for Cut off Sensitivity Specificity AUC SE P 95% CI ultrasonographic BWT and DWT (mm) (%) (%) Full BWT 0.68 0.05 .002 0.58-0.78 4.25 59 74 4.35 59 76 4.45 50 80 Full DWT 0.63 0.06 .023 0.52-0.74 1.85 36 86 1.95 36 90 2.05 20 94 Empty BWT 0.72 0.05 < .001 0.62-0.82 5.85 53 88 5.95 51 90 6.05 49 90 Empty DWT 0.74 0.05 < .001 0.64-0.83 2.15 59 80 2.25 57 82 2.35 53 82 Full BWT/Full DDT 0.45 0.06 .345 0.33-0.56 ------
AUC: Area under curve; SE: Standard error; CI: Confidence interval; BWT: Bladder wall thickness; DWT: Detrussor wall thickness; ROC: receiver operating characteristic P <.05 was considered statistically significant. March 2021 KUWAIT MEDICAL JOURNAL 22
for empty DWT (Table 4). The most statistically significant among these parameters are empty DWT (AUC=0.74), empty BWT (AUC=0.72), full BWT (AUC=0.68) and full DWT (AUC=0.63). Multivariate regression analysis was used to determine which variables were independent predictors for BWT and DWT increase in full and empty bladder (Table 5). After controlling for possible confounders, the presence of urge incontinence was determined as the only significant independent factor for full BWT increase (P <.001). For empty BWT increase, it was found that woman’s age ≥60 years (P=.008) and presence of DOI (P <.001) were significant independent variables. When the same analysis was performed for DWT increase in full and empty bladder, BMI ≥30 kg/m2 (P=.034) and presence of DOI (P=.013) was found to be independent effective factors for full BWT increase. Additionally, presence of DOI (P <.001) and menopausal status (P=.037) were independently effective in terms of empty DWT increase.
DISCUSSION In this study, we have found that transvaginal ultrasonographic BWT and DWT in full and empty bladder is associated with presence of DOI and can be useful in the diagnosis of UI as a noninvasive, cheap and accessible method. It has been shown that BWT or DWT Fig 2: Receiver-operating characteristic curve of transvaginal increases in DOI[13]. It is believed that patients with DOI ultrasonographic bladder and detrussor wall thickness measurements and detrusor over activity incontinence have frequent isometric detrusor contractions during storage phase. Secondary to these contractions, muscle 90% specificity for full DWT; 5.95 mm with 51% bulk increases and bladder wall hypertrophy occurs. sensitivity and 90% specificity for empty BWT and Therefore, BWT or DWT increases[14]. In our study, we 2.25 mm with 57% sensitivity and 82% specificity have found that ultrasonographic measurements of
Table 5: Multivariate regression analysis of factors for BWT and DWT increase in full and empty bladder
Multivariate regression analysis of factors for BWT Full BWT Increase Empty BWT Increase and DWT increase in full and empty bladder Wald OR 95% CI P Wald OR 95% CI P Age (<60; ≥60 years) 0.2 0.8 0.3-2.2 .664 7.1 9.1 1.8-45.8 .008 BMI (<30; ≥30 kg/m2) 0.1 0.9 0.4-1.9 .756 1.0 0.6 0.2- 1.6 .324 Vaginal delivery (Primi/multiparous) 0.5 1.5 0.5-4.8 .459 0.1 1.0 0.2-4.0 .948 Cesarean section 0.9 1.9 0.5-7.1 .355 2.3 4.0 0.7-24.9 .132 Current smoking 0.1 1.1 0.4-3.1 .920 0.4 0.7 0.2-2.4 .538 Menopausal status 0.1 1.2 0.4-3.3 .755 0.2 0.7 0.2-2.8 .633 Incontinence subtype (SUI/DOI) 17.0 4.7 2.3-9.9 <.001 27.5 14.3 5.3-38.4 <.001 Full DWT Increase Empty DWT Increase Wald OR Wald OR Wald OR Wald OR Age (<60; ≥60 years) 1.0 0.5 0.2-1.8 0.318 1.7 0.5 0.1-1.5 0.187 BMI (<30; ≥30 kg/m2) 4.5 2.5 1.1-5.9 0.034 0.3 1.3 0.6-2.8 0.571 Vaginal delivery (Primi/multiparous) 0.3 0.7 0.2-2.6 0.588 0.4 1.5 0.4-5.2 0.504 Cesarean section 0.3 1.6 0.3-7.2 0.568 2.3 3.1 0.7-13.5 0.130 Current smoking 0.1 1.2 0.4-4.0 0.774 0.1 0.9 0.3-2.7 0.809 Menopausal status 07 1.7 0.5-5.6 0.391 4.3 3.7 1.0-12.5 0.037 Incontinence subtype (SUI/DOI) 6.2 2.8 1.2-6.2 0.013 21.6 6.7 3.0-15.1 <0.001
BWT: Bladder wall thickness; DWT: Detrussor wall thickness; BMI: Body mass index; SUI: Stress urinary incontinence; DOI:Detrusor over activity incontinence; OR: Odds ratio; CI: Confidence interval P <.05 was considered statistically significant. 23 The role of ultrasonographic measurement of bladder and detrusor wall thickness in diagnosis of urinary... March 2021 both BWT and DWT in full and empty bladder were DWT was measured at three different sites (trigone, greater in patients with DOI than in continent women. dome and anterior wall) and the mean calculated after Also, presence of DOI was detected as an independent voiding with a ≤50 ml bladder volume by translabial factor for BWT and DWT increase in full and empty approach. They reported higher mean DWT values bladder. Our results indicate a possible bladder wall in DOI group than in non DOI group, and also hypertrophy in diagnosis of DOI. DWT measurement had poor sensitivity but high It is known that BWT and DWT can be measured specificity for diagnosing DOI. Minardi et al reported ultrasonographically by three different approaches similar results in a prospective, controlled study, which are transvaginal, transperineal and suprapubic, confirming that translabial measurement of DWT and all of these methods are effective in determining was higher in women with DOI than in women with detrusor hypertrophy. However, these methods have SUI or healthy controls[6]. In this study, we measured been reported to vary in terms of image quality, both BWT and DWT in full and empty bladder via necessity of bladder filling during measurement transvaginal ultrasonography. We found that these and invasiveness rates[15]. We preferred transvaginal parameters increased in DOI group compared to SUI ultrasonography in our study because of its and continent group. We also determined that a full reliability in obese patients with minimal bone and BWT >4.35 mm predicted DOI with a sensitivity of soft tissue artefact, and higher frequency of probe 59% and a specificity of 76%; a full DWT >1.95 mm measurements[16]. with a sensitivity of 36% and a specificity of 90%; In healthy women, BWT measurement ranges an empty BWT >5.95 mm with a sensitivity of 51% from 3 to 5 mm and until 50 ml of bladder fullness, and a specificity of 90%; and an empty BWT >2.25 BWT does not change significantly; between 50-250 mm with a sensitivity of 57% and specificity of 82%. ml, BWT thins down rapidly and above 250 ml it This low sensitivity and relatively high specificity tends to remain constant[15-17]. Therefore in our study, values indicate that BWT and DWT measurements empty bladder measurements for BWT and DWT by transvaginal ultrasonography may be useful were performed with a bladder volume <50 cc and full parameters for clinicians to confirm the presence of bladder measurements with a volume of 250-300 cc. DOI, especially to identify women who are unlikely Previous studies using ≥5 MHz transvaginal probe to have DOI. have noted significantly higher BWT measurements in Our study has some strong sides. There is a lack patients with DOI than in SUI or continent women, but of data in literature about the role of ultrasonographic cut-off values for diagnosis of DOI varied between the measurement of BWT in prediction of SUI. In our studies[5,12,18]. Khullar et al stated that the mean BWT study, we could compare both BWT and DWT in >5 mm had a sensitivity of 84% and specificity of 89% full and empty bladder between SUI and continent for diagnosis of detrusor overactivity[19]. However, group. We have found that BWT and DWT have no Robinson et al proposed a BWT cut off of 6 mm as a predictive role in diagnosis of SUI. In addition, when highly suggestive value for DOI[10]. Serati et al evaluated the literature is reviewed, it is seen that there is no the BWT measurements in different incontinence types proportional calculations including BWT and DWT in and found that a cut-off value of 6.5 mm had a 100% any study other than our work, and it is also seen that positive predictive value for all DOI (including DOI the importance of that in diagnosis is not taken into associated with SUI), and 71.4% for pure DOI, but this consideration. We also compared four ratios between method could not replace urodynamic test[20]. In 2010, the groups and did not report any predictive role for a systematic review performed by Latthe et al after any ratio. However, we believe that these topics need assessment of the methodological quality of 190 studies, some more studies to reach exact recommendations. included only five for further analysis and concluded In our study, the presence of a sufficient number of that using a 5-mm cut-off for BWT for identifying patients with homogenous demographic characteristics DOI, the sensitivity varied between 40% and 84%, and seems to be an advantage to minimize biased errors specificity between 78-89%[21]. All of these studies were for the interpretation of the results of ultrasonographic performed by transvaginal ultrasound at <50 ml. About measurements. We also think that there is insufficient DWT, there is few data published for women. Kuo et al data in the literature for measurements in the presence measured DWT via transvaginal ultrasonography and of full bladder, and the examination of these data in did not find an increase in women with DOI compared our study creates awareness for our work. On the with other diagnoses[14]. However, in Kuo’s study, contrary, we think that our results are a disadvantage measurements were taken from the bladder neck, in accepting for wider populations, because our study anterior wall, posterior wall and bladder base, rather is done only in Turkish society and due to the exclusion than the more commonly used trigone, anterior wall of some factors that may be effective in urinating and dome. In another study by Lekskulchai et al[12], physiology. March 2021 KUWAIT MEDICAL JOURNAL 24
CONCLUSION transvaginal bladder wall thickness: does the Transvaginal ultrasonographic measurement measurement discriminate between urodynamic of BWT and DWT in full and empty bladder can be diagnoses? Neurourol Urodyn 2011; 30(3):325-328. useful in diagnosing of UI subtype. This leads to future 8. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al; Standardisation Sub-committee of the studies to strengthen the use of ultrasonography, International Continence Society. The standardisation which is less invasive, easier to access and cheaper of terminology of lower urinary tract function: than using urodynamics to diagnose UI. report from the Standardisation Sub-committee of the International Continence Society. Urology 2003; 61(1):37-49. ACKNOWLEDGMENT 9. Haylen BT. Verification of the accuracy and range of Conflict of interest: The authors report no conflict of transvaginal ultrasound in measuring bladder volumes interest. in women. Br J Urol 1989; 64(4):350-352. Funding: This study was not financially supported 10. Robinson D, Anders K, Cardozo L, Bidmead J, Toozs-Hobson P, Khullar V. Can ultrasound replace by any funding. It was originally conducted as a ambulatory urodynamics when investigating women graduation thesis in Obstetrics and Gynecology. with irritative urinary symptoms? BJOG 2002; Author contribution: 109(2):145-148. OS Kinci: Project development, data collection, 11. Abou-Gamrah A, Fawzy M, Sammour H, Tadros S. manuscript writing Ultrasound assessment of bladder wall thickness as a MF Kinci: Data collection, manuscript writing screening test for detrusor instability. Arch Gynecol MK Kokanali: Project development, manuscript Obstet 2014; 289(5):1023-1028. writing 12. Lekskulchai O, Dietz HP. Detrusor wall thickness as Y Taşçi: Project development a test for detrusor overactivity in women. Ultrasound Obstet Gynecol 2008; 32(4):535-539. 13. Bogusiewicz M. Ultrasound imaging in urogynecology - state of the art 2016. Prz Menopauzalny 2016; REFERENCES 15(3):123-132. 14. Kuo HC. Measurement of detrusor wall thickness in 1. Buckley BS, Lapitan MC; Epidemiology Committee of women with overactive bladder by transvaginal and the Fourth International Consultation on Incontinence. transabdominal sonography. Int Urogynecol J Pelvic Prevalence of urinary incontinence in men, women, Floor Dysfunct 2009; 20(11):1293-1299. and children-current evidence: Findings of the Fourth 15. Klingler HC, Madersbacher S, Djavan B, Schatzl G, International Consultation on Incontinence. Urology Marberger M, Schmidbauer CP. Morbidity of the 2010; 76(2):265-270. evaluation of the lower urinary tract with transurethral 2. Cerruto MA, D’Elia C, Aloisi A, Fabrello M, Artibani multichannel pressure-flow studies. J Urol 1998; W. Prevalence, incidence and obstetric factors’ impact 159(1):191-194. on female urinary incontinence in Europe: A systematic 16. Kuhn A, Bank S, Robinson D, Klimek M, Kuhn P, Raio review. Urol Int 2013; 90(1):1-9. L. How should bladder wall thickness be measured? 3. Çoşkun B, Aksakal OS, Çoşkun B, Yurtçu E, Akkurt A comparison of vaginal, perineal and abdominal MO, Kafadar O, et al. The impact of concurrent pelvic ultrasound. Neurourol Urodyn 2010; 29(8):1393-1396. organ prolapse reconstructive surgery on midurethral 17. Kim SH, Cho JY, Lee HJ, Sung CK, Kim SH. Ultrasound sling procedure outcome. Ginekol Pol 2018; 89(4):190- of the urinary bladder, revisited. J Med Ultrasound 195. 2007; 15(2):77-90. 4. Haylen BT, de Ridder D, Freeman RM, Cosson M, Davila 18. Khullar V, Salvatore S, Cardozo L, Bourne TH, Abbott GW, Deprest J, et al. An International Urogynecological D, Kelleher C. A novel technique for measuring bladder Association (IUGA) / International Continence Society wall thickness in women using transvaginal ultrasound. (ICS) joint report on the terminology for female pelvic Ultrasound Obstet Gynecol 1994; 4(3):220-223. floor dysfunction. Int Urogynecol J 2010; 21:5-26. 19. Khullar V, Cardozo L. Imaging in urogynaecology. Br J 5. Oelke M, Khullar V, Wijkstra H. Review on ultrasound Obstet Gynaecol 1996; 103(11):1061-1067. measurement of bladder or detrusor wall thickness 20. Serati M, Salvatore S, Cattoni E, Soligo M, Cromi in women: techniques, diagnostic utility, and use in A, Fabio Ghezzi F. Ultrasound measurement of clinical trials. World J Urol 2013; 31(5):1093-1104. bladder wall thickness in different forms of detrusor 6. Minardi D, Piloni V, Amadi A, El Asmar Z, Milanese G, overactivity. Int Urogynecol J 2010; 21(11):1405-1411. Muzzonigro G. Correlation between urodynamics and 21. Latthe PM, Champaneria R, Khan KS. Systematic perineal ultrasound in female patients with urinary review of the accuracy of ultrasound as the method of incontinence. Neurourol Urodyn 2007; 26(2):176-182. measuring bladder wall thickness in the diagnosis of 7. Kuhn A, Genoud S, Robinson D, Herrmann detrusor overactivity. Int Urogynecol J 2010; 21(8):1019- G, Günthert A, Brandner S, et al. Sonographic 1024. 25 KUWAIT MEDICAL JOURNAL March 2021
Original Article Serotonin Transporter Gene Polymorphism (5- HTTLPR and VNTR) among Sudanese patients with Irritable Bowel Syndrome (IBS)
Entsar Elamin1, Nasma Elshaikh1, Sara Abdelghani1, Mohammed Madani1, Hisham Ali Waggiallah2, Lienda Bashier Eltayeb2 1Department of Parasitology, Faculty of Medical Laboratory Sciences, Al-Neelain University, Sudan 2Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdul-Aziz University, Alkharj, Saudi Arabia
Kuwait Medical Journal 2021; 53 (1): 25 - 30
ABSTRACT
Objective: To determine the frequency of serotonin Sudanese IBS patients following parasitic infections. transporter gene (SERT) (5-HTTLPR) and VNTR Results: SERT polymorphisms were found to be significantly polymorphism in patients with post infectious irritable increased in IBS patients in comparison with controls bowel syndrome (IBS) (P=.05), as well as patients with a family history of IBS. Design: This is a cross sectional study. According to bowel habits, diarrhea (n=18) and constipation Setting: The study was carried out in gastroenterology (n=26) were predominant individually, and ten patients outpatient clinics at Omdurman teaching hospital, Khartoum alternated between diarrhea and constipation. We found State, Sudan. that the 5-HTTLPR allele LL genotype occurred with greater Subjects: Fifty-four consecutive IBS patients between 18 frequency in the group with predominant diarrhea than in and 73 years old who were referred to gastroenterology the other two subgroups (P=.05). outpatient clinics and 50 apparently health controls (their Conclusion: Family history plays a major role in the age ranging from 19-68 years old) were examined and presence of IBS. We found that the LS and SS genotypes are enrolled between April 2016 and April 2017. significantly correlated with IBS. No relationship was found Intervention: Collection of venous blood samples between IBS and SERT gene polymorphism. The presence of Main outcome measures: Determining overall frequency of the /S genotype in IBS patients carries an increased risk of the gene SERT (5- HTTLPR and VNTR) polymorphism among constipation predominant type of IBS.
KEY WORDS: Irritable Bowel Syndrome, serotonin
INTRODUCTION persistent carriage. It is estimated that 7-31% of patients Irritable bowel syndrome (IBS) is a chronic with infectious gastroenteritis go on to develop IBS disease characterized by impaired bowel function (post-infectious IBS)[4,5]. Also, a gene-environment and abdomen pain and changes in bowel habit has been proposed for IBS, whereby a combination (constipation and/or diarrhea). It has been reported of genetic determinants and environmental factors to have an incidence of 20% in developed countries[1]. gives rise to alterations in gastrointestinal sensation IBS is a complex, heterogeneous disorder, whose and motor functions. Serotonin transporter (SERT) is development is widely considered as multifactorial in a protein which reuptakes 5-hydroxytryptamine (5- nature[2,3]. Persistent low-grade inflammation may play HT) in synaptic cleft and then reduces the functions of a role in IBS and it is one of the proposed mechanisms 5-HT such as inducing urgency, cramps, diarrhea and of IBS through persistent antigenic exposure, as in vomiting[6,7].
Address correspondence to: Dr. Linda Bashier Eltayeb, PhD, Assistant Professor of Medical Microbiology, College of Applied Medical Sciences, Prince Sattam University, Al-Kharj, Riyadh, Saudi Arabia. E-mail: [email protected]; Mobile: 0507158210 March 2021 KUWAIT MEDICAL JOURNAL 26
Serotonin 5-HT acts as a main regulator in gut. It Inclusion criteria plays an important role in the motility and secretion of Patients were recruited in the study if they the gut, secretion and sensory signaling, and also plays experienced symptoms that fulfilled the Rome III a pivotal role in the control of mood at the central criteria for IBS for at least six months. nervous system level[8,9]. The magnitude and duration of 5-HT actions depend mostly on 5-HT transporter Exclusion criteria (SERT), which mediates the extracellular reuptake Patients with the following conditions were of 5-HT, thus ensuring its recycling and catabolic excluded: severe organic diseases; history of major breakdown[10,11]. abdominal surgery; severe psychiatric disorders; The lower expression of SERT will indicate higher organic lesions at colonoscopy or abdominal levels of 5-HT, which may be associated with bowel ultrasonography; lactose intolerance. symptoms in IBS patients. The two well investigated polymorphism regions are variable number tandem Sampling technique and sample size repeat (VNTR) and serotonin transporter linked A non-probability sampling technique, namely polymorphic region (5-HT transporter length convenience sampling method, was followed (where polymorphic region (5-HTTLPR)). samples are selected from the population randomly Up to now, the genes associated with serotonin, because they are conveniently available to researchers). inflammation, adrenergic, mucosal barrier and The total sample size is 54 IBS patients and 50 control psychology which may play a role in IBS have been subjects. Five mL of venous blood was collected from widely examined[12]. each subject, immediately transferred into EDTA tubes One of the first SERT polymorphisms characterized (EDTA as anticoagulant) and stored at 4 ºC for DNA was the VNTR in intron 2 of the gene and consists of extraction. 17 base pair (bp) repeats[13]. The promoter region of human SERT gene is located on chromosome 17q11.2, Methods contains a polymorphism, designated as 5-HTTLPR, Insertion/deletion polymorphism (with variants which consists of a 44 bp deletion/insertion, resulting 484 and 528) was analyzed by polymerase chain in a short (S) and long (L) allele[13,14]. The implications reaction (PCR), as described by Heils et al[19]. DNA was of this polymorphism in IBS are currently under extracted from the blood samples using salting out evaluation since, as compared with LL genotype, SS method. Sample quality was detected by performing or LS genotypes are associated with lower levels of gel electrophoresis. The reaction was performed in SERT mRNA transcripts, and thereby lower levels 20μl volume using Maxime PCR PreMix Kit (i- Taq): of SERT expression and lower efficiency of 5-HT Product Catalog No.25025 (for 20μL rxn, 96 tubes), reuptake[15,16]. There were studies that supported that iNtRON biotechnology (Made in china - Model the SERT polymorphism or a polymorphism in linkage number: JY- 02S - Serial number: 0903002D). The PCR disequilibrium with the SERT polymorphism might master mix for one reaction was prepared as follows: play a role in the development of IBS[7]. A second 0.5 μL of forward primer, 0.5 μL of reverse primer SERT polymorphism, VNTR STin2, located in intron (Made in Korea by MacrogenInc – dong Geumchun) 2 and consisting of a variable number (usually 9, 10, and 16 μL sterile water to PCR Premix tube and finally or 12) of nearly identical 17-bp segments, had been 3 μL of DNA, making a total volume of 20 μL. The found to be associated with IBS in one study, with mixture was amplified in thermo-cycling conditions, the 10/12 genotype more frequent in Chinese patients which were initial denaturation at 95 ºC for 10 minutes than in controls[8]. Most authors, however, had found followed by 40 cycles of denaturation at 95 ºC for 60 no association between STin2 VNTRs and IBS[7,17,18]. s, annealing at 59 ºC for 60 s and template extension Therefore, the current study aimed to investigate at 72 ºC for 60 s. The cycle was repeated 40 times with the association of the 5-HTTLPR and VNTR gene a final extension at 72 ºC for seven minutes, 10 μl of polymorphism among Sudanese IBS patients. the amplified product was subjected to direct analysis by gel electrophoresis in 2%. PCR primers for intron 2 SUBJECTS AND METHODS polymorphism were described by Lesch et al in 1996; Study design the conditions were modified from those described This was an analytical cross-sectional study previously[16]. A deletion/insertion polymorphism conducted from April 2016 to April 2017. Fifty-four (5-HTTLPR) in the promoter region of the SERT gene consecutive IBS patients (age range: 18-73 years) who was typed by PCR using flanking primers (forward) were referred to gastroenterology outpatient clinics at 5- GGCGTTGCCGCTCTGAATGC-3 and (reversed) 5 Omdurman teaching hospital, Khartoum State, and 50 GAGGGACTGAGCTGGACAACCAC-3. STin 2.9, STin apparently healthy controls, their age ranging from 19- 2.10, and STin 2.12. VNTR polymorphism in intron 2 of 68 years old, were included in the study. the SERT gene was typed by PCR using primers 5-HTT 27 Serotonin Transporter Gene Polymorphism (5- HTTLPR and VNTR) among Sudanese patients with Irritable ... March 2021
Table 1: Association between socio-demographic variables and SERT gene 5-HTTLPR and VNTR polymorphism among IBS patients
Respondent's 5-HTTLPR n(%) VNTR n(%) characteristics Allele L/L Allele L/S Allele S/S Total STin2.10/10 STin2.10/12 STin2.12/12 Total Age group 18-30 1(1.9%) 2(3.7%) 2(3.7%) 5(9.6%) 0(0.0%) 2(3.7%) 3(5.6%) 5(9.3%) 31-50 3(5.6%) 10(18.5%) 12(22.2%) 25(46.3%) 5(9.3%) 10(18.5%) 10(18.5%) 25(46.3%) 51-70 6(11.1%) 9(16.7%) 9(16.9%) 24(44.4%) 2(3.7%) 8(14.8%) 14(25.9%) 24(44.4%) Gender Male 6(11.1%) 9(16.7%) 11(20.4%) 26(48.1) 3(5.6%) 13(24.1%) 10(18.5) 26(48.1%) Female 4(7.4%) 12(22.2%) 12(22.2%) 28(51.9%) 4(7.4%) 7(13%) 17(31.5%) 28(51.9%) Period 1 to less than 5 years 4(7.4%) 6(11.1%) 8(14.8%) 18(33.3%) 4(4.4%) 5(9.3%) 9(16.7%) 18(33.3%) 5 to less than 10 years 0(0.0%) 7(13.0%) 10(18.5%) 17(31.5%) 2(3.7%) 5(9.3%) 10(18.5%) 17(31.5%) >10 years 6(11.1%) 8(14.8%) 5(9.3%) 19(35.2%) 1(1.9%) 10(18.5%) 8(14.8%) 19(35.2%) Family history* Yes 9(16.7%)* 9(16.7%) 11(20.4%) 29(53.7%) 4(7.4%) 11(20.4%) 14(25.9%) 29(53.7%) No 1(1.9%) 12(22.2%) 12(22.2%) 25(46.3%) 3(5.6%) 9(16.7%) 13(24.1%) 25(46.3)
*Statistically significant at P <.05. Figures in parenthesis indicate percentage. Not statistically significant at P >.05 L: long allele; S: short allele; 5-HTTLPR: 5-HT transporter length polymorphic region; VNTR: variable number tandem repeat
F 5-TGGATTTCCTTCTCTCAGTGATTGG-3 and 5-HTT R 5-TCATGTTC- CTAGTCTTACGCCAGTG-3. Amplification products were resolved by electrophoresis on 2% agarose gels and visualized with ethidium bromide staining. Alleles were designated S (484 bp) and L (528 bp) according to Lesch et al[14].
Statistical analysis Statistical analysis of the data was conducted with the SPSS version 20.0 statistics package program. In addition to descriptive statistics (e.g., frequency and percentage), chi-square test were used. The threshold for statistical significance was P <.05.
Ethical approval Fig. 1. Comparison between IBS patients control. 5-HTTLPR The study was approved by the Ethics Committee of Al-Neelain University. The participants gave written and control groups, and the expression of 5-HTTLPR informed consent to participate in the research. and VNTR gene was significantly more in IBS patients compared to controls (P=.05 and P=.006 respectively) RESULTS (Figure 1, Table 2). Demographic characteristics Out of 54 participants, 26 (48.1%) were male and 28 (51.9%) were female, their age ranging between 18-70 Table 2: Comparison of 5-HTTLPR and VNTR between IBS years. The majority of them 25 (46.3%) were in the 31- patients and control. 50 years age group. Regarding period of illness, about Respondents IBS patients Control P-value 35.2% of patients had IBS for more than 10 years. There 5-HTTLPR .05 was significant association between family history and Allele L/L 10(9.6%) 20(19.9%) the expression of 5-HTTLPR alleles in IBS patients Allele L/S 21(20.2%) 15(14.4%) (P ≥.05), and in other socio-demographic variables Allele S/S 23(22.1%) 15(14.4%) including age group, gender and period of IBS, no Total 54(51.9%) 50(48.1%) VNTR .006 significant association was found (Table 1). STin2.10/10 27(26.0) 13(12.5) STin2.10/12 20(19.2) 18(17.3) Genotype and allele frequencies STin2.12/12 7(6.7) 19(18.3) Genotype distributions for the 5-HTTLPR, STin2 Total 54(51.9) 50(48.1) VNTR polymorphisms were checked. VNTR and 5-HTTLPR: 5-HT transporter length polymorphic region; VNTR: 5-HTTLPR alleles were present in all patients in the IBS variable number tandem repeat March 2021 KUWAIT MEDICAL JOURNAL 28
A total of 54 IBS patients (26 had a constipation predominant bowel pattern (IBS-C), 18 had a diarrhea predominant bowel pattern (IBS-D), and the remaining 10 had a bowel pattern alternating between diarrhea and constipation) participated in this study. Table 3 summarizes Serotonin Gene 5-HTTLPR and VNTR allele distributions in IBS according to predominant bowel habit. However, there is no significant association of gene 5- HTTLPR alleles in IBS patient according to predominant bowel habit, but S/S genotype occurred with greater frequency in the constipation predominant group than in the other two Fig. 2. Spectrum of intestinal parasites in IBS patients and control subgroups. Moreover, in comparison of SERT gene VNTR alleles in IBS patients STin2.12/12 allele is more than STin2.10/10, and STin2.10/12 alleles (50%, 37.1%, 12.9% respectively). pathogenically associated with IBS. Furthermore, since genetic factors do not act necessarily as risk factors but can also impact clinical phenotypes, great attention Table 3: Serotonin Gene 5-HTTLPR and VNTR alleles is also being paid to possible relationships linking distributions in IBS according to predominant bowel habit genetic polymorphisms to intermediate phenotypes[23]. Genotype IBS-D IBS-C IBS-M Total P-value Generally, 5-HTTLPR subtypes were significantly 5-HTTLPR .239 increased in IBS patients when it was compared with L/L 3(5.6%) 4(7.4%) 3(5.5%) 10(46.5%) controls; 22.1% of IBS patients had S/S genotype L/S 6(11.1%) 8(14.8%) 7(13%) 21(38%) compared with control (14.4%). The SERT protein S/S 9(16.6%) 14(25.9%) 0(0.0%) 23(15.5%) Total 18(33.3%) 26(48.1%) 10(18.5%) 54(100%) is responsible for reuptake of 5-HT in serotonergic VNTR .469 nerves and mucosa of bowel and is a factor that STin2.10/10 2(3.7) 5(9.3) 0 7(12.9%) determines 5-HT activity. In a lymphoblast cell line, STin2.10/12 8(14.8) 9(16.7) 3(5.6) 20(37.1%) S/S genotype at promoter polymorphic site of SERT STin2.12/12 8(14.8) 12(22.2) 7(13) 27(50%) Total 18(33.3) 26(48.1) 10(18.5) 54(100%) gene was associated with lower transcriptional efficiency, resulting in lower SERT expression and 5-HTTLPR: 5-HT transporter length polymorphic region; VNTR: therefore lower cellular uptake of 5-HT[24,25]. These variable number tandem repeat studies support and explain our results. For VNTR, there were significant associations DISCUSSION found (P=.006), with the 12/12 genotype more frequent A number of studies have implicated a among Sudanese patients than in controls (26% and correlation between IBS and SERT polymorphisms 19% respectively). This is apparently different from in the differential diagnosis of IBS, since they cause Yuan et al’s[25] result, who found 11/11 genotype was significant flares of IBS with acquisition. This isthe more frequent. One of the reasons for the variety first study in Sudan; we studied two alleles 5-HTTLPR was the heterogeneous pathogenesis. IBS may be and VNTR. Findings of this study agree with many heterogeneous in different populations as it is a similar works[20,21]. syndrome diagnosed using symptom based criteria, In our study, we found that a majority of patients its prevalence being variable in different countries in the age group 31-50 years old and the frequency with different ethnicity[26,27]. Such heterogeneity in of females (51.1%%) more than males (48.9%), since phenotypes may also partly explain the result of female sex hormone such as estrogen affect the bowel genetic studies. habits, had IBS. These findings are in agreement with Moreover, our results showed a lack of significant Eltayeb et al[21]. About 53.7% of participants had a interaction between bowel habits and the two family history of IBS. Regarding 5-HTTLPR gene, we genotypes studied (5-HTTLPR and VNTR), and found that family history has a significant correlation this is in agreement with the majority of previous with L/S genotype expression (P ≤.05), which agreed studies[28,29]. While most authors did not find specific with Saito et al[12] and Adam et al[22]. Studies on families links of 5-HTTLPR with IBS-C or IBS-D[30,31], others or twins have given support to the hypothesis of a have reported significant associations of SS with genetic background in IBS and consequently, intensive IBS-D, SS with IBS-C[32]. However, it is conceivable that efforts are being made to evaluate whether specific the presence of the S/S genotype in IBS patients carries polymorphisms of a number of candidate genes are an increased risk of IBS-C. 29 Serotonin Transporter Gene Polymorphism (5- HTTLPR and VNTR) among Sudanese patients with Irritable ... March 2021
Among the variety of factors which might account 4. Wang J, Lu S, Zhao S. Post-infectious and non-post- for the heterogeneity of these observations, the most infectious irritable bowel syndrome: A comparative relevant relies perhaps in the different distribution of study. Pak J Med Sci 2016; 32(1):116-119. 5-HTTLPR genotypes among different populations. 5. Rodriguez LA, Ruigomez A. Increased risk of irritable bowel syndrome after bacterial gastroenteritis: cohort In a more recent study conducted by Mohammadi [33] study. BMJ 1999; 318(7183):565-566. et al about SLC6A4 polymorphism, they found 6. Camilleri M, Atanasova E, Carlson PJ, Ahmad that SLC6A4 is a possible candidate gene associated U, Kim HJ, Viramontes BE, et al. Serotonin- with the pathogenesis of IBS-C. In addition, Yubing transporter polymorphism pharmacogenetics in Zhu et al indicated that the SERT insertion/deletion diarrhea-predominant irritable bowel syndrome. polymorphism may serve as a genetic biomarker of Gastroenterology 2002; 123(2):425-432. IBS in Asians and Caucasians and it is significantly 7. Yeo A, Boyd P, Lumsden S, Saunders T, Handley A, correlated with the risk of IBS-C; their results support Stubbins M, et al. Association between a functional our findings[34]. polymorphism in the serotonin transporter gene and diarrhea predominant irritable bowel syndrome in women. Gut 2004; 53(10):1452-1458. CONCLUSION 8. Kim DY, Camilleri M. Serotonin: a mediator of the In conclusion, the present study suggests that the brain-gut connection. Am J Gastroenterol 2000; LS and SS genotypes are significantly correlated with 95(10):2698-2709. IBS symptom severity, although their possible direct 9. Gershon MD. Nerves, reflexes, and the enteric nervous causal role remains to be proven. In addition, our system: pathogenesis of the irritable bowel syndrome. result did not find an association of 5-HTTLPR and/or J Clin Gastroenterol 2005; 39(5 Suppl 3):S184-S193. VNTR with IBS or its clinical presentation in terms of 10. Chen JX, Pan H, Rothman TP, Wade PR, Gershon MD. bowel habit predominance. Guinea pig 5- HT transporter: cloning, expression, distribution, and function in intestinal sensory reception. Am J Physiol 1998; 275(3):G433-G448. ACKNOWLEDGMENT 11. Mawe GM, Coates MD, Moses PL. Review article: This publication was supported by the Deanship intestinal serotonin signalling in irritable bowel of scientific research at Prince Sattam bin Abdul-Aziz syndrome. Aliment Pharmacol Ther 2006; 23(8):1067- University. 1076. We would like to thank all the participants and staff 12. Saito YA. The role of genetics in IBS. Gastroenterol Clin in the faculty of Medical laboratory sciences and Post North Am 2011; 40(1):45-67. graduate Research Center at Al-Neelain University, 13. Anguelova M, Benkelfat C, Turecki G. A systematic Khartoum, Sudan for helping with recruitment for the review of association studies investigating genes coding for serotonin receptors and the serotonin study. transporter: II. Suicidal behavior. Mol Psychiatry 2003; Conflict of interest statement: The authors declare 8(7):646-653. that they have no conflict of interest. 14. Lesch KP. Variation of serotonergic gene Author’s contribution: Entsar Elamin and Nasma expression: neurodevelopment and the complexity Elshaikh contributed in sample collection and of response to psychopharmacologic drugs. Eur laboratory works. Sara Abdelghani performed the Neuropsychopharmacol 2001; 11(6):457-474. calibration of machines, prepared the study protocol 15. Wang YM, Chang Y, Chang YY, Cheng J, Li J, et and Standard Operating Procedures. Mohammed al. Serotonin transporter gene promoter region Madani Eltayeb was in charge of purchasing reagents. polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome Hisham Ali Waggiallah did the statistical analysis patients. Neurogastroenterol Motil 2012; 24:560-565. of data. Lienda Bashier Eltayeb was responsible for 16. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, scientific writing of manuscript. Petri S, et al. Association of anxiety related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274(5292):1527-1531. REFERENCES 17. Pata C, Erdal ME, Derici E, Yazar A, Kanik A, Ulu O. Serotonin transporter gene polymorphism in irritable 1. Olden KW, Schuster MM. Irritable bowel syndrome. bowel syndrome. Am J Gastroenterol 2002; 97(7):1780- In: Feldman M, Scharschmidt BF, Sleisenger MH, eds. 1784. Gastrointestinal and liver disease. Philadelphia: WB 18. Li Y, Nie Y, Xie J, Tang W, Liang P, Sha W, et al. Saunders, 1998:1536-1546. The association of serotonin transporter genetic 2. Ohman L, Simren M. New insights into the polymorphisms and irritable bowel syndrome and its pathogenesis and pathophysiology of irritable bowel influence on tegaserod treatment in Chinese patients. syndrome. Dig Liver Dis 2007; 39(3):201-215. Dig Dis Sci 2007; 52(11):2942-2949. 3. Hasler WL. Traditional thoughts on the 19. Heils A, Teufel A, Petri S, et al. Allelic variation of pathophysiology of irritable bowel syndrome. human serotonin transporter gene expression. J Gastroenterol Clin North Am 2011; 40(1):21-43. Neurochem 1996; 66:2621-2624. March 2021 KUWAIT MEDICAL JOURNAL 30
20. Colucci R, Gambaccini D, Ghisu N, Rossi G, Costa F, PJ, Rimmer MJ. Increased platelet depleted plasma Tuccori M, et al. Influence of the serotonin transporter 5-hydroxytryptamine concentration following meal 5HTTLPR polymorphism on symptom severity in ingestion in symptomatic female subjects with Irritable Bowel Syndrome. PLoS One 2013; 8(2):e54831. diarrhoea predominant irritable bowel syndrome. 21. Eltayeb LB, Aljafari AS, Brair LS, Algazy SA, Nail AM. Gut 2003; 52(5):663-670. Assessment and evaluation of the effect of Irritable 29. Markoutsaki T, Karantanos T, Gazouli M, Anagnou Bowel Syndrome (IBS) on the health related quality of NP, Ladas SD, Karamanolis DG. Serotonin transporter life among Sudanese patients. Am J Life Sci Res 2015; and G protein beta 3 subunit gene polymorphisms in 3(4):254-259. Greeks with irritable bowel syndrome. Dig Dis Sci 22. Adam B, Liebregts T, Holtmann G. Mechanisms 2011; 56(11):3276-3280. of disease: genetics of functional gastrointestinal 30. Kohen R, Jarrett ME, Cain KC, Jun SE, Navaja disorders–searching the genes that matter. Nat Clin GP, Symonds S, et al. The serotonin transporter Pract Gastroenterol Hepatol 2007; 4(2):102-110. polymorphism rs25531 is associated with irritable 23. Camilleri M, Busciglio I, Carlson P, McKinzie S, bowel syndrome. Dig Dis Sci 2009; 54(12):2663-2670. Burton D, Baxter K, et al. Candidate genes and 31. Niesler B, Kapeller J, Fell C, Atkinson W, Moller D, et al. sensory functions in health and irritable bowel 5-HTTLPR and STin2 polymorphisms in the serotonin syndrome. Am J Physiol Gastrointest Liver Physiol transporter gene and irritable bowel syndrome: effect 2008; 295(2):G219-G225 of bowel habit and sex. Eur J Gastroenterol Hepatol 24. Jarrett ME, Kohen R, Cain KC, Burr RL, Poppe A, 2010; 22:856-861. Navaja GP, et al. Relationship of SERT polymorphisms 32. Sikander A, Rana SV, Sinha SK, Prasad KK, Arora to depressive and anxiety symptoms in irritable bowel SK, Sharma SK, et al. Serotonin transporter promoter syndrome. Biol Res Nurs 2007; 9(2):161-169. variant: Analysis in Indian IBS patients and control 25. Yuan J, Kang C, Wang M, Wang Q, Li P, Liu H, et al. population. J Clin Gastroenterol 2009; 43(10):957-961. Association study of serotonin transporter SLC6A4 33. Mohammadi M, Abdar HT, Mollaei HR, Hajghani gene with Chinese Han Irritable Bowel Syndrome. H, Baneshi MR, Hayatbakhsh MM. Serotonin PLoS One 2014; 9(1):e84414. Transporter Gene (SLC6A4) polymorphism and 26. Chang FY, Lu CL, Chen TS. The current prevalence of mucosal serotonin levels in Southeastern Iranian irritable bowel syndrome in Asia. J Neurogastroenterol patients with Irritable Bowel Syndrome. Middle East Motil 2010; 16(4):389-400. J Dig Dis 2017; 9(1):26-32. 27. Lee OY. Prevalence and risk factors of irritable bowel 34. Zhu Y, Zheng G, Hu Z. Association between SERT syndrome in Asia. J Neurogastroenterol Motil 2010; insertion/deletion polymorphism and the risk of 16(1):5-7. irritable bowel syndrome: A meta-analysis based on 28. Houghton LA, Atkinson W, Whitaker RP, Whorwell 7039 subjects. Gene 2018; 679:133-137. 31 KUWAIT MEDICAL JOURNAL March 2021
Original Article Retrospective evaluation of cancer patients in Intensive Care Unit
Arslan Gulten, Cevik E Banu Department of Anesthesiology and Reanimation, University of Health Sciences Kartal Dr Lütfi Kırdar Training and Research Hospital, Istanbul, Turkey
Kuwait Medical Journal 2021; 53 (1): 31 - 37
ABSTRACT
Objective: We aimed to investigate factors affecting the recorded. prognosis of cancer patients in an intensive care unit Results: We observed significantly lower survival rates and provide guidelines for the admission and follow-up among patients who were diagnosed with breast or processes. hematological cancer; who had comorbid conditions or Design: Retrospective study metastases; who underwent surgeries; who were admitted to Setting: Health Sciences University, Kartal Dr Lütfi Kırdar the intensive care unit due to septic shock, cerebral infarction, Training and Research Hospital, Istanbul, Turkey cardiopulmonary resuscitation, or multiple organ failure; Subjects: In total, 965 patients admitted to the general who were on mechanical ventilation; who had been treated intensive care unit during a one-year period from July 2017 with hemofiltration; or who had received inotropic support. to July 2018 were studied. However, multivariate analysis showed that presence of Intervention: Cancer patients comorbid diseases, presence of metastases, admission to Main outcome measure: Age, sex, malignancy type, the intensive care unit and inotropic support were the only comorbidities, presence of metastasis and surgeries, reason independent factors that negatively affected patient survival. for intensive care unit admission, length of stay, hospital unit Conclusions: Patients with cancer having high risk of referring the patient to the intensive care unit, mechanical mortality may be provided hospice or palliative intensive ventilator, inotropic drug administered, hemofiltration care instead of admission to the limited number of general requirements, resuscitation history and survival rates were intensive care units.
KEY WORDS: intensive care unit, mortality, oncological patients, prognosis, survival
INTRODUCTION prolonged by the therapies being administered[3]. Cancer has become an important health problem Indications for admission to an ICU may be cancer- worldwide in recent years in terms of its associated related causes such as organ involvement and morbidity and mortality rates. Among deaths with a pulmonary embolism, but may also be treatment- known cause, it is the second leading cause of death related factors, such as sepsis and drug toxicity, or after cardiovascular diseases[1]. However, cancer- comorbid diseases such as renal failure, heart failure related deaths have been reduced by improvements and chronic obstructive pulmonary disease[4,5]. in diagnostic tools, introduction of new and successful Although the advances in healthcare services have therapies into the field of oncology and advanced improved survival compared with previous years, supportive care, whereas there has been a rise in the persistently high mortality rates indicate that the number of people living with cancer with the growing management of these patients is still important. The elderly population[2]. aim of the present study was to investigate the factors Cancer patients require monitoring in the intensive affecting outcomes in cancer patients admitted to the care unit (ICU) due to reasons related to the disease ICU of our hospital, which is a major oncology center, and treatment throughout their lifespan, which is by retrospectively reviewing the data in patient charts
Address correspondence to: Gulten Arslan, MD, Department of Anesthesiology and Reanimation, University of Health Sciences Kartal Dr Lütfi Kırdar Training and Research Hospital, Cevizli Mh., Şemsi Denizer Cad. E-5 Karayolu Cevizli Mevkii, 34890 Kartal, Istanbul, Turkey. Tel: +90 (532) 3620366; E-mail: gulten.arslan@ yahoo.com.tr March 2021 KUWAIT MEDICAL JOURNAL 32 and archived records, and to provide an insight into cancer, 3.3% (n=8) with bladder cancer, 3.3% (n=8) the admission and follow-up processes and the use of with breast cancer, 2.5% (n=6) with liver cancer, 1.2% ICU facilities, which are limited in Turkey and around (n=3) with prostate cancer, 1.2% (n=3) with unknown the world. primary cancer and 0.8% (n=2) with adrenal carcinoma. When these cancers were grouped under seven main SUBJECTS AND METHODS headings, gastrointestinal tract (GIT) cancers were the In our study, following approval by the ethics most common type of cancer (n=132, 54.8%; Table 1). committee, the records of patients who were diagnosed with cancer and followed up in the general ICU of our Table 1: Demographic data of patients hospital’s Anesthesiology and Reanimation Clinic during a one-year period from July 2017 to July 2018 Demographic parameters Data (n=244) were retrospectively reviewed. Pediatric patients with cancer were excluded from the study. In cases with Age (years, average) 64.7±13.3 Age group, n (%) multiple admissions, only the first admission was <65 years 112(45.9%) considered. Age, sex, malignancy type, comorbidities >65 years 132(54.1%) (hypertension, diabetes mellitus, coronary artery Sex diseases, heart or renal failure, chronic obstructive Male 134(54.9%) Female 110(45.1%) pulmonary disease, hyper or hypothyroidism, Cancer type, n (%) cerebrovascular disease, connective tissue diseases, GITa 132(54.8%) liver diseases, etc.), metastasis and surgical history, Respiratoryb 55(22.8%) reason for admission to the ICU, length of stay, unit Brain 25(10.2%) Urologicalc 11(4.6%) prior to ICU admission, mechanical ventilator (MV) Hematological 10(4.1%) use, inotropic drug use, hemofiltration requirement, Breast 8(3.3%) cardiopulmonary resuscitation (CPR) history and Unknown primary 3(1.2%) survival were recorded. Comorbidity rate, n (%) 196(80.3%) Metastasis, n (%) 86(35.2%) The data obtained in the study were statistically Reason for admission to ICU, n (%) analyzed using SPSS version 18.0. The variables were Respiratory failure 132(54.1%) expressed using mean and maximum and minimum Septic shock 26(10.7%) values, and percentages were used for expressing Sepsis 23(9.4%) MOF 20(8.2%) qualitative variables. Student’s t-test was used for Hemorrhagic shock, DICd 18(7.4%) comparisons between the groups, Pearson’s chi-square Post-CPR 17(7.0%) test in the analysis of qualitative variables and Fisher’s Renal failure 6(2.5%) exact test in case of small sample size. Posthoc analysis Cerebral infarction 2(0.8%) Length of stay in ICU (days) 8.0±27.4 was also performed with Bonferroni correction. A P-value <.05 was considered to be statistically aGIT: gastric, colon, rectal, pancreatic, and adrenal cancers; significant. For multivariate analysis, statistically bRespiratory: lung, larynx, pharynx, and tongue cancers; cUrological: significant parameters in the single variable analysis bladder and prostate cancers; dDIC: disseminated intravascular were used, and the hazard ratios were calculated. coagulation; MOF: Multiple organ failure
RESULTS In the comparison among cancer types, there Of the 965 patients who were hospitalized in the was no significant difference between the groups in general ICU of our hospital’s Anesthesiology and terms of mean age (P=.217), age group (P=.424), and Reanimation Clinic during a one-year period and presence of comorbidity (P=.323), whereas there was whose data were accessible, 244 (25.28%) had been a significant difference in terms of sex and metastasis diagnosed with cancer. The mean age of the patients (P<.001 and P=.001, respectively). In patients with GIT with cancer was 64.7±13.3 years, and the majority of and brain cancers, sex distribution was approximately the patients were male. The mean length of stay in the equal, and there was a difference in sex distribution ICU was 8.0±27.4 days. The demographic data of the patterns among patients with respiratory, urological, patients are shown in Table 1. In total, 24.6% (n=60) hematological and breast cancers. A higher number of the patients were diagnosed with rectal cancer, of metastasis was found in patients with breast and 16.4% (n=40) with lung cancer, 11.5% (n=28) with hematological cancers (P<.001; Table 2). colon cancer, 10.2% (n=25) with gastric cancer, 10.2% It was observed that 62.3% of patients (n=152) were (n=25) with brain cancer, 6.1% (n=15) with laryngeal, admitted to the ICU postoperatively, whereas 20.9% pharyngeal or tongue cancer, 4.5% (n=11) with (n=51) were transferred from the regular ward and pancreatic cancer, 4.1% (n=10) with hematological 16.8% (n=419) were transferred from the emergency 33 Retrospective evaluation of cancer patients in Intensive Care Unit March 2021
Table 2: Comparison of cancer groups*
GIT Respiratory Brain Urological Hematological Breast Characteristics of cancer groups (n=244) P-value (n=132) (n=55) (n=25) (n=11) (n=10) (n=8) Age (years) 66.0±12.7 62.8±10.9 61.4±16.9 72.4±11.1 58.7±19.6 64.0±17.8 .217 Age range .424 <65 years 59(44.7%) 27(49.1%) 13(52.0%) 5(45.4%) 6(60.0%) 4(50.0%) >65 years 73(55.3%) 28(50.9%) 12(48.0%) 6(54.6%) 4(40.0%) 4(50.0%) Sex <.001 Male 62(47.0%) 46(83.6%) 14(56.0%) 7(63.6%) 2(20.0%) - Female 70(53.0%) 9(16.4%) 11(44.0%) 4(36.4%) 8(80.0%) 8(100%) Presence of comorbidity n (%) 109(82.6%) 44(80.0%) 16(64.0%) 8(72.7%) 9(90.0%) 7(87.5%) .323 Presence of metastasis n (%) 37(28.0%) 22(40.0%) 5(20.0%) 5(45.5%) 7(70.0%) 7(87.5%) .001 Operation rate n (%) 100(75.8%) 36(65.5%) 16(64.0%) 7(63.6%) 1(10.0%) 3(37.5%) <.001 Department prior to ICU admission n(%) <.001 Emergency room 12(9.1%) 17(30.9%) - 1(9.1%) 5(50.0%) 4(50.0%) Other units 25(18.9%) 8(14.5%) 9(36.0%) 3(27.3%) 4(40.0%) 2(25.0%) Postoperative 95(72.0%) 30(54.5%) 16(64.0%) 7(63.6%) 1(10.0%) 2(25.0%) Length of stay in the ICU (days) 6.9±30.5 7.5±12.8 15.2±45.1 5.6±6.3 9.1±11.7 9.5±11.3 .703
*Since the number of patients with unknown primary cancer was very low (n=3), it was excluded. room. Of the patients, 67.6% (n=163) were admitted to multiple organ failure (MOF; P=.735), hemorrhagic the ICU due to conditions that occurred after surgeries. shock or disseminated intravascular coagulation There was a statistically significant difference in both (P=.261), postoperative CPR (P=.686), and renal the referring ward and surgical history among the failure (P=.592). While age, age group and sex had no cancer groups (P<.001 and P<.001, respectively). effect on admission to the ICU (P>.05), the incidence Patients with GIT, respiratory, urological, and brain of respiratory failure was higher in patients who cancers were most commonly admitted to the ICU underwent surgeries (67.7% vs. 26.3%, P<.001) and due to a postoperative event, and those with breast the incidence of MOF was higher in patients who did and hematological cancers were most commonly not undergo surgery (21.3% vs. 1.8%, P<.001); patients transferred to the ICU from the regular ward or who were admitted after undergoing CPR were mostly emergency room (Table 2). those who did not undergo surgery (16.3% vs. 2.4%, When posthoc analysis was performed with P<.001). Bonferroni correction, there was a difference between It was found that 69.7% (n=170) of patients received patients with GIT cancers and those with lung cancer MV support and 12.7% (n=31) required hemofiltration. (P<.0001) and between patients with lung cancer and Inotropic support was required by 50% (n=122) of those with breast and between those with lung cancer patients and 25% (n=61) underwent CPR at least once. and those with hematological cancers in terms of Of cancer patients followed up in the ICU, 43.9% sex (P<.0001, P=.001, respectively). When metastasis (n=107) died and 56.1% (n=137) survived. The mean was compared using the same method, there was age of survivors was 64.0±12.9 years and the mean age a significant difference between patients with GIT of non-survivors was 65.7±13.8 years. The mortality cancers and those with breast cancer (P=.007) and rate of patients was 40.2% for GIT cancers, 45.5% between patients with brain cancer and those with for respiratory tract cancers, 36% for brain cancers, breast cancer (P=.005). There was a difference between 36.4% for urological cancers, whereas it was 87.5% for patients with GIT cancers and those with hematological breast cancer and 70% for hematological cancers. The cancers (P<.0001) and between patients with lung mortality rate was 20.5% for respiratory failure, 43.5% cancer and those with hematological cancers (P=.006) for sepsis, 50% for hemorrhagic shock or disseminated in terms of operation rate. When a posthoc analysis intravascular coagulation, 50% for renal failure, was performed in terms of the unit of admission to the 84.6% for septic shock, 90% for MOF, 94.1% for ICU ICU, there was a difference only between patients with admission after CPR and 100% for cerebral infarction. lung cancer and those with brain cancer (P=.005). Age (P=.337), sex (P=.272) and age being above 65 The most common reason for admission to the ICU years (P=.625) had no effect on survival, whereas a was respiratory failure (n=132, 54.1%; Table 1). Among significantly higher number of deaths were observed in the cancer types, there was no statistical difference patients with breast or hematological cancers (P=.002); in terms of reason for admission to the ICU (P=.601). in patients with a comorbid condition (P=0.001) and There was no difference among the cancer groups metastasis (P<.001); in those who underwent surgeries in terms of admission to the ICU due to respiratory (P<.001); in those admitted to the ICU due to septic failure (P=.544), septic shock (P=.563), sepsis (P=.870), shock, cerebral infarction, MOF, or after undergoing March 2021 KUWAIT MEDICAL JOURNAL 34
Table 3: Factors affecting survival
Factors affecting survival Ratios* Univariate Multivariate Hazard Ratio Male vs. Female 47.0% vs. 40.0% 0.272 Age <65 vs. ≥65 years 45.5% vs. 42.4% 0.625 With vs. without breast or hematological cancer 78.8% vs. 40.2% 0.002 0.103 1.125 With vs. without comorbidity 49.0% vs 22.9% 0.001 0.01 2.444 With vs. without metastasis <72.1% vs. 28.5% <0.001 0.02 2.288 With vs. without surgery <81.3% vs. ≥18.8% <0.001 0.001 3.249 Septic shock, cerebral infarction, or MOF vs. others 89.3% vs. 27.4% <0.001 0.05 1.914 Received vs. did not receive MV support 61.2% vs. 4.1% <0.001 0.08 1.723 With vs. without hemofiltration 80.6% vs 38.5% <0.001 0.340 0.954 With vs. without inotropic support 78.7% vs 9% <0.001 <0.0001 6.296
*Rates are mortality rates in the mentioned variables MOF: multiple organ failure; MV: mechanical ventilation
CPR (P<.001); in those who received MV support patients aged <70 years and 6.52 days in patients aged (P<.001) or underwent hemofiltration (P<.001); and ≥70 years, with a mean of 4.69 days[8]. in those who required inotropic support (P<.001). In A study by Silva et al involving 177 patients with multivariate analysis, comorbidity (P=.01); metastasis cancer who were admitted to medical and surgical (P=.02); admission to the ICU without undergoing oncology ICUs reported that the mean age was surgery (P=.001); admission to the ICU due to septic 52.4±17.25 years, the male-to-female ratio was 1.49, shock, cerebral infarction, MOF or CPR (P=.05); and gynecologic (29.4%) and GIT (22.6%) cancers were the inotropic support (P<.0001) were factors that had an first and second most common cancers, respectively, independent adverse effect on survival (Table 3). and the mean length of stay in the ICU was three (1-6) days[9]. DISCUSSION In a multicenter study by Taccone et al involving Admission of patients with cancer to ICUs, which a total of 3,147 patients in 198 ICUs in 24 European have a limited number of beds and equipment in countries, 473 (15%) patients with malignancies were Turkey, is a very controversial and sensitive issue. investigated. They reported that the male-to-female Improvements in cancer therapies, supportive ratio was 1.27, the mean age was 66.4±12.1 years in management of organ dysfunctions and infections, patients with solid tumors and 62.1±15.9 years in those and advances in ICU interventions have improved with hematological cancers, and the mean length of the survival rates of critically ill cancer patients[6]. As stay in the ICU was three (1.8±6.4) days in patients patients with malignancies constitute 15-20% of all with solid tumors and 3.8 (1.7±8.6) days in those with ICU patients and still have higher mortality rates than hematological cancers[10]. other patient groups (39-77%)[7], there are problems In a retrospective study by Tow et al, in which considering ICU bed numbers and the financial patients with solid tumors were analyzed by the Mayo budget of hospitals. Therefore, it may be possible Clinic Institutional Review Board between 2008 and to improve and enhance intensive care services by 2009, 120 patients were investigated, and it was found determining the mortality risk factors and deficiencies that GIT (34.1%) and lung cancers (28.3%) were the and taking precautions. The aim of this retrospective first and second most common cancers, respectively[11]. study was to evaluate the demographic characteristics, In our study, 25.28% of patients admitted to the comorbidities, mean length of stay and its causes, and ICU were diagnosed with cancer. The mean age was factors affecting mortality in patients with cancer who 64.7±13.3 years, the male-to-female ratio was 1.21, the were treated in the ICU of our hospital, which also mean length of stay in the ICU was 8±27.4 days, and serves as a major oncology center, and whose patient gastrointestinal and respiratory tract cancers were the records were retrieved. first and second most common cancers, respectively. In a retrospective review of 2,240 patients who were The higher proportion of patients with malignancy in admitted to the ICU between 2011 and 2012, Aksoy et our ICU compared with that in other studies may be al reported that 23.9% of the patients were diagnosed because our hospital is an oncology center. According with malignancy, the mean age was 59.9 years, the to the data of the Ministry of Health and the World male-to-female ratio was 1.55, colorectal (19.71%), Health Organization[12], cancer is more common in lung (15.77%), and GIT cancers (11.62%) were the first, males, and our findings are consistent with these data second, and third most common cancers, respectively, and those of other researchers. The longer stay in the and the mean length of stay in the ICU was 3.94 days in ICU in our study may be due to higher mean age 35 Retrospective evaluation of cancer patients in Intensive Care Unit March 2021 and higher comorbidity rate. In addition, consistent were admitted after a planned surgery, 37% among with many other studies, we found that the first and patients who were transferred from the emergency second most common cancers in our oncology patients room and as high as 58% among patients who were admitted to the ICU were GIT and respiratory tract admitted after medical complications[5]. The results of cancers[8,11]. our study supported their results. We determined that According to recent data of the Turkish Ministry the mortality rate in patients with cancer who were of Health, the most common cancer type in Turkey is admitted to the ICU postoperatively was lower than lung cancer, followed by prostate and bladder cancers in those who were admitted to the ICU due to medical in males, and breast cancer followed by thyroid and reasons, such as MOF, CPR and cerebral infarction. In gynecological cancers in females[13]. In our study, their study, Silva et al reported a 21.4% mortality rate consistent with these data, we found that the most in the ICU and found that this rate is as high as 81.6% common cancer type in ICU patients was respiratory among patients with failure in three or more organs[9]. cancer followed by urological cancers in males, and Mokart et al[14] reported an ICU mortality rate of 32%, breast cancer followed by hematological cancers in whereas Hawari et al[18] reported a rate of 36.5% in a females. five-year study. In our study, the ICU mortality rate in Furthermore, 57% of 717 patients reported by patients with cancer was 43.9%. We consider that these Soares et al[5], 66% of 177 patients reported by Silva et different results can be attributed to patient selection al[9], and 59.1% of 482 patients reported by Aksoy et al[8] criteria, differences in cancer types and stages, presence were admitted to the ICU in the postoperative period. of comorbid conditions, patients being terminally ill or Consistent with the results of the previous studies, of not, and ICU admission criteria. 244 patients with cancer in the present study, 62.3% Different studies have indicated various were admitted to the ICU postoperatively, 20.9% were independent risk factors for ICU mortality in patients transferred from the relevant wards and 16.8% were with cancer. Silva et al determined that the length of transferred from the emergency room. stay in the ICU, a Charlson comorbidity index of The reasons for admission to the ICU in patients >2 and vasopressor requirement are independent with cancer are variable among studies; however, the prognostic factors for mortality after discharge from most common reason is respiratory failure[14,15]. In the ICU, and vasopressor requirement and APACHE many studies, the most common reasons for admission II score are independent prognostic factors for ICU to ICU were respiratory failure, shock, sepsis, and mortality[9]. Mokart et al reported that malignancy renal failure[15-17]. Similarly, in our study, we found characteristics, age and neutropenia had no effect on that the most common reason for admission to the ICU mortality, whereas high logistic organ dysfunction in patients with cancer was acute respiratory failure score on day 7 and viral infection and/or reactivation (54.1%), followed by septic shock (10.7%), sepsis (9.4%) were associated with mortality[14]. Soares et al found and MOF (8.2%), and the reason for admission had an that MOF, performance status and MV requirement effect on the mortality rate. had more effect on mortality in patients with cancer In studies involving patients with various types than cancer-related factors, such as malignancy type[5]. of cancer, variable mortality rates (30-90%) have been Many researchers have also found that neutropenia, reported in patients with malignancies followed up in use of chemotherapy in the terminal phase, and ICUs. In the study by Aksoy et al, malignancies with autologous stem cell transplantation had no effect; the highest mortality rate were hematological cancer positive blood culture, antibiotic combinations in (81%), breast cancer (72%) and lung cancer (68%), neutropenic sepsis and removal of central venous line respectively[8]. Consistent with the rates reported in had little effect; and age, tumor stage, number and previous studies, the rates in our study were 70%, severity of organ failures, acute respiratory failure, 87.5% and 45.5%, respectively. Considering the fact need for invasive MV, ICU admission in the late period that patients with hematological and breast cancers or after cardiac arrest, comorbidities, prehospital are terminally ill cancer patients with widespread performance status, development of acute graft metastases who are referred from clinics, such as versus host syndrome following allogeneic stem cell internal medicine or oncology clinics, or from the transplantation and invasive pulmonary aspergillosis emergency room, these results are significant. had considerable effect on the short-term mortality of In a study of 717 patients with cancer who were patients with cancer who were admitted to ICUs[4,19- admitted to the ICUs of 28 hospitals in Brazil, Soares 21]. The same authors have also concluded that the et al reported that the reasons for admission to the characteristics and prognostic features of malignancy ICU was postoperative care in 57%, sepsis in 15% and affected mortality in the long term in these patients. respiratory failure in 10%, and among these patients, Consistent with the results of studies conducted the mortality rate was 11% among patients who by various researchers, the present study found a March 2021 KUWAIT MEDICAL JOURNAL 36 significantly higher number of deaths among patients Rezende E, et al. Outcomes for patients with cancer with breast or hematological cancers; patients with admitted to the ICU requiring ventilatory support. comorbid conditions and metastasis; patients who did Results from a prospective multicenter study. Chest not undergo surgeries; patients who were admitted 2014; 146(2):257-266. 4. Azoulay E, Soares M, Darmon M, Benoit D, Pastores to the ICU due to septic shock, cerebral infarction, S, Afessa B. Intensive care of the cancer patient: recent MOF or after undergoing CPR; patients who received achievements and remaining challenges. Ann Intensive MV support or underwent hemofiltration; and Care 2011; 1(1):5. patients who required inotropic support. However, in 5. Soares M, Caruso P, Silva E, Teles JM, Lobo SM, multivariate analysis, the presence of comorbidity or Friedman G, et al. Characteristics and outcomes of metastasis; admission to the ICU without undergoing patients with cancer requiring admission to intensive surgery; admission to the ICU due to septic shock, care units: a prospective multicenter study. Crit Care cerebral infarction, MOF or after undergoing CPR; Med 2010; 38(1):9-15. and inotropic support were factors that independently 6. Brenner H. Long term survival rates of cancer patients achieved by the end of the 20th century: a period of affected survival. analysis. Lancet 2002; 360(9340):1131-1135. 7. Staudinger T, Stoiser B, Mullner M, Locker GJ, Laczika CONCLUSION K, Knapp S, et al. Outcome and prognostic factors in In conclusion, the presence of comorbid conditions critically ill cancer patients admitted to the intensive and metastasis, admission to the ICU without care unit. Crit Care Med 2000; 28(5):1322-1328. undergoing surgery and due to septic shock, cerebral 8. Aksoy Y, Kaydu A, Sahin OF, Kacar CK. Analysis of infarction, MOF or after undergoing CPR, and the need cancer patients admitted to intensive care unit. North for inotropic support should be regarded as strong Clin Istanb 2017; 3(3):217-221. predictors of increased mortality of patients in the ICU. 9. Namendys-Silva SA, Texcocano-Becerra J, Herrera- Gomez A. Prognostic factors in critically ill patients For this reason, we consider that cancer patients with with solid tumours admitted to an oncological intensive these risk factors should be evaluated more carefully care unit. Anaesth Intensive Care 2010; 38(2):317-324. while deciding on the admission to and follow-up in 10. Taccone FS, Artigas AA, Sprung CL, Moreno R, Sakr the ICU. It can be concluded that the establishment of Y, Vincent JL. Characteristics and outcomes of cancer new regulatory protocols and the creation of new ICU patients in European ICUs. Crit Care 2009; 13(1):R15. concepts, including hospice and palliative intensive 11. Tow S, Jatoi A. End-of-life hospital costs in cancer care, may be more useful in the management of these patients: Do advance directives or routes of hospital patients. In our country, there has been progress in this admission make a difference? Oncology 2011; 80(1- regard, and in future, such patients will be admitted 2):118-122. 12. World Health Organization (WHO) 2015. (Accessed to hospice and palliative ICUs, to ensure that their August 10, 2015, at https://gco.iarc.fr/). admission to general ICUs reduces. 13. Turkey Cancer Statistics. T. C. Public Health Agency of Turkey Ministry of Health, Department of Cancer, ACKNOWLEDGMENT Ankara 2017. (Accessed September 13, 2017, at http:// Conflict of interest:The authors declare no conflict www.cancer.gov.tr/). of interest. 14. Mokart D, Ettenne A, Esternı B, Brun JP, Chow-Chine Author contributions: Cevik EB contributed to L, Sannini A, et al. Critically ill cancer patients in the conception, supervision, materials, data collection, intensive care unit: short-term outcome and 1-year analysis and interpretation, literature review, critical mortality. Acta Anaesthesiol Scand 2012; 56(2):178-189. 15. Thiery G, Azoulay E, Darmon M, Ciroldi M, De Miranda review and manuscript preparation for the study. S, Lévy V, et al. Outcome of cancer patients considered Arslan G worked on the study design, supervision, for intensive care unit admission: a hospital-wide funding, materials, analysis and interpretation, prospective study. J Clin Oncol 2005; 23(19):4406-4413. literature review, critical review and manuscript 16. Soares M, Salluh JI, Torres VB, Leal JV, Spector N. Short preparation. and long-term outcomes of critically ill patients with cancer and prolonged ICU length of stay. Chest 2008; REFERENCES 134(3):520-526. 17. Kılınç G. Evaluation of the processes of malignancy 1. Turkey Statistical Institute ‘Cause of Death Statistics, patients followed up in intensive care unit. Pamukkale 2017. (Accessed January 16, 2017, at http://www. tuik. University Open Access Archive 2015. (Accessed gov.tr/). January 18, 2016, at http://acikerisim.pau.edu.tr). 2. Coleman MP, Quaresma M, Berrino F, Lutz JM, De 18. Hawari FI, Nazer LH, Addassi A, Rimawi D, Jamal K. Angelis R, Capocaccia R, et al. Cancer survival in five Predictors of ICU admission in patients with cancer continents: a worldwide population-based study and the related characteristics and outcomes: A 5-year (CONCORD). Lancet Oncol 2008; 9(8):730-756. registry-based study. Crit Care Med 2016; 44(3):548- 3. Azevedo LC, Caruso P, Silva UV, Torelly AP, Silva E, 553. 37 Retrospective evaluation of cancer patients in Intensive Care Unit March 2021
19. Puxty K, McLoone P, Quasim T, Kinsella J, Morrison D. data from France and Belgium-a groupe de recherche Survival in solid cancer patients following intensive care respiratoire en reanimation onco-hematologique study. unit admission. Intensive Care Med 2014; 40(10):1409- J Clin Oncol 2013; 31(22):2810-2818. 1428. 21. Biskup E, Cai F, Vetter M, Marsch S. Oncological 20. Azoulay E, Mokart D, Pene F, Lambert J, Kouatchet A, patients in the intensive care unit: prognosis, decision- Mayaux J, et al. Outcomes of critically ill patients with making, therapies and end-of-life care. Swiss Med hematologic malignancies: prospective multicenter Wkly 2017; 147:w14481. March 2021 KUWAIT MEDICAL JOURNAL 38
Original Article Does bipolar transuretral resection of prostate increase the incidence of urethral stricture?
Eray Hasirci, Enis Kervancioglu, Hakan Ozkardes Department of Urology, Baskent University Faculty of Medicine, Ankara, Turkey
Kuwait Medical Journal 2021; 53 (1): 38 - 43
ABSTRACT
Objective: Transurethral resection of the prostate (TURP) of resection, length of hospital stay, irrigation duration, remains the gold standard surgical method for patients with changes in serum haemoglobin, changes in maximum flow benign prostate obstruction. The aim of this study was to rate, changes in amount of post-voiding residual urine and compare the efficacy and complication rates of bipolar TURP complications. applied with saline and monopolar TURP applied with Main Outcome Measure: Urethral stricture glycine, performed by the same surgeon. Results: The operating time was longer in the bipolar group Design: Retrospective study and associated with that, the resection speed was lower. Setting:Department of Urology, Baskent University, Ankara, Urethral stricture was found to be greater in the bipolar Turkey group (11 cases of the 58 bipolar TURP patients (18.96%) and Subjects: Ninety-two patients who were scheduled for in 2 cases of the 34 monopolar TURP patient (5.88%), P=.045). monopolar and bipolar TURP Conclusions: Bipolar TURP is as effective a technique Intervention: All the surgical procedures were applied under as conventional TURP. However, urethral strictures spinal anesthesia and the procedure was done by the same significantly exist in bipolar group, even if it was done by surgeon. The cases were compared in respect of the time the same surgeon. of the procedure, the amount of resected tissue, the speed
KEY WORDS: benign prostatic hyperplasia, prostate, transurethral resection of prostate, urethral stricture
INTRODUCTION prospective, multi-centre study of 10,654 benign Benign prostate hyperplasia (BPH) is a progressive prostate obstruction patients, treatment with TURP disorder in elderly males that manifests with lower was found to have reduced mortality (0.1%), but urinary tract symptoms[1]. There remains a need for despite this reduction, the morbidity rate was observed additional studies of the effects on quality of life and to still be high (11.1%)[5]. the use of treatment resources on healthcare costs[2]. Various technologies with minimal risk and Transurethral resection of the prostate (TURP) acceptable efficacy in the treatment of BPH have been is a well-documented procedure which has been a developed in the last 20 years. In recent years, fewer cornerstone of surgical treatment for many years complications in short and long-term follow-up and because of the long-term results provided[3]. However, comparable results to standard TURP (monopolar much minimally invasive procedures are currently TURP, mTURP) have been obtained with the use of used, TURP remains the gold standard procedure. bipolar electrosurgery technology (bipolar TURP, Nevertheless, there are still concerns related to bTURP)[6]. complications such as transurethral resection (TUR) Monopolar energy is electric energy with ≥100,000 syndrome, bleeding and urethral stricture[4]. In a KHz frequency which reaches power of 200W[7]. The
Address correspondence to: Eray Hasirci, Department of Urology, Faculty of Medicine, Baskent University School of Medicine, Maresal Fevzi Cakmak Cd. 5. Sok. No:48, 06490, Bahçelievler, Ankara, Turkey. Tel: +90 3122120630; Fax: +90 3122154283; E-mail: [email protected]; ORCID Number: 0000-0002-4147-2966 39 Does bipolar transuretral resection of prostate increase the incidence of urethral stricture? March 2021 passive electrode is on the patient’s body in the form same techniques (58 bTURP, 34 mTURP). The surgeon of a plate and the active electrode is attached to the started resection with the ventral parts of the gland resectoscope. Tissue resection is applied with a current (between 11 and 1 o’clock), followed by both lateral passing the loop. That 10% of the electric current leaves lobes, the midlobe and finishing with the apex at the the device in the middle of the urethra is accepted whole procedure, as described in Nesbit techniques. as the most important reason for urethral stricture Comparison was made in respect of the fall in which may develop associated with the procedure[8]. haemoglobin (Hb) values, increase in urine peak flow Resection and coagulation cannot be made without rate (Qmax), reduction in post-void residual urine, conduction of the fluid used. The most frequently used operating time, amount of resection, speed of resection, fluids in the procedure are 1.5% glycine and sorbitol length of stay in hospital and duration of irrigation. solutions which are hypotonic. Therefore, there is a To evaluate perioperative blood loss, blood samples risk (1-2%) of fluid retention during the procedure were taken preoperatively and within 1 and 24 hours and as a result, hypervolemic hyponatremia (TUR postoperatively. The longest follow-up period was 16 syndrome)[9]. Consequently, attention must be taken months. to keep the operating time short, otherwise there can The patients treated with surgery were patients with be unwanted situations, such as a reduced amount lower urinary tract symptoms who were unresponsive of resected tissue, ineffective control of bleeding and to medical treatment with α-blockers and 5α reductase prolonged hospitalisation. The basis of bipolar energy inhibitors as recommended in the European Urology constitutes a new radio frequency system. This energy Association guidelines[13]. Inclusion criteria of the is a part of the electromagnetic spectrum. Frequency study were indications for surgical treatment for BPH. varies between 3 KHz and 300 GHz. Completion of Exclusion criteria were patients with prostate cancer the bipolar current is necessary in the electrode used. or prostate cancer determined after surgery, those The use of different techniques for this can transform with bladder stones, neurogenic bladder dysfunction, the current emerging from the end of the electrode to urethral stricture, coagulopathy or a history of prostate a parallel second electrode[10]. Isotonic saline is used as surgery. the fluid. As the electric current does not pass through In the mTURP operations, a 24-Charrière Storz the ureter, less risk of urethral stricture has been resectoscope (Karl Storz® Endoscopy, Anklin AG, shown and as hypotonic fluid is not used, there is less CH-4102 Binningen, Switzerland) was used with risk of subsequent TUR syndrome[11]. In a study by de continuous high-pressure irrigation. The fluid used Sio et al, the durations of hospitalisation and urethral in mTURP was electrolyte-free mannitol-sorbitol catheterisation were reported to be shorter in bTURP solution (Purisole SM, Fresenius-Kabi Deutchland compared to mTURP [12]. GmbH, Bad Hamburg, Germany). For bipolar TURP, The aim of this study was to compare the efficacy the Gyrus™ Plasmakinetic Superpulse System is and possible complications of mTURP and bTURP as currently used together with the Supersect Loop. For surgical treatment options for BPH. bipolar resection, normal saline solution was used (NaCl 0.9%; Dr G Bichsel AG, Interlaken, Switzerland). MATERIALS AND METHODS The PlasmaKinetic device had a maximum power of A retrospective examination was made of a total of 200 W and delivered a radio frequency wavelength 505 cases applied with TURP (332 bTURP, 173 mTURP) of 320-450 kHz and a voltage range of 254-350 V. The for a diagnosis of BPH unresponsive to medical TUR loop consisted of an 80/20 platinum/iridium alloy treatment in our clinic beween January 2011 and electrode with the active and return electrode on the December 2017. Until June 2013, mTURP procedures same axis (axipolar) separated by a ceramic insulator. were applied with power settings of 120 W and 80 W All the surgical procedures were applied under spinal for cutting and coagulating currents respectively, and anaesthesia with the patient in the lithotomy position. after that time, bTURP started to be applied with power The operating time was calculated as the time from the setting of 150 W for cutting and 100 W for coagulation. first tissue resection to the placement of the urethral The information of all the patients was retrieved from catheter. In both groups, a 24-Charriere irrigation hospital records and patient files and was examined catheter was used postoperatively, and in patients retrospectively. The patients with available information requiring irrigation, this was applied until the fluid were separated into two groups according to the ran clear. technique applied and they were compared in respect At the 6-week, 6-month and 12-month follow- of efficacy and complications. To be able to compare ups, all patients were called to evaluate. All patients the two techniques, the patients included were cases underwent control in the 6th week after surgery with that had been operated on by the same experienced uroflowmetry. They had well maximum urinary flow surgeon (a urologist for more than 25 years) and by the rate as expected. At the next visit, if they had a urinary March 2021 KUWAIT MEDICAL JOURNAL 40
Table 1: Summary of the variables measured
bTURP mTURP Variables Mean (SD) Mean (SD) Pre-op Mean (SD) P Pre-op Post-op P Age (Years) 70.6 (8.75) 72.9 (8.02) .056 Qmax (mL/sn) 7.29 (4.56) 19.05 (9.74) .001** 3.94 (4.51) 15.85 (7.12) .001** PVR (mL) 228.36 (156.13) 48.48 (49.29) .001** 386.67 (160.41) 73 (44.81) .001** Hb (g/dL) 14.48 (1.50) 13.55 (1.43) .001** 13.60 (1.25) 12.19 (2.54) .001**
TURP: transurethral resection of the prostate; bTURP: bipolar TURP; mTURP: monopolar TURP; Qmax: peak flow rate; PVR: post- void residual urine; Hb: hemoglobin **P-value is statistically significant
flow problem (Qmax <10 ml/sn), cystoscopy was was the failure of medical treatment. The mean age of applied and the problem was understood. the patients was 72.9 years (range: 52-85 years) in the This study was approved by Baskent University mTURP group and 70.6 years (range: 55-92 years) in Institutional Review Board (Project no:KA18/269). the bTURP group (Table 1). A statistically significant increase was determined Statistical analyses in the mean peak flow volume values of both groups Statistical evaluation of the study data was made (P <.01). The post-void residual urine values were using SPSS 20 software (IBM Corp. Released 2011. IBM determined to have statistically significantly decreased. SPSS Statistics for Windows, Version 20.0. Armonk, No statistically significant difference was determined NY, USA). Variables were stated as mean ± standard between the preoperative and postoperative Hb values deviation (SD), median (minimum-maximum), number in the two methods. (n) and percentage (%) values. As a precondition of the The mean amount of resected tissue was 18.7gm in parametric tests, variance homogeneity was assessed the bTURP group and 21.7 gm in the mTURP group with the Levene test. Conformity to normal distribution (Table 2). was examined with the Shapiro Wilk test. To evaluate Urethral stricture was observed in 11 cases of the differences between two groups when parametric 58 bTURP patients (18.96%) and in two cases of the conditions were met, the Student’s t-test was applied, mTURP patients (5.88%) (P=.045). The mean time to otherwise the Mann Whitney U-test. Differences postoperative diagnosis of the urethral stricture was between two dependent groups were evaluated 4.8 months (range: 2-11 months) in the bTURP group with the Paired Samples t-test when parametric test and after 7 months (range: 6-8 months) in the mTURP preconditions were met, otherwise the Wilcoxon test group. was applied. Complications were evaluated with the 2 ratio Z test. Values of P <.05 and P <.01 were accepted DISCUSSION as statistically significant. Transurethral prostate resection of an approximate volume of 80-100 cc is the gold standard treatment RESULTS for BPH which is unresponsive to medical treatment. A final evaluation of the data of 92 patients was To be able to remove prostate tissue rapidly and made.The main indication for surgical intervention effectively, basic electrosurgery techniques are used
Table 2: mTURP and bTURP results
Surgical Parameters bTURP mTURP P Operating time (mins) 83.55±26.16 53.41±22.64 .001** Resection (gm) 21.77±16.14 18.77±9.5 .330 Resection speed (gr/min) 0.22±0.08 0.42±0.26 .001** Length of stay in hospital (hrs) 56.36±33.75 80.91±34.19 .001** Irrigation duration (hrs) 3.64±10.67 20.94±9.41 .001** Hb changes (mg/dl) -0.93±1 -1.41±2.09 .140 Qmax changes (ml/min) 11.76±9.52 11.91±7.39 .940 PVR difference (ml) -179.88±150.14 -313.67±166.8 .001**
Hb: hemoglobin; Qmax: peak flow rate; PVR: post-voiding residual urine; bTURP: bipolar transurethral resection of the prostate; mTURP: monopolar transurethral resection of the prostate 41 Does bipolar transuretral resection of prostate increase the incidence of urethral stricture? March 2021 in standard transurethral resection. However, since in the current study, Poh et al also found no difference the introduction of the use of bipolar energy, reduced between the two techniques in respect to Hb changes rates of complications have been seen. Although there and the amount of resected tissue[22]. Similarly, Ho et is no risk of potentially life-threatening TUR syndrome al reported no significant difference between the two with the use of normal saline in bipolar energy, the groups[6]. Attention should be paid to the fact that the operating time is prolonged compared to the traditional fall in Hb during the longer procedure in the bipolar method. Associated with this, prostate volumes have group occurs in a short time in the monopolar group. increased and reached a limit of approximately 120- Although not statistically significant, this fall in the 130 cc. On the other hand, prolonged operating time monopolar group was numerically greater. However, has provided increased amounts of resected tissue and it can be considered that the longer operating time in more effective bleeding control. An outcome of this the bTURP group provided the possibility of better has been reduced speed of resection. bleeding control to be applied and this could have The TUR-related mortality rates are extremely had positive effects on the blood loss and duration of low (<0.25%). Nevertheless, complications have been postoperative irrigation. reported such as blood loss, a requirement for blood The mean duration of irrigation was determined transfusion and TUR syndrome (2%). There are studies as 3.64 hours in bTURP patients and 20.9 hours in which have suggested that these complications have the mTURP group. This advantage is due to the been prevented with the reduced hyponatremia risk better haemostatic action of plasmakinetics. This also and the hemostasis that develops throughout the resulted in the shorter length of hospital stay observed plasmakinetic procedure[14,15]. The bipolar surgical in the bipolar group (56.3 hrs vs 80.9 hrs, P=.001). equipment vaporises tissue during resection, brings In a meta-analysis by Mamoulakis et al which bleeding under control effectively and fully closes included 1177 patients, the two methods were compared bleeding points[16]. The systematic absorption of with respect to urethral stricture, bladder neck glycine leads to TUR syndrome. If the duration of stricture and meatal stenosis[23]. Urethral complications resection exceeds 90 minutes, the risk increases from were observed in 10 cases of the monopolar group 0.7% to 2%[14]. The use of normal saline as the irrigation and in 13 of the bipolar group with no statistically fluid reduces the risk in bipolar energy procedures. In significant difference determined (P=.58). Although the current study, no TUR syndrome was observed in not compared, another study reported the incidence of any case of either group. urethral stricture following monopolar TURP as only The results of the current study showed that the 6 of 2271 patients (0.002%)[24]. In contrast, the number operating time of the bTURP group was longer (83.5 of patients with postoperative urethral stricture in the mins vs. 53.4 mins). Similar results were seen in a current study were greater in the bTURP group than in study by Engeler et al with operating times of 50.3±20.8 the mTURP group (11 vs. 2 patients, P=.045). Although mins in the bipolar group and 41.8±17.5 mins in the the current in the resectoscope we used is returned monopolar group (P=.002)[17]. In contrast to the current through the resecting loop by itself and did not cause study, in a randomised controlled study of 202 cases urethral overheating, urethral stricture was seen to be by Fagerström et al, the operating time of the bipolar statistically significantly greater in the bTURP group. group (62±23 mins) was found to be shorter than that This can be explained to be due to the long bipolar of the monopolar group (66±23 mins)[18]. Singhania et al energy procedure applied with the aim of a problem- also investigated the efficacy and reliability of bipolar free postoperative follow-up period as there is no risk resection compared with monopolar TUR and reported of TUR syndrome. As the resectoscope remains in the the time to be shorter in the bipolar group (55.1±13.3 urethra for a longer period during the procedure, this mins) compared to the monopolar group (56.76±14.51 is thought to lead to minor urethral trauma, albeit mins)[19]. The differences in operating times can be mild, which predisposes to stricture. considered to be most probably dependent on the Two patients with urethral stricture in the mTURP surgeon and related to familiarity with use of the group were out of follow-up. In the bTURP group resectoscope. with urethral stricture, all patients have performed Blood loss is one of the most frequently laser uretratomy. Seven patients had no problem after encountered complications of TURP. In the current uretratomy procedure. The remaining four patients study, no difference was seen between the two groups still perform self catheterization monthly. with respect to the fall in Hb (P=.140). However, some The main limitation of this study was that it was studies have reported results in favour of bipolar[20,21]. a retrospective study and also changes in serum The reason for less postoperative bleeding in a bipolar sodium were not examined in the patients. This was group has been reported to be possibly associated with not included in the assessments as the data were the deeper coagulation made in bipolar resection. As retrospective and there were no pre and postoperative March 2021 KUWAIT MEDICAL JOURNAL 42 serum sodium data available. A small sample size is 7. Barba M, Fastenmeier K, Hartung R. Electrocautery: the other limitation of this study. We were interested principles and practice. J Endourol 2003; 17(8):541- in the work of a single surgeon, which caused our 555. sample size to be small. 8. Flachenecker G, Fastenmeier K. High frequency current effects during transurethral resection. J Urol 1979; 122(3):336-341. CONCLUSION 9. Issa MM, Young MR, Bullock AR, Bouet R, Petros While the results of the study showed that there JA. Dilutional hyponatremia of TURP syndrome: a was no extra benefit of bipolar TURP with respect to historical event in the 21st century. Urology 2004; the amount of resection or Hb and Qmax changes, 64(2):298-301. on the other hand, bipolar TURP was associated with 10. Alschibaja M, May F, Treiber U, Paul R, Hartung less irrigation time and shorter hospital stay. The R. Recent improvements in transurethral high- operating time was also seen to be longer in bTURP. frequency electrosurgery of the prostate. BJU Int This increased the possibility of urethral stricture and 2006; 97(2):243-246. 11. Starkman JS, Santucci RA. Comparison of bipolar can be considered to expose the patients to further transurethral resection of the prostate with standard procedures. Understanding whether bTURP is related transurethral prostatectomy: shorter stay, earlier with more urethral stricture or not can be made catheter removal and fewer complications. BJU Int possible with a study that includes a greater number 2005; 95(1):69-71. of patients and randomised control trials. 12. de Sio M, Autorino R, Quarto G, Damiano R, Perdona S, di Lorenzo G, et al. Gyrus bipolar versus standard ACKNOWLEDGMENT monopolar transurethral resection of the prostate: a Authors contribution: Hakan Ozkardes reviewed randomized prospective trial. Urology 2006; 67(1):69- the study protocol and the manuscript, as well as 72. 13. Gravas S, Cornu JN, Drake MJ, Gacci M, Gratzke the editing. Eray Hasirci wrote the study protocol C, Herrman TRW, Madersbacher S, Mamoulakis C, and performed data collection, data entry, statistical Tikkinen KAO, Guidelines Associates: Karavitakis analysis and manuscript writing. Enis Kervancioglu M, Kyriazis I, Malde S, Sakkalis V, Umbach R. EAU also wrote the study protocol and was involved in data 2016 guidelines on Management of Non-neurogenic collection and entry. Male LUTS. Disclosure statement: None of the authors had any 14. Cetinkaya M, Ozturk B, Akdemir O, Ozden C, Aki FT. commercial associations that might pose a conflict of A comparison of fluid absorption during transurethral interest and there was no funding source used in this resection and transurethral vaporization for benign study. prostatic hyperplasia. BJU Int 2000; 86(7):820-823. 15. Eaton AC, Francis RN. The provision of transurethral prostatectomy on a day-case basis using bipolar REFERENCES plasma kinetic technology. BJU Int 2002; 89(6):534- 547. 1. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The 16. Gallucci M, Puppo P, Perachino M, Fortunato P, Muto development of human benign prostatic hyperplasia G, Breda G, et al. Transurethral electrovaporization with age. J Urol 1984; 132(3):474-479. of the prostate vs. transurethral resection. Results 2. Wei JT, Calhoun E, Jacobsen SJ. Urologic diseases in of a multicentric, randomized clinical study on 150 America project: benign prostatic hyperplasia. J Urol patients. Eur Urol 1998; 33(4):359-364. 2008; 173(4):1256-1261. 17. Engeler DS, Schwab C, Neyer M, Grun T, Reissigl 3. Reich O, Gratzke C, Stief CG. Techniques and long- A, Schmid HP. Bipolar versus monopolar TURP: a term results of surgical procedures for BPH. Eur Urol prospective controlled study at two urology centers. 2006; 49(6):970-978. Prostate Cancer Prostatic Dis 2010; 13(3):285-291. 4. Rassweiler J, Teber D, Kuntz R, Hofmann R. 18. Fagerstrom T, Nyman CR, Hahn RG. Bipolar Complications of transurethral resection of the transurethral resection of the prostate causes less prostate (TURP)-incidence, management, and bleeding than the monopolar technique: a single- prevention. Eur Urol 2006; 50(5):969-979. centre randomized trial of 202 patients. BJU Int 2010; 5. Reich O, Gratzke C, Bachmann A, Seitz M, Schlenker 105(11):1560-1564. B, Hermanek P, et al. Morbidity, mortality and early 19. Singhania P, Nandini D, Sarita F, Hemant P, outcome of transurethral resection of the prostate: a Hemalata I. Transurethral resection of prostate: a prospective multicenter evaluation of 10,654 patients. comparison of standard monopolar versus bipolar J Urol 2008; 180(1):246-249. saline resection. Int Braz J Urol 2010; 36(2):183-189. 6. Ho HS, Yip SK, Lim KB, Fook S, Foo KT, Cheng 20. Huang X, Wang L, Wang XH, Shi HB, Zhang XJ, Yu CW. A prospective randomized study comparing ZY. Bipolar transurethral resection of the prostate monopolar and bipolar transurethral resection causes deeper coagulation depth and less bleeding of prostate using transurethral resection in saline than monopolar transurethral prostatectomy. (TURIS) system. Eur Urol 2007; 52(2):517-522. Urology 2012; 80(5):1116-1120. 43 Does bipolar transuretral resection of prostate increase the incidence of urethral stricture? March 2021
21. Kong CH, Ibrahim MF, Zainuddin ZM. A prospective, 23. Mamoulakis C, Ubbink DT, de la Rosette JJ. Bipolar randomized clinical trial comparing bipolar plasma versus monopolar transurethral resection of the kinetic resection of the prostate versus conventional prostate: a systematic review and meta-analysis monopolar transurethral resection of the prostate in of randomized controlled trials. Eur Urol 2009; the treatment of benign prostatic hyperplasia. Ann 56(5):798-809. Saudi Med 2009; 29(6):429-432. 24. Guo RQ, Yu W, Meng YS, Zhang K, Xu B, Xiao YX, et 22. Poh BK, Mancer K, Goh D, Lim T, Ng V, Ng KK, et al. Correlation of benign prostatic obstruction-related al. PlasmaKinetic (bipolar) transurethral resection complications with clinical outcomes in patients after of prostate: a prospective trial to study pathological transurethral resection of the prostate. Kaohsiung J artefacts, surgical parameters and clinical outcomes. Med Sci 2017; 33(3):144-151. Singapore Med J 2011; 52(5):336-339. March 2021 KUWAIT MEDICAL JOURNAL 44
Original Article Ten years clinical and epidemiological picture of cutaneous Leishmaniasis in the Dasht-e-Azadegan County, Southwestern Iran
Hamid Kassiri1, Ahmad Jalali2, Masoumeh Mardani Kataki3, Masoud Lotfi1,4 1Department of Medical Entomology and Vector Control, School of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 2Communicable Diseases Department, Khuzestan Province Health Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 3Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 4Abdanan Health Center, Ilam University of Medical Sciences, Ilam, Iran
Kuwait Medical Journal 2021; 53 (1): 44 - 50
ABSTRACT
Objectives: To identify the epidemiological and clinical statistics. aspects of cutaneous Leishmaniasis (CL) in cases reported Main outcome measure: Demographic and epidemiological from an endemic focus, Dasht-e-Azadegan county, between parameters: patient’s age, gender, place of residence (city, 2005 and 2014. village), season, month, location of ulcers on the body and Design: Descriptive-analytical study number of body lesions. Setting: School of Health, Ahvaz Jundishapur University of Results: Overall, 1749 patients were referred to the county Medical Sciences, Ahvaz, Iran health center for treatment. In the present study, 961 (55%) of Subjects: Patients who were definitely infected with the cases lived in urban areas and 52.6% of the patients were leishmaniasis (N=1749) males. The maximum lesions were in the hands (34.5%); 48.2% Intervention: All patients were diagnosed with positive of the cases had just one wound and most of the patients were direct smear for CL among the individuals living in the in the age group of 11-30 years (45%). Our findings showed above county of the Khuzestan Province, southwestern Iran. that the most incidence of CL occurred in winter (51.6%). Doubtful active ulcers of all patients were scraped, smeared Conclusion: A majority of patients in the age group 11-30 on the slides, stained and examined microscopically for years showed that the active population is at risk of CL and the presence of Leishmania amastigotes. Information was educating this age group is important for the control of this collected by means of a checklist, including clinical and socio- disease. Due to the findings of this study, CL seemed to be of demographic data. SPSS software was used for descriptive the wet form in Dasht-e-Azadegan.
KEY WORDS: active ulcer, demography, incidence, sand fly, zoonosis
INTRODUCTION in the genus Leishmania. The disease is transmitted to Cutaneous leishmaniasis (CL) is a common parasitic humans by the bite of infected female sand flies that disease between humans and animals and a major usually live in the forests, caves and the nests of small health issue[1]. It appears as small bumps (papules), rodents[2]. CL can be seen in two forms: rural or wet which gradually enlarge to form ulcers. This disease (zoonotic) and urban or dry (anthroponotic)[3]. inflicts heavy economic burdens on families, Unlike other infectious diseases, the prevalence of communities and countries, especially in developing this disease is increasing[4]; so that one person gets countries. This disease is caused by various parasites infected with CL every second. It is endemic in 88
Address correspondence to: Hamid Kassiri, Department of Medical Entomology and Vector Control, School of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Tel: +98-61133738269; Fax: +98-61133738282; E-mail: [email protected] 45 Ten years clinical and epidemiological picture of cutaneous Leishmaniasis in the Dasht-e-Azadegan County,... March 2021 countries and a health problem in many countries in AJUMS.REC.1397.257 and Approval Date: 2018-06-23). the Middle East, Africa, Central Asia, South America, The confidentiality of the records of patients was etc[5-7]. Annually, 2 million new cases of infection with assured. Informed consent was obtained from all leishmaniasis are observed, of which half a million are participants after explaining the study purpose, with associated with visceral leishmaniasis and 1.5 million the verbal consent of the infected individuals. For are related to CL[8]. Ninety percent of cases of CL occur children participating in the study, informed consent in 7 countries, namely Afghanistan, Algeria, Brazil, form was completed by their parents. Written consent Iran, Peru, Saudi Arabia and Syria[9]. was not obtainable because most of the subjects In Iran, about 20,000 cases of CL are reported from involved in the study were of low literacy in Persian different parts of the country each year; while its actual language. The study has been done in accordance with rate is estimated to be several times higher than the the provisions of the Helsinki Declaration. No reported rate[10]. The prevalence of this disease is high photographs or names of individuals or patients are in Khorasan, Fars, Isfahan, Khuzestan and Kerman found in the article. Provinces. In recent years, provinces such as Ilam, Dasht-e-Azadegan is one of the counties of Yazd and Bushehr had the highest incidence of new Khuzestan Province in the southwest of Iran. The cases of this disease. In general, provinces such as center of this county is the city of Susangerd. This Yazd, Bushehr, Khorasan, Fars, Ilam, Khuzestan and county is bordered to the east by the counties of Shoush Isfahan, with an average incidence of 166 cases per and Ahvaz. Based on the 2016 census conducted by the 100,000 people, have the highest incidence of this Statistical Center of Iran, the population of this county disease; and the western and northwestern provinces was estimated to be 107,000. Due to its close proximity of the country have the lowest incidence of infection to Saudi Arabia and Iraq, the weather of this county is with CL (less than 10 per 100,000 people) in the affected by the hot dry winds blowing from these two country[11,12] . countries. The relative humidity of this region is high Studies show that the number of leishmaniasis in all seasons due to its proximity to the Hawr- al- cases is increasing due to human-induced Azim, Arvand River and the Persian Gulf. environmental changes, such as uncontrolled This cross-sectional descriptive-analytical study exploitation of wood resources, mining, damming, was conducted to investigate the epidemiological expansion of agricultural lands, new irrigation status of CL in the county of Dasht-e-Azadegan. The practices, road development in forests and extensive statistical population consisted of all individuals migration to cities and urbanization. In addition, diagnosed with CL from 2005 to 2014 through poverty and malnutrition are among the most verification of clinical laboratory tests (biopsy of important factors affecting the spread of disease. In suspicious lesions, preparation of smears, examination general, risk factors are expressed based on parameters of parasites and clinical approval) and treated in the such as age, gender, economic conditions and other health center of Dasht-e-Azadegan. Slit-skin method social factors[13]. was applicated for getting the sample, which was next Given the above-mentioned reasons, the importance extended on a glass slide. In order to identify the of addressing this disease is evident. Ecological and leishman-donovan bodies (amastigotes), the provided epidemiological studies that evaluate the important smear was stained by Giemsa, and subsequently risk factors for the spread of CL in different parts of examined under light microscopy. Iran are of great importance due to their effective role The population under research was selected among in controlling the disease and taking preventive the people clinically doubtful to CL who were referred measures. Over the past years, several studies have to the Parasitology Lab of the Health Center of Dasht- been conducted on the epidemiology of CL in different e-Azadegan, Ahvaz Jundishapur University of Medical parts of Iran. Given the lack of any similar study in Sciences, Ahvaz, Iran. With regard to the inclusion and recent years in the county of Dasht-e-Azadegan, which exclusion criteria, all people who were settling in is one of the oldest counties of Khuzestan Province Dasht-e-Azadegan County for one year prior to with a high incidence of this disease, this study aimed appearance of the ulcer and had minimum one lesion to evaluate the epidemiological and clinical aspects of doubtful to CL were included in this research. Those CL in this county from 2005 to 2014. people whose smears displayed negative result in terms of viewing Leishmania parasites and had any trip SUBJECTS AND METHODS six months prior to appearance of the ulcer were Ethics statement excluded from the research. A consent form was This study has been ethically approved by the obtained from each patient. Information such as research ethics committee of the Ahvaz Jundishapur patient’s age, gender, place of residence (city, village), University of Medical Sciences, Iran (Approval ID: IR. season, month, location of ulcers on the body and the March 2021 KUWAIT MEDICAL JOURNAL 46
Table 1: Distribution of cutaneous leishmaniasis cases in Dasht-e-Azadegan County, southwestern Iran (2005-2014) based on gender, lesion sites on the body and age group
Gender Lesion sites Age group Years Female Male Hands Feet Faces Others 0-10 11-30 >31 n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) 2005 195 (54.3) 164 (45.7) 126 (35.1) 108 (30.1) 76 (21.2) 49 (13.6) 148 (41.2) 158 (44.0) 53 (14.8) 2006 132 (50.2) 131(49.8) 97 (36.9) 78 (29.7) 65 (24.7) 23 (8.7) 130 (49.4) 106 (40.3) 27 (10.3) 2007 31 (31.3) 68 (68.7) 31 (31.3) 28 (28.3) 25 (25.3) 15 (15.1) 40 (40.4) 49 (49.5) 10 (10.1) 2008 46 (47.0) 52 (53.0) 34 (34.7) 33 (33.7) 25 (25.5) 6 (6.1) 40 (40.8) 55 (56.1) 3 (3.1) 2009 35 (49.3) 36 (50.7) 31 (43.6) 21 (29.6) 10 (14.1) 9(12.7) 34 (47.9) 36 (50.7) 1 (1.4) 2010 30 (42.9) 40 (57.1) 36 (51.4) 19 (27.1) 12 (17.2) 3 (4.3) 25 (35.7) 37 (52.9) 8 (11.4) 2011 94 (49.0) 98 (51.0) 77 (40.1) 59 ((30.7) 44 (22.9) 12 (6.3) 91 (47.4) 74 (38.5) 27 (14.1) 2012 38 (47.5) 42 (52.5) 24 (30.0) 28 (35.0) 22 (27.5) 6 (7.5) 39 (48.8) 30 (37.5) 11 (13.7) 2013 22 (25.9) 63 (74.1) 24 (28.2) 28 (32.9) 27 (31.8) 6 (7.1) 24 (28.2) 48 (56.5) 13 (15.3) 2014 206 (47.7) 226 (52.3) 124 (28.7) 136 (31.5) 116 (26.8) 56 (13.0) 181 (41.9) 194 (44.9) 57 (13.2) Total 829 (47.4) 920 (52.6) 604 (34.5) 538 (30.8) 422(24.1) 185 (10.6) 752 (43.0) 787 (45.0) 210 (12.0) number of body lesions was recorded for each patient The highest number of patients with CL was in the checklist using the face to face interview method. observed in the age group 11-30 years (45%) and the After collecting the data, they were analyzed using lowest number was observed in the age group over 30 SPSS 18, as well as descriptive statistics and chi-square years (12%). The results showed that there was a test. Significance level was considered to beP <.05 at all significant difference between the age groups and the stages of the study. incidence of CL (P <.05) (Table 1). The gender-based study of the frequency of CL cases showed that 52.6% RESULTS of the cases were male and 47.4% were female (Table During the period 2005-2014, the data of 1749 1). There was no significant difference between the patients with CL who visited the disease prevention incidence of the disease and gender. The hands (34.5%), and control unit affiliated to the Health Center of the feet (30.8%), face (24.1%) and other limbs (10.6%) were county of Dasht-e-Azadegan were recorded. The the most frequent sites of involvement. The chi-square incidence of the disease during this 10-year period test showed a significant difference between the followed an ascending and descending trend; so that anatomic sites of the lesions and the incidence of CL (P the number of cases in 2005 with 359 people was higher <.05) (Table 1). than that of the following years, and then a descending In terms of month, the highest and lowest incidence trend continued for 8 years, and again the incidence of the disease was observed during January (19.2%) rate rose in 2014 with 432 cases of disease. Regarding and August (2.4%) respectively (Table 2). The study of the results of the regression between the variables of the incidence of this disease in terms of season showed time and the incidence of the disease, the descending that 10.5%, 10.4%, 27.5% and 51.6% of the cases were trend was significant during the years 2005 to 2014 observed in spring, summer, autumn and winter (R=0.65). respectively (Table 3). There was a significant difference
Table 2: Distribution of cutaneous leishmaniasis cases in Dasht-e-Azadegan County, southwestern Iran (2005-2014) based on month
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Total Month n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) April 29 (8.1) 14 (5.3) 9 (9.1) 3 (3.1) 6 (8.5) 1 (1.4) 4 (2.1) 11 (13.7) 2 (2.3) 3 (0.7) 82 (4.7) May 15 (4.2) 18 (6.8) 3(3.0) 2 (2.0) 0 (0.0) 0 (0.0) 7 (3.6) 4 (5.0) 3 (3.5) 4 (0.9) 56 (3.2) June 5 (1.4) 15 (5.7) 0 (0.0) 4 (4.1) 4 (5.6) 0 (0.0) 2 (1.0) 8 (10.0) 3 (3.5) 5 (1.1) 46 (2.6) July 8 (2.2) 16 (6.1) 7 (7.1) 3 (3.1) 0 (0.0) 0 (0.0 4 (2.1) 3 (3.75) 3 (3.5) 10 (2.3) 54 (3.1) August 8 (2.2) 6 (2.3) 4 (4.0) 5 (5.1) 1 (1.4) 0 (0.0) 4 (2.1) 2 (2.5) 3 (31) 8 (1.9) 41 (2.4) September 33 (9.2) 10 (3.8) 4 (4.0) 3 (3.1) 2 (2.8) 2 (2.9) 17 (8.9) 4 (5.0) 3 (3.5) 8 (1.9) 86 (4.9) October 28 (7.8) 20 (7.6) 4 (4.0) 4 (4.1) 4 (5.6) 5 (7.1) 19 (9.9) 5 (6.2) 4 (4.7) 8 (1.9) 101 (5.8) November 24 (6.7) 29 (11.0) 4 (4.0) 8 (8.2) 6 (8.5) 8 (11.4) 8 (4.2) 4 (5.0) 2 (2.4) 38 (8.8) 131 (7.5) December 48 (13.4) 40 (15.2) 24 (24.3) 24 (24.5) 4 (5.6) 9 (12.9) 20 (10.4) 11 (13.7) 8 (9.5) 61 (14.1) 249 (14.2) January 45 (12.4) 53 (20.2) 22 (22.2) 12 (12.2) 17 (24.0) 18(25.7) 43 (22.4) 9 (11.2) 18 (12.2) 99 (22.9) 336 (19.2) February 48 (13.4) 30 (11.4) 14 (14.3) 18 (18.4) 23 (32.4) 17 (24.3) 30 (15.6) 13 (16.2) 22 (25.9) 118(27.3) 333 (19.0) March 68 (19.0) 12 (4.6) 4 (4.0) 12 (12.2) 4 (5.6) 10 (14.3) 34 (17.7) 6 (7.5) 14 (16.4) 70 (16.2) 234 (13.4) Total 359 (100) 263 (100) 99 (100) 98 (100) 71 (100) 70 (100) 192 (100) 80 (100) 85(100) 432(100) 1749 (100) 47 Ten years clinical and epidemiological picture of cutaneous Leishmaniasis in the Dasht-e-Azadegan County,... March 2021
Table 3: Distribution of cutaneous leishmaniasis cases in Dasht-e-Azadegan County, southwestern Iran (2005-2014) based on lesion frequency, residential area and season
Lesion frequency Residential Area Seasons Years 1 2 ≥3 Urban Village Spring Summer Autumn Winter n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) 2005 183 (51.0) 88 (24.5) 88 (24.5) 211 (58.8) 148 (41.2) 49 (13.6) 49 (13.6) 100 (27.8) 161(44.8) 2006 157 (59.7) 45 (17.1) 61 (23.2) 162 (61.6) 101 (38.4) 47 (17.9) 32 (12.2) 89 (33.8) 95 (36.1) 2007 46 (46.5) 22 (22.2) 31(31.3) 58 (58.6) 41 (41.4) 12 (12.1) 15 (15.2) 32 (32.3) 40 (40.4) 2008 48 (49.0) 27 (27.5) 23 (23.5) 40 (40.8) 58 (59.2) 9 (9.2) 11 (11.2) 36 (36.7) 42 (42.9) 2009 36 (50.7) 18 (25.4) 17 (23.9) 44 (62.0) 27 (38.0) 10 (14.1) 3 (4.2) 14 (19.7) 44 (62.0) 2010 37 (52.9) 19 (27.1) 14 (20.0) 32 (45.7) 38 (54.3) 1 (1.4) 2 (2.9) 22 (31.4) 45 (64.3) 2011 107 (55.7) 61 (31.8) 24 (12.5) 104 (54.2) 88 (45.8) 13 (6.8) 25 (13.0) 47 (24.5) 107 (55.7) 2012 36 (45.0) 22 (27.5) 22 (27.5) 40 (50.0) 40 (50.0) 23 (28.8) 9 (11.2) 20 (25.0) 28 (35.0) 2013 37 (43.5) 27 (31.8) 21 (24.7) 29 (34.1) 56 (65.9) 8 (9.4) 9 (10.6) 14 (16.5) 54 (63.5) 2014 156 (36.1) 124 (28.7) 152 (35.2) 241 (55.8) 191 (44.2) 12 (2.8) 26 (6.0) 107 (24.8) 287 (66.4) Total 843 (48.2) 453 (25.9) 453 (25.9) 961 (55.0) 788 (45.0) 184(10.5) 181(10.4) 481 (27.5) 903 (51.6) between the incidence rate of CL, seasons and months under-10 age group, which was not consistent with the (P <.05). Table 3 shows that most cases of CL lived in results of the present study. urban areas (55%). There was no statistically significant In this study, 52.6% of the patients were males and difference in the incidence rate of CL in urban and 47.4% were females. In the studies conducted in the rural areas. Meanwhile, most of the patients (48.2%) counties of Gonbad and Neyshabur, similar to our had an ulcer on the body (Table 3). Statistical analysis study, there was no significant difference between the showed a significant difference between the number of two genders in terms of the incidence rate of CL. The ulcers on the body and frequency of CL cases (P <.05). absence of a difference in the prevalence of the disease between the two genders indicates that in this area, all DISCUSSION individuals were equally exposed to sandflies[22,23]. Epidemiologic studies that identify and assess the Moreover, the study by Fazaeli et al, who examined risk factors for the spread of CL and ultimately improve about 3100 patients during the years 2007-2008, did not disease control are of great importance[14]. The present show any significant difference between the two study investigated the epidemiology of cases of CL genders in terms of the incidence rate of this disease[19], visiting the health center of Dasht-e-Azadegan from which was consistent with the results of the present 2005 to 2014. During these years, a high oscillation in study. However, in the studies by Bahrami and the incidence of CL was observed. The incidence of the Momeni, males were more infected with CL than disease in 2005 was 3.3 cases per one thousand people, females[24,25]. The study by Ayatollahi et al in Abarkuh and then the rate of incidence declined for 8 years until County of Yazd Province in 2006 showed that the it increased again in 2014, with 4 cases per one incidence rate of CL was higher in females than in thousand people. One of the risk factors of this disease males[26]. The relatively high proportion of males is to travel to areas where it is endemic. If, for whatever compared to females in some studies can be due to reason, people, especially non-natives, are exposed to males’ weaker immune system, occupations, lower the vectors of the disease, the incidence rate of the clothing coverage, warm weather and more exposure disease will increase[15]. War and disasters cause to sandflies. changes in the trend of the disease in the affected areas In this study, most of the lesions were observed on due to migration and population changes. In fact, the hands and then on the feet. In a research by population displacement is a very important factor in Doroodgar et al in Kashan, 46.6% of the ulcers were on the epidemic of CL, especially its urban type[16]. the hands and the rest on the feet, face and other parts One of the objectives of this study was to investigate of the body, which was consistent with the results of the age distribution of patients. The age distribution of the present study[18]. However, the study by Uzun et al patients showed that a significant percentage (45.2%) in Turkey showed that most of the lesions are on the of patients were in the age group 10-30 years, which face, feet and other limbs respectively[27]. In the studies constitute the active and dynamic age of the by Fazaeli et al in Mirjawa[19], Gurel et al in Turkey[28], community. The results of the present study were and Ullah et al in Pakistan[29], the highest incidence consistent with the results of the study by Hamzavi et rates of ulcers were reported to be on the face, hands al in Kermanshah[17] and Doroodgar et al. Doroodgar et and feet respectively. In general, cutaneous lesions in al[18], Fazaeli et al[19], Sharifiet al[20] and Sufizadehet al[21] CL usually occur on the exposed parts of the body and reported the highest incidence rate of the disease in the in places most exposed to the bites of sand flies. March 2021 KUWAIT MEDICAL JOURNAL 48
Considering the fact that other parts of the body are seasons for the proliferation and activity of sandflies. covered and hands and feet are not covered, especially In the hot summer days, from June to September, the in children who sleep early, these areas are more like lowest incidence rate of this disease is observed in to be bitten by the infected sandflies, and consequently Dasht-e-Azadegan, which is due to decreased activity the likelihood of lesion in these areas increases. and proliferation of carriers (sandflies) in these In this study, in terms of the number of lesions, months. most patients had only one lesion. In a study by Sharifi et al in the county of Bam, 60% of patients had one CONCLUSION ulcer[30]. In the study by Hamzavi, the number of active According to the findings of the present study, it lesions on the body of each patient varied between can be easily inferred that in this county and its 1-23, with an average of 2.24 ulcers per person. Totally, neighboring cities, including urban and rural areas, 54.5% of the patients had one ulcer, 19.2% had two the transmission of the disease is indigenous and easily ulcers, 9.6% had three ulcers, and the rest had four carried out by the disease-vector sandflies. Indigenous ulcers and more[31]. However, in the studies by Rafati transmission phenomenon can be exacerbated due to in Damghan[32] and Abbasi in Gorgan[33], over 60% of the presence of reservoirs, leading to the complete the patients had more than one ulcer on their bodies. establishment of the disease in the region and increased The number of lesions may be due to the infected bites disease endemicity in this county and other favorable at different times or autoinoculation through parts of Khuzestan Province. Given the complications scratching. and the high costs of treatment, and in order to prevent In the present study, the number of cases of CL was mental and psychological trauma caused by CL, higher among urban dwellers than among rural effective measures should be taken to prevent the dwellers. This might be due to the presence of large disease. The use of window nets, bed nets and creeks and soil grounds near Dasht-e-Azadegan, repellents will be effective in preventing the disease. marginalization, large number of reservoirs on the Training the community with the importance of using outskirts of the city, lack of programs to control vectors full coverage of body, environmental health measures (sand flies) and reservoirs, lack of sufficient training (including collection of garbage and construction available for the people, lack of environmental waste), control of stray dogs, rapid diagnosis and improvement, people’s occupation, lack of timely treatment of infected people can help reduce disease treatment of the disease and the density of human cases in the region. population in these areas. Therefore, basic measures must be taken to reduce the incidence of this disease in ACKNOWLEDGMENTS urban areas. Authors wish to express their sincere thanks to all One of the most important factors affecting CL is staff of the Health Centers in the Dasht-e-Azadegan the type of weather, which is subject to different County, Ahvaz Jundishapur University of Medical conditions such as seasons and months. The results of Sciences, who sincerely helped in data collection. This this study showed that the incidence rate of CL is project has been supported by Student Research higher in winter and autumn. On the other hand, the Committee, Chancellor for Research Affairs of Ahvaz accuracy of the seasonal dispersal pattern of the Jundishapur University of Medical Sciences with disease in the county of Dasht-e-Azadegan confirms project number 96S.89. the existence of local disease transmission very well. Conflict of interest statement: The authors report In a study conducted in the county of Ghasreshirin, no conflict of interest. most cases were reported in autumn (34%) and winter Authors’ Contribution: Hamid Kassiri: Manuscript (19%)[34]. In Kassiri’s studies conducted in Genaveh, preparation, research project director, scientific Shushtar, Ahvaz and Shadegan, it was found that advisor, technical advisor, data analysis, development most cases of this disease were observed in winter of study idea, experimental work, abstracted data, (56.3%) and autumn (24.4%) in Genaveh; in Shushtar, writing the manuscript and corresponding author; most cases of the disease were observed in winter Ahmad Jalali: Fieldwork and data collection; (38.8%) and autumn (29.6%); in Ahvaz, in winter Masoumeh Mardani Kataki: research project director; (58.1%) and autumn (19.7%); and in Shadegan, in Masoud Lotfi: Manuscript preparation and data winter (45%) and spring (26%)[35-38]. The present study analysis. shows that the disease does not have the same seasonal distribution, and the incidence of the disease REFERENCES is not the same throughout the year, which is one of the characteristics of rural CL. It is noteworthy that, 1. Alrajhi AA, Ibrahim EA, De Vol EB, Khairat M, Faris in the western and southern counties of Khuzestan RM, Maguire JH. Fluconazole for the treatment of Province, autumn and winter are relatively favorable cutaneous leishmaniasis caused by Leishmania major. N Engl J Med 2002; 346(12):891-895. 49 Ten years clinical and epidemiological picture of cutaneous Leishmaniasis in the Dasht-e-Azadegan County,... March 2021
2. Shirazi MH, Ranjbar R, Asgari V, Mohebali M, Doroodgar M. [An epidemiological study of cutaneous Hamidian M. Study of bacterial infections among the leishmaniasis in Kashan (2007-2008)]. Koomesh 2009; patients with suspected cutaneous leishmaniasis. Pak J 10(3):177-184. Article in Persian. Biol Sci 2007; 10(24):4555-4558. 19. Fazaeli A, Fouladi B, Sharifi I. [Emergence of cutaneous 3. Kassiri H, Mehr-Aghaei M. First report on various leishmaniasis in a border area at southeast of Iran: an aspects of focus on cutaneous leishmaniosis in epidemiological survey]. J Vector Borne Dis 2009; Southwestern Iran. Entomol Appl Sci Lett 2018; 5(4):103- 46(1):36-42. 111. 20. Sharifi I, Poursmaelian S, Aflatoonian MR, Ardakani 4. Doroudgar A, Tashakkor Z. [Effect of education on RF, Mirzaei M, Fekri AR, et al. Emergence of a new teachers’ knowledge towards leishmaniasis in Kashan]. focus of anthroponotic cutaneous leishmaniasis due to KAUMS Journal (FEYZ) 2003; 7(3):57-63. Article in Leishmania tropica in rural communities of Bam district Persian. after the earthquake, Iran. Trop Med Int Health 2011; 5. Gramiccia M, Gradoni L. The current status of zoonotic 16(4):510-513. leishmaniasis and approaches to disease control. Int J 21. Sufizadeh A, Farajifar AA, Charabin M, Sarali J, Gharavi Parasitol 2005; 35(11-12):1169-1180. MY, Mehravaran A. [Cutaneous leishmaniasis in 6. Blum JA, Hatz CF. Treatment of cutaneous leishmaniasis Gonbad Kavous district, 2009-2010]. J Gorgan Univ in travelers. Journal of Travel Medicine 2009; 16(2):123- Med Sci 2012; 14(4):100-106. Article in Persian. 131. 22. Pagheh AS, Fakhar M, Mesgarian F, Gholami SH, 7. Bailey MS, Lockwood DNJ. Cutaneous leishmaniasis. Badiee F. [Detection and identification of causative Clin Dermatol 2007; 25(2):203-211. agent of cutaneous leishmaniasisin referred patients to 8. Ashford RW, Bern C, Boelaert M, Bryceson A, Chappuis the Health Center of Gonbade-Qabus from Golestan F, Croft S, et al. Control of the leishmaniases: report of a province using specific PCR]. J Mazandaran Univ Med meeting of the WHO Expert Committee on the Control Sci 2012; 21(Supp1):85-92. Article in Persian. of Leishmaniases, Geneva, 22-26 March 2010. World 23. Mohajery M, Hajaran H, Shamsian AA, Tavakol Afshari Health Organ Tech Rep Ser 2010; 949:1-186. J, Sasabadi F. [Detecting leishmaniasis agents in 9. Torgerson PR, Macpherson CN. The socioeconomic Nieshabour using RAPD-PCR technique]. J Mashhad burden of parasitic zoonoses: Global trends. Vet Uni Med Sci. 2008; 51:74-86. Article in Persian. Parasitol 2011; 182(1):79-95. 24. Bahrami AM, Delpisheh A, Zamandousti A. 10. Ershadi MR, Zahraei-Ramezani AR, Akhavan AA, [Epidemiologic aspects of cutaneous leishmaniasis and Jalali-Zand AR. Rodent control operations against trapeutic effect of traditional ointment containing onion zoonotic cutaneous leishmaniasis in rural Iran. Ann juice compared with Amphotricin B]. J Kermanshah Saudi Med 2005; 25(4):305-318. Univ Med Sci 2011; 15(4):e79304. Article in Persian. 11. Saghafipour A, Rassi Y, Abai MR, Oshaghi MA, 25. Momeni AZ, Aminjavaheri M. Clinical picture of Farzinnia B, Mostafavi R, et al. [Outbreak of zoonotic cutaneous leishmaniasis in Isfahan, Iran. Int J Dermatol cutaneous leishmaniasis: A report]. Arch Hyg Sci 2013; 1994; 33(4):260-265. 2(2):48-54. Article in Persian. 26. Ayatollahi J, Karimi M. [Cutaneous leishmaniasis 12. Kassiri H, Mortazavi SH, Kazemi S. [The epidemiological prevalence in Abarkuh-Yazd]. Iranian J Infect Dis 2005; study of cutaneous leishmaniasis in Khorram-shahr 10(30):13-18. Article in Persian. city, Khuzestan province, South- West of Iran]. 27. Uzun S, Uslular C, Yücel A, Acar M, Ozpoyraz M, Jundishapur Journal of Health Sciences 2011; 3(2):11-20. Memişoğlu HR. Cutaneous leishmaniasis: evaluation of Article in Persian. 3,074 cases in the Cukurova region of Turkey. Br J 13. Desjeux P. Leishmaniasis: current situation and new Dermatol 1999; 140(2):347-350 perspectives. Comp Immunol Microbiol Infect Dis 2004; 28. Gurel MS, Ulukanligil M, Ozbilge H. Cutaneous 27(5): 305-318. leishmaniasis in Sanliurfa: epidemiologic and clinical 14. Jacobson RL. Leishmania tropica (Kinetoplastida: features of the last four years (1997–2000). Int J Dermatol Trypanosomatidae) - a perplexing parasite. Folia 2002; 41(1):32-37. Parasitol (Praha) 2003; 50(4):241-250. 29. Ullah S, Jan AH, Wazir SM, Ali N. Prevalence of 15. Jahani MR, Shirzad H. [A survey on the cutaneous cutaneous leishmaniasis in lower Dir District (NWFP), leishmaniasis in disciplinary units of Isfahan, Ilam, Pakistan. Journal of Pakistan Association of Bushehr, Khorasan and Khuzestan provinces,1997-1999]. Dermatologists 2009; 19(4):212-215. Journal of Teb- e –Nezami 2001; 3(3):97-101. Article in 30. Sharifi I, Fekri AR, Aflatonian MR, Nadim A, Nikian Y, Persian. Kamesipour A. Cutaneous leishmaniasis in primary 16. Aflatunian MR, Sharifi I. [Frequency of cutaneous school children in the south-eastern Iranian city of Bam, leishmaniasis in the patients referred to health centers 1994-95. Bull World Health Organ 1998; 76(3):289-293. of Bam district, 2000-2004]. Journal of Rafsanjan Uni 31. Hamzavi Y, Sobhi S A, Rezaei M. [Epidemiology of Med Sc 2006; 5(2):123-128. Article in Persian. cutaneous Leishmaniasis in patients referred to health 17. Hamzavi Y, Khademi N. [The analytical study of centers of Kermanshah provinces, 2001-2006]. J cutaneous leishmaniasis in Kermanshah (2011-2012)]. J Kermanshah Univ Med Sci 2009; 2(41):151-61. Article in Kermanshah Univ Med Sci 2013; 17(9): 582-89. Article Persian. in Persian. 32. Rafati N, Shapori-Moghadam A, Ghorbani R. 18. Doroodgar A, Mahbobi S, Nemetian M, Sayyah M, [Epidemiological survey of cutaneous leishmaniasis in March 2021 KUWAIT MEDICAL JOURNAL 50
Damghan1999-2005]. Sci J Semnan Univ Med Sci 2004; Southern Iran. J Coast Life Med 2014; 2(12):1002- 2(1):247-253. Article in Persian. 1006. 33. Abbasi A, Ghanbary M, Kazem-Nejad K. [Epidemiology 36. Kassiri H, Kassiri A, Lotfi M, Farajifard P, Kassiri E. of cutaneous leishmaniasis in Gorgan, 1998-2001]. Laboratory diagnosis, clinical manifestations, Journal of Army University of Medical Sciences of the epidemiological situation and public health importance Iran 2004; 2(1):275-278. Article in Persian. of cutaneous leishmaniasis in Shushtar County, 34. Yazdanpanah H, Baratian A, Karimi S. The relationship Southwestern Iran. J Acute Dis 2014; 3:93-98. between climatic factors on the incidence of cutaneous 37. Kassiri H, Ebrahimi A, Lotfi M. The prevalence of leishmaniasis in the city Ghasreshirin. Spatial planning cutaneous leishmaniasis in East of Ahvaz County, (geography) 2013; 3(3):69-86. South-Western Iran. Indo Am J P Sci 2017; 4(11). 35. Kassiri H, Kassiri A, Najafi H, Lotfi M, Kassiri E. 38. Feiz-Haddad M, Kassiri H, Kassiri N, Panahandeh A, Epidemiological features, clinical manifestation and Lotfi M. Prevalence and epidemiologic profile of acute laboratory findings of patients with cutaneous cutaneous leishmaniasis in an endemic focus, leishmaniasis in Genaveh County, Bushehr Province, Southwestern Iran. J Acute Dis 2015; 4(4):292-297. 51 KUWAIT MEDICAL JOURNAL March 2021
Original Article Considering the effect of Stapes Footplate’s macroscopic vision on surgical complication rate
Serkan Cayir1, Mehmet Ali Cetin2, Hacer Baran3, Serdar Ensari4, Haci Huseyin Dere5 1Department of Ear Nose and Throat and Head and Neck Surgery, Aksaray University Faculty of Medicine, Turkey 2Department of Ear Nose and Throat and Head and Neck Surgery, Ankara Numune Training and Research Hospital, Ankara, Turkey 3Department of Ear Nose and Throat and Head and Neck Surgery, Ardahan Public Hospital, Ardahan, Turkey 4Department of Ear Nose and Throat and Head and Neck Surgery, Karabük University Faculty of Medicine, Karabük, Turkey 5Department of Ear Nose and Throat and Head and Neck Surgery, Ankara Yıldırım Beyazıt University Faculty of Medicine, Ankara, Turkey
Kuwait Medical Journal 2021; 53 (1): 51 - 55
ABSTRACT
Objective: To determine the effect of stapes footplates Results: In the white otosclerosis group, female gender color on the intraoperative complications and outcomes of (P=.013) and bilaterality (P=.032) rates were higher than the otosclerosis surgery blue otosclerosis group. The air-bone gap closure was 22 Design: Retrospective study dB in white otosclerosis, 15 dB in blue otosclerosis and 16 Setting: Ankara Numune Hospital database records dB in obliterative otosclerosis. The groups were evaluated between 2008 and 2011 in terms of the footplate complications that occur during Subjects: Eighty-six patients who underwent otosclerosis the operation. It was estimated that 44.2% of footplate surgery between 2008 and 2011 (38 male and 48 female) complications were seen in white otosclerosis, while this were conducted to the study. percentage was 3.4% in blue otosclerosis. No footplate Intervention: Patients were classified into three groups complications were found in obliterative otosclerosis. according to the stapes footplates macroscopic view before Conclusion: The intraoperative macroscopic evaluation stapedectomy application as blue (67%), white (21%) and of the color changes of stapes footplate was found to be obliterative (12%). significant in terms of intraoperative complications. Related Main outcome measures: Among the groups, with this, to decrease intraoperative complication rate, well- demographical variables, preoperative and postoperative experienced surgeons should evaluate the stapes footplate air-bone gap, gain scores and intraoperative complications color before stapedectomy procedure and beginner surgeons were investigated. should gain experience in cases of blue otosclerosis.
KEY WORDS: footplates color, otosclerosis, stapes surgery
INTRODUCTION Regarding the etiology of otosclerosis, there have Otosclerosis is a primary disease of the otic capsule been various theories put forth, such as hereditary, and it is commonly seen in female gender between endocrine, biochemical, metabolic, vascular, infectious the ages of 15-45 years[1]. In pathophysiology, the and the anatomic or histological abnormalities of the hearing loss occurs due to the abnormal destruction otic capsule. The main complaint of otosclerosis is and formation of the labyrinthine capsule. According hearing loss which is related with the location and to the location of otosclerotic focus, otosclerosis was the severity of the otosclerotic focus. A majority of classified as stapedial (fenestral), cohlear or mixed patients (80-90%) with otosclerosis are affected by type[2,3]. fissula antefenestram localized at the anterior of the
Address correspondence to: Serkan Çayir MD, Otorhinolaryngologist, Department of Ear Nose and Throat and Head and Neck Surgery, Aksaray University Faculty of Medicine, Turkey. Tel: +905054358634; Fax: +903822129109; E-mail: [email protected] March 2021 KUWAIT MEDICAL JOURNAL 52 oval window, and when the fissula antefenastram variables were shown as median (minimum - is involved, the location and range affects both the maximum) or as number of subjects and percentage. clinical presentation of the disease and the macroscopic The significance of the difference between the groups appearance of the footplate. Also, round window in terms of continuous variables was analyzed by is involved in 31% of cases, 12% footplate and 14% using bivariate t-test and the significance of difference anteroinferior cochlea substructure is kept[4]. Although in terms of gradable variables was analyzed by using otosclerosis does not have a cure, the treatment of Kruskal Wallis test. In case the result of The Single the symptoms (i.e., hearing loss) is possible and the Direction Variance Analysis or the Kruskal Wallis test results are satisfactory. Recently Malafronte et al had statistic was found to be significant, the post hoc Tukey classified otosclerosis as blue, white and obliterative or multiple comparison tests was used to determine according to the color of the stapes footplate in the conditions causing the difference. The nominal macroscopic view, and they had reported significant variables were assessed with Pearson’s Chi Square relationship between the macroscopic appearance test. Results for P <.05 were considered statistically and the frequency of complication[4]. The aim of this significant. Written informed consent was obtained study is to investigate the relationship between the from all participants as well as from the local Ethics demographic data, hearing results and intraoperative Committee. complication rates of the patients according to their footplate color. RESULTS Thirty-eight (44.2%) of the 86 patients participating SUBJECTS AND METHODS in the study were male and 48 (55.8%) were female. The The data of 86 patients who attended our clinic mean age of the patients was 39.5±10.0 years (range: with a complaint of hearing loss between January 2008 17-61 years). Bilateral hearing loss was determined in and September 2011 and who were operated with a 23 (53%) patients and four (9.3%) patients had a history pre-diagnosis of otosclerosis were included in this of otosclerosis in the family. The mean duration of retrospective chart study. The surgery notes, surgery hearing loss complaint of the patients was 5.2 (±3.0) videos, audiometric examinations, tympanometry, (range: 1-15) years. Twenty-four patients (55.8%) had acoustic reflex test and temporal CT results of the tinnitus and one patient (2.3%) had vertigo. patients were assessed retrospectively. All patients In the intraoperative macroscopic assessment, blue preoperative and postoperative pure tone audiometry otosclerosis was detected in 58 (67.4%) patients, white scores were calculated at the frequencies of 0.25, 0.5, 1, otosclerosis in 18 (20.9%) patients and obliterative 2, and 4 kHz.(8q), speech discrimination scores, graft otosclerosis in 10 (11.6%) patients. The comparison of status, gain scores and air-bone gaps (ABG) recorded the demographic variables for groups was shown in in controls of 1, 2, 3, 6 and 12 months. Intact graft Table 1. and dry ear on the operated side and ABG under 10 db were taken as success. Gain score was obtained by calculating the difference of postoperative and Table 1: Comparison of demographic variables between groups preoperative ABG scores. Classification according Characteristics The same surgeon performed all surgeries by using to the footplate types transmeatal modified rosen incision. The surgery notes Group Blue White Obliterative of the patients were investigated and scanned, and the Incidence rate 67% 21% 12% patients were grouped as blue, white, and obliterative Average of age 39 42 45 according to the footplate color and pathology. In all Gender distribution Female 52%* 100%* 20% cases, “small fenestra” stapedotomy was performed Male 48% 0% 80% and 0.6 mm teflon piston was used. The length of Average hearing loss period (year) 5 6.5 4 the prosthesis was determined by measuring the Tinnitus 55.2%* 78%* 80%* incus long arm and the footplate and this length was Bilaterality ratio 44.8%* 66.7%* 80%* Family history 7%* 22%* 0% between 4.25-4.75 mm. Postoperative patients were hospitalized for three days on average. The follow- * Statistically significant (P <.005) up period for the patients regarding postoperative complications after the surgery was 12.3±2.8 (8-24) When postoperative hearing results were months in average. compared, mean airway threshold gain in patients The data were analyzed using SPSS for Windows was 18.7 dB, bone way threshold gain was 4 dB and 11.5 package. The descriptive statistics for continuous ABG gain was 14.72 dB in blue otosclerosis group. variables were indicated as mean ± standard deviation While a statistically significant gain in airway (P=.001) and for nominal variables, they were indicated as and ABG (P=.001) was detected in blue otosclerosis the number of subjects and percentage. The gradable group, the recovery in bone way (P=.12) was not 53 Considering the effect of Stapes Footplate’s macroscopic vision on surgical complication rate March 2021 found to be significant. Mean airway gain in patients stage with major risk in failure on surgical outcomes is with white otosclerosis was determined as 24.1 dB, the stapedectomy and placing the hearing prosthesis. bone way gain as 2.4 dB and the ABG gain was 21.6 To foresee the complications which may occur at this dB. While a statistically significant gain was detected stage, different factors like narrow footplate, broken in airway (P=.002) and ABG (P=.001), the recovery in or floating footplate and the effect of removing the bone way (P=.57) was not found to be significant. Mean footplate partially or in whole were asserted[7,8]. airway gain in patients with obliterative otosclerosis Recently in a study conducted by Malafronte was detected as 16.8 dB, bone way gain was 1.2 dB et al, the complication occurrence according to the and the ABG gain was 15.6 dB. While no statistically macroscopic appearance of the footplate in 106 significant gain was obtained in airway (P=.14) and otosclerosis patients were investigated and it was in bone way (P=.87), the recovery in the ABG (P=.01) reported that footplate complications were more was determined to be significant. The incidence of common in white otosclerosis than blue otosclerosis bilaterality (P=.012), tinnitus (P=.035) and family by using manual perforator (54.5%). It was history (P=.22) was significantly high in obliterative emphasized that white otosclerosis surgery requires and white otosclerosis group rather than blue based more experience, and the importance of using laser in otosclerosis. such patients was highlighted[4]. In this study, it was Dehiscence of facial canal was detected in one reported that macroscopic footplate view was useful patient in blue otosclerosis group and two patients in to predict possible complications during footplate white otosclerosis group. Additionally, protrude facial perforation. In terms of pathogenesis, the places of canal was found in one patient in blue otosclerosis otosclerosis focus in blue and white footplates and the group, three patients in white otosclerosis group and difference of their density were highlighted and they three patients in obliterative otosclerosis group. showed that, while the footplate was typically limited In white otosclerosis group, footplate complication to the oval window rim and has an isolated uptake in rate was statistically higher than the blue otosclerosis blue otosclerosis, the white otosclerosis was denser group (Table 2). Six footplate fractures, one perilymph and has a generalized uptake. Due to these differences, gusher and one floating footplate were found in white they reported that there are fewer complications in otosclerosis group. However, only two footplate blue otosclerosis group at the footplate mobilization fractures were seen in blue otosclerosis group. stage. In our study, when the demographic findings of Table 2: Perioperative findings of patients the patients were compared according to the footplate color, although there was significant difference in the Classification according average age of the patients in blue otosclerosis group, Characteristics to the footplate types they were younger (P=.033). Here, at the early stages Blue White Obliterative of otosclerosis, as the metabolic stability was not Perioperative footplate totally accomplished and as the otosclerosis focuses complication ratio 3.4% 44.2% 0% were localized in anterior fenestra, it is possible to say Facial nerve abnormalities 3.4% 27.5% 30% Postoperative Air - Bone gap that blue footplate is in favor of occurring at younger gain (dB) 14.7 21.6 15.6 ages. In the formation of otosclerosis focus, there is an early spongiotic phase, then a fibrotic phase and In patients with obliterative otosclerosis group, at last a sclerotic phase[9]. When it is evaluated in this protrude facial canal was detected in three patients context, it is possible to tell that the bluish appearance and no footplate complications were found. of the footplate macroscopically arises from increased vascularity on the footplate at the early phase and the DISCUSSION accumulation of plenty of monocyte, osteoblast and The stapes surgery maintains its characteristics osteoclast as isolated at the antefenestra. At the sclerotic to be the fundamental method in the treatment of phase, which occurs with the decrease of osteoblast on otosclerosis since the mobilization surgery that Rosen the footplate with the progress in the process of the started in 1950’s. To obtain the most satisfactory disease, formation of new bone tissue consisting of outcomes from the surgery, various methods such as plenty of collagen tissue and little connective tissue, stapedectomy, stapedotomy, stapedotomy with stapes the footplate is monitored as white or obliterative tendon reconstruction and laser stapedotomy were macroscopically. In other words, we think that while defined[5,6]. Otosclerosis surgery requires particular blue otosclerosis represents a form at an early or more attention in every stage and surgeon’s experience is limited stage, white and obliterative otosclerosis are a very important. Every stage of surgery includes its form of otosclerosis that progress more aggressively or selfish complication risk; however, the most critical with a more extensive uptake. March 2021 KUWAIT MEDICAL JOURNAL 54
The female to male ratio in patients with otosclerosis connected to the pathological vascularization of the was reported to be 1.6/1 - 2/1[10]. As it is more common in otosclerosis lesion in labyrinth capsule[18]. In white women than men, although it is debated, the hormonal and obliterative otosclerosis, which we consider as the factors were charged with otosclerosis relation. Despite advanced stage of the disease, the increased frequency the effect of hormonal factors on the disease, question of tinnitus reinforces our thesis. marks arise as the symptoms do not deteriorate while When it is assessed in terms of perioperative taking oral contraceptives and throughout pregnancy. footplate complications, 3.4% of footplate complications The increase in the frequency within a short period was detected in blue otosclerosis and 44.2% in white after pregnancy and the female dominance in the otosclerosis (P=.001). Most of the blue footplate is disease support the idea that hormonal factors may be constituted by healthy and elastic bone, resistant to effective, which should be investigated[11,12]. trauma owing to the performing of the footplate hole Again, parallel to this idea, as all the patients with and the removal of stapes superstructure. In white white otosclerosis were females (P=.013) and due to otosclerosis, the footplate is well welded to the annular higher bilaterality rates (P=.032), this may indicate ligament by the otosclerotic focus that involves most that there is an effect of hormonal and genetic factors of the footplate, which becomes white, fragile and typically charged for the occurrence of footplate less resistant to trauma[19]. Thus, as the force applied color and disease etiopathogenesis[13]. In addition, to the hard footplate would cause further multiple a difference by 10 times between the occurrence of and unforeseen footplate fractures, the footplate clinical otosclerosis and histological otosclerosis complications are more frequent in white otosclerosis. findings also reveals the existence of multifactorial Again, as white otosclerosis is more vulnerable against factors in the reflection to clinic and the progress rate trauma compared to blue otosclerosis, vestibule of the otosclerosis disease[14]. As our study clinically damages due to uncontrolled force applied with focused on complications, we think that analyzing manual perforator and the occurrence of perilymph the variability of demographic, hormonal and genetic fistula is more possible than in blue otosclerosis. factors according to footplate color in terms of In our study, the complication ratio of the footplate histopathology in further studies may be more useful. in obliterative otosclerosis was significantly low When the effect of footplate color on hearing level compared to white otosclerosis (P=013). Here, the was investigated, while significant hearing gain was lower complication ratio in obliterative otosclerosis provided in both postoperative groups, more recovery may be linked to the fewer number of patients and in white otosclerosis was detected in terms of ABG the surgeons increased attention when obliteration is gain. The better gain scores in white otosclerosis, as detected during surgery. a result of the total uptake of the footplate, causes a The success and the decrease in the complication worse airway hearing threshold in white otosclerosis rates in tympanoplasty surgeries are directly related to (white: 57.4 dB, blue: 50.5 dB) and it arises from a the experience of the surgeon. In the study conducted better airway gain in white otosclerosis after footplate by Emir et al, the success ratio of the surgeries mobilization compared to blue footplate otosclerosis. performed by the specialists was 16% rather than Sensorineural hearing lose may be seen with the residents’ operation success and pointed out that fenestral otosclerosis with the incidence of 10% the increased experience in tympanoplasty surgery additive to conductive otosclerosis due to the contact increases the success rate[20]. Likewise, using footplate of toxic proteolytic enzymes produced in otosclerotic color classification may be effective in decreasing foci to inner ear[15,16]. Later on, atrophy of the spiral the complication rates and in increasing success in ligament and stria vascularis, as well as the formation otosclerosis surgery. of hyalinization in the spiral ligament, have been One of the most critical points in stepedectomy seen to be responsible for hearing impairment surgery is footplate perforation, and complications by hindering recycling ions and by reducing the in different ratios are observed depending on the endocochlear potential with subsequent cochlear hair perforation method used. In the review of Wegner cell dysfunction[17]. With these findings, we consider et al, in laser assisted stapedotomy procedures, less that failing to achieve hearing results in obliterative footplate fractures and sensorineural hearing loss otosclerosis as good as in white otosclerosis (preop occurrence was reported compared to conventional bone ways: obliterative-28 dB, white-22.56 dB) may stapedotomy procedures, and they recommended laser occur as a result in the increased sensorineural utilization[21]. In the study of Malafronte et al conducted damage, with the otosclerosis reaching the cochlear in 2011, where the effect of footplate color in the endosteum due to the progress of the disease. Again, selection of perforation method was analyzed, it was the frequency of tinnitus in the advanced stages of stated that more footplate complications occur when otosclerosis and in cochlear uptake is asserted to be conventional technique was applied in otosclerosis 55 Considering the effect of Stapes Footplate’s macroscopic vision on surgical complication rate March 2021 with white footplate due to the excessively fragile 5. Rizer FM, Lippey WH. Evolution of techniques of footplate and therefore, using laser in white otosclerosis stapedectomy from the total stapedectomy to the small would reduce these complications[22]. In the study fenestra stapedectomy. Otolaryngol Clin North Am we conducted, a perforation was performed using 1993; 26(3):443-451. 6. Shea JJ. Stapedectomy- technique and results. Am J conventional method as routine in the stapes footplate Otol 1985; 6(1):61-62. and the complication ratios in white otosclerosis were 7. Fisch U. Stapedetomy versus stapedectomy. Am J Otol determined to be higher. Therefore, in compliance 1982; 4(2):112-117. with the literature, we think it would be more effective 8. Bailey Jr HA, Pappas JJ, Graham SS. Small fenestra that surgeons with insufficient experience prefer laser stapedectomy technique: reducing risk and improving stapedotomy to reduce complications when they hearing. Otolaryngol Head Neck Surg 1983; 91(5):516- encounter white footplate appearance. Additionally, 520. to ensure the ability to foresee the color of the footplate 9. Lim DJ, Robinson M, Saunders WH. Morphologic and to start the surgery as prepared, it would be and immunohistochemical observation of otosclerotic stapes: a preliminary study. Am J Otolaryngol 1987; appropriate to conduct new researches. 8(5):282-295. 10. Arnold W, Niedermeyer HP, Schuster M, Neubert WJ, CONCLUSION Baumann C, Sedlmeier R. Persistent measles virus Considering the footplate’s color intraoperatively infection and otosclerosis. Ann Otol Rhinol Laryngol is a critical fact in the predictability of complication 2001; 110(10):897-903. formation. Intraoperative macroscopic evaluation of 11. Lippy WH, Berenholz LP, Schuring AG, Burkey JM. stapes footplate color was found to be significant in Does pregnancy affect otosclerosis? Laryngoscope terms of intraoperative complications. Related with 2005; 115(10):1833-1836. this, to decrease intraoperative complication rate, 12. Vessey M, Painter R. Oral contraception and ear disease: findings in a large cohort study. Contraception well-experienced surgeons should evaluate the stapes 2001; 63(2):61-63. footplate color before stapedectomy procedure and 13. Morrison AW. Genetic factors in otosclerosis. Ann R beginner surgeons should gain experience in cases of Coll Surg Engl 1967; 41(2):202-237. blue otosclerosis. 14. Declau F, Van Spaendonck M, Timmermans JP, Michaels L, Liang J, Qiu JP, et al. Prevalence of ACKNOWLEDGMENTS otosclerosis in an unselected series of temporal bones. Consent: Written informed consent was obtained Otol Neurotol 2001; 22(5):596-602. from all participants as well as from the local Ethics 15. Karosi T, Sziklai I. Etiopathogenesis of otosclerosis. Committee. Eur Arch Otorhinolaryngol 2010; 267(9):1337-1349. 16. Schrauwen I, Van Camp G. The etiology of otosclerosis: Conflict of Interest:No conflict of interest was declared a combination of genes and environment. by the authors. Laryngoscope 2010; 120(6):1195-1202. Financial Disclosure: This was not an industry- 17. Doherty JK, Linthicum FH Jr. Spiral ligament and stria supported study. The authors declare that this study vascularis changes in cochlear otosclerosis: effect on has received no financial support. hearing level. Otol Neurotol 2004; 25(4):457-464. Author contribution: Serkan Cayir wrote the 18. Cureoglu S, Baylan MY, Paparella MM. Cochlear manuscript, Mehmet Ali Cetin did the critical review, otosclerosis. Curr Opin Otolaryngol Head Neck Surg Hacer Baran reviewed the literature, Serdar Ensari 2010; 18(5):357-362. designed the study and Haci Huseyin Dere created the 19. Malafronte G, Filosa B. Fisch’s reversal steps stapedotomy: when to use it? Otol Neurotol 2009; study concept. 30(8):1128-1130. 20. Emir H, Ceylan K, Kizilkaya Z, Gocmen H, REFERENCES Uzunkulaoglu H, Samim E. Success is a matter of experience: type 1 tympanoplasty: influencing factors 1. Gapany-Gapanavicius B. The incidence of otosclerosis on type 1 tympanoplasty. Eur Arch Otorhinolaryngol in the general population. Isr J Med Sci 1975; 11(5):465- 2007; 264(6):595-599. 468. 21. Wegner I, Kamalski DM, Tange RA, Vincent R, Stegeman 2. Schuknecht HF, Kirchner JC. Cochlear otosclerosis: fact I, van der Heijden GJ, et al. Laser versus conventional or fantasy. Laryngoscope 1974; 84(5):766-782. fenestration in stapedotomy for otosclerosis: A 3. Hueb MM, Goycoolea MV, Paparella MM, Oliveira JA. systematic review. Laryngoscope 2014; 124(7):1687- Otosclerosis: the University of Minnesota temporal 1693. bone collection. Otolaryngol Head Neck Surg 1991; 22. Malafronte G, Filosa B, Barillari MR. Stapedotomy: is 105(3):396-405. the color of the footplate important in the choice of 4. Malafronte G, Filosa B, Cantone E. New macroscopic the type of perforator? Otol Neurotol 2011; 32(7):1047- classification of stapedio-ovalar otosclerosis: a 1049. simplified rating for training in stapedotomy. Otol Neurotol 2008; 29(7):889-892. March 2021 KUWAIT MEDICAL JOURNAL 56
Original Article Preliminary findings: Functionality in patients with migraine
Fatos Kirteke1, Nilufer Cetisli-Korkmaz2, Taskin Duman3 1Department of Therapy and Rehabilitation, Nevsehir Haci Bektas Veli University, Kozakli Vocational School, Nevsehir, Turkey 2School of Physiotherapy and Rehabilitation, Pamukkale University, Denizli, Turkey 3Tayfur Ata Sokmen Medicine Faculty, Department of Neurology, Hatay Mustafa Kemal University, Hatay, Turkey
Kuwait Medical Journal 2021; 53 (1): 56 - 62
ABSTRACT
Objective: Migraine-related pain is not only an unpleasant intensity and the effects of pain on daily life, fine hand experience, but also has negative effects on all aspects of dexterity, strength and endurance of lower extremity and life. Although some disability parameters were handled balance were analyzed. in migraineurs, differential effects of migraine on hand Main Outcome Measures: Migraine Disability dexterity, dynamic balance and balance-related lower Assessment Scale, Nine Hole Peg Test, Four Step Square extremity muscle strength and endurance have not been Test, 11 Step Stair Climbing Test and Beck Depression reported yet. The aim of this study was to explore the Inventory functionality and disability levels of migraine patients. Results: It was determined that fine hand dexterity and Design: A cross-sectional study coordination and dynamic balance functions of migraine- Setting: Mustafa Kemal University, Tayfur Ata Sokmen diagnosed individuals were significantly affected Medicine Faculty (Department of Neurology, Headache compared to the migraine-free participants (P<.001, Clinic) and School of Physiotherapy and Rehabilitation, P<0.000). In terms of lower extremity muscle strength and Hatay, Turkey endurance, it was found that they were not different from Subjects: Forty volunteers aged between 18-55 years who migraine-free individuals (P>.05). were diagnosed with migraine and 40 age and gender- Conclusions: The migraine patients’ needs and preferences matched migraine-free individuals regarding functionality should be taken into consideration Intervention: In addition to the questionnaire including by neurologists and physiotherapists while planning and demographic information, emotional status, pain deciding treatment according to desired goals.
KEY WORDS: balance, dexterity, disability, endurance, migraine
INTRODUCTION brain, with peripheral consequences[3]. The association Migraine is a common headache disorder of migraine with vertigo and balance disorders is well characterized by nausea, hypersensitivity to various known. Migraine patients have been shown to have sensory inputs and recurrent attacks of moderate to balance problems, changes in stability limits, reduced severe, usually unilateral headache that lasts 4-72 walking and tandem walking speeds[4-8]. On the other hours, overlapping with various symptoms such hand, studies on balance function in migraine without as cognitive, emotional and motor symptoms[1,2]. aura have conflicting results. Although migraine is considered as a neurovascular The majority of migraine literature focuses on the disorder, current understanding points to the fact that trigeminal system and trigeminal associated areas; the migraine primary events happen at the level of the cerebellum has been included in migraine and interictal
Address correspondence to: Nilufer Cetisli Korkmaz, PT, PhD, Prof., Pamukkale Universitesi, Fizik Tedavi ve Rehabilitasyon Yuksekokulu, A Blok, 3. Kat, Kinikli Yerleskesi, 20070 Kinikli, Denizli, Turkey. Tel: 0090 258 2964289; Fax: 0090 258 2964494; E-mail: [email protected], [email protected]. ORCID ID: https://orcid. org/0000-0003-3471-8240 57 Preliminary findings: Functionality in patients with migraine March 2021 neurological signs for many years. The cerebellum than 18 and older than 55 were excluded from the participates in various forms of motor control and study. This study was approved by the local Ethics coordination[1]. In a study conducted in paediatric Committee of Mustafa Kemal University (326-221-33- migraine patients evaluating motor coordination, 17), in accordance with the Helsinki Declaration of children with migraine without aura showed poor 1975. Each volunteer participant signed the informed motor coordination skills compared to the control consent forms prior to the study procedure. group[9]. Several studies highlighted several functional outcomes in different medical conditions. Although Procedures influences of migraine on some disability parameters Migraineurs were tested during a headache- are handled with Migraine Disability Assessment free period, at least three days after the attack. In Scale (MIDAS), only few data are available about the addition to the structured questionnaire including clinical and functional outcomes of migraineurs. demographic characteristics, duration of migraine By identifying the high priority factors for illness and attack, headaches per month and associated functionality in migraine, a guideline for clinicians and headache symptoms, each patient’s functionality physiotherapists to adequately manage disability could levels were analyzed with the MIDAS, Nine Hole Peg be suggested. As such, the purpose of this study was to Test (NHPT), Four Step Square Test (4SST) and finally determine the level of depression, disability, fine hand 11 Step Stair Climbing Test (11SSCT). Questionnaires dexterity, dynamic balance, balance-related lower and functional tests were applied to all participants by extremity muscle strength and endurance in migraine the same physiotherapist in the clinical setting. patients without aura and to compare them with Beck Depression Inventory (BDI) is a 21-item scale migraine-free individuals to identify the functionality developed to measure the severity of depression. Each implications for migraine patients without aura. item can score from 0 to 3 and the total score is between 0 to 63. BDI scores between 0 and 9 are considered to SUBJECTS AND METHODS denote no depression, 10-18 denote mild depression, Study design 19-29 denote moderate depression and 30-63 denote This study is designed to determine the level of severe depression[10]. depression, disability, fine hand dexterity, dynamic MIDAS is a scale used to determine how severely balance, balance-related lower extremity muscle migraine affects a patient’s life. Patents who suffer strength and endurance in patients with migraine headache are asked to answer five questions related to with a cross-sectional design. This study is reported their days of partial or total loss within the past three in accordance with the Strengthening the Reporting of months with respect to paid work or school, household Observational studies in Epidemiology requirements. chores and family, social and leisure activities. Disability level is identified as little or no disability (0- Participants 5); mild disability (6-10); moderate disability (11-20) This cross-sectional study was performed in or severe disability (21 or higher). MIDAS evaluates headache outpatient clinic of Neurology Department. headache frequency and pain intensity (0: no pain; 10: Forty migraine participants between the ages of 18- very severe pain) over the past three months[10,11]. 55 years who were diagnosed with migraine by a NHPT is a simple and fast dexterity test that is neurologist with expertise in headache and who used to observe the fine hand motor coordination and volunteered to participate were included to the manual skills. Test material consists of 9 small sticks study. Forty age and gender matched migraine-free and a 9-hole board. The test is done with both right and volunteer individuals were also included. Any and left hands three times and evaluated by calculating participants with severe systemic and orthopedic the average of them[12]. 11SSCT is used to evaluate problems, who are pregnant and who are younger lower extremity muscle strength and endurance[13].
Table 1: Demographic and clinical characteristics
Diagnosis with migraine Migraine-free control Demographics X SD X SD t P Age (year) 36.750 10.33 36.750 10.330 0.000 1.000 Height (cm) 164.950 6.516 164.600 7.808 1.042 .301 Weight (kg) 25.497 4.629 26.239 4.389 -0.736 .464 BDI 69.225 11.898 71.200 13.321 -0.699 .486 MIDAS 21.050 19.595 - - - - t: Independent Samples t Test; P<.05; BDI: Beck Depression Inventory; MIDAS: Migraine Disability Assessment Scale. March 2021 KUWAIT MEDICAL JOURNAL 58
Table 2: Comorbidities
Diagnosis with migraine Migraine-free control Comorbidities Within the Within the n Total (%) n Total (%) χ2 P group (%) group (%) Asthma 1.053 .305 No 37 92.5 46.2 39 97.5 48.8 Yes 3 7.5 3.8 1 2.5 1.2 Allergic Illnesses 0.392 .531 No 33 82.5 41.2 35 87.5 43.8 Yes 7 17.5 8.8 5 12.5 6.2 Disk Herniation 4.943 .026* No 24 60 30 33 82.5 41.2 Yes 16 40 20 7 17.5 8.8 Panic Attacks 0.346 .556 No 38 95 47.5 39 97.5 48.8 Yes 2 5 2.5 1 2.5 1.2
χ2 Test, *P<.05
Patients were requested to step up in an 11-step stair with respect to age, body weight and height (P>.05, with normal daily walking speeds and not wait to Table 1). step down. The time was started with the first step It was observed that the percentage of individuals and was terminated when the last step was taken. The with asthma, allergic illnesses and panic attacks was test was repeated three times with three minute rest low in both groups (P >.05). While 16 of the participants intervals and the average of the durations was taken had cervical disk herniation in the migraine group, in seconds[14]. 4SST is used to test dynamic balance. only seven had cervical disk herniation in the control Four frames are created on a flat surface for testing. All group and the difference of distribution between the squares are numbered. At the start of the test, patient two groups was statistically significant (P <.05, Table 2). steps rapidly in a sequential manner (2-3-4-1-4-3-2-1) The emotional status of the individuals with frames[15,16]. migraine and the migraine-free individuals were analyzed according to their mean BDI score and the Statistical analysis level of their emotional status. While there was no Mean and standard deviation were used for significant difference among the groups’ mean BDI descriptive statistics. Comparisons between groups scores (P >.05, Table 1), the distribution of participants were conducted by Independent Sample t-Test according to the emotional status level was statistically (Statistical Package for Social Sciences 15.0). For different between the groups (P=.005, Table 3). We categorical variables, chi-square test was used. For recorded that 17.5% of individuals diagnosed with the multiple comparisons, P<.05 was considered migraine and 50% of the migraine-free individuals had significant. normal emotional status, while 35% of the individuals diagnosed with migraine and 10% of the migraine-free RESULTS individuals had medium level depression (Table 3). The age of the participants with migraine ranged We compared the groups’ functional level with between 18-55 years. The mean age of the participants different functionality-based tests. NHPT mean score with migraine and migraine-free individuals were for right hand in migraine group was 17.85±1.64 36.75±10.33 years. The groups had a similar distribution sec and 16.01±1.24 sec in the control group, while
Table 3: Emotional status
Diagnosis with migraine Migraine-free control Emotional status Within the Within the n Total (%) n Total (%) χ2 P group (%) group (%) Normal 7 17.5 8.8 20 50 25 12.847 .005* Mild 16 40 20 15 37.5 18.8 Moderate 14 35 17.5 4 10 5 Severe 3 7.5 3.8 1 2.5 1.2
χ2 Test, *P=.005 59 Preliminary findings: Functionality in patients with migraine March 2021
Table 4: Functionality levels
Diagnosis with migraine Migraine-free control Functionality levels min. max. X SD min. max. X SD t P NHPT (sec) Right 14.49 21.34 17.85 1.64 13.78 18.40 16.01 1.24 5.662 .000* Left 14.84 23.63 19.12 2.15 13.54 20.18 17.36 1.57 4.180 .000* 11SSCT (sec) 8.25 17.76 11.83 2.25 7.63 18.05 11.37 2.12 0.943 .350 4SST (sec) 5.63 11.60 8.18 1.30 5.48 9.61 7.17 1.02 3.877 .000* t: Independent Samples t Test; * P<.001. NHPT: Nine Hole Peg Test; 11SSCT: 11 Steps Stair Climbing Test; 4SST: Four Steps Square Test the left-hand averages were 19.12±2.15 sec and activities at home and at the workplace[20]. Our subjects 17.36±1.57 sec, respectively (P <.001). The 11SSCT denoted an intermediate level disability according to mean scores were 11.83±2.25 sec and 11.37±2.12 sec the MIDAS score (21.05±19.60, Table 1). Our migraine and respectively (P >.05). Additionally, the mean patients’ mean MIDAS score was similar with the other 4SST scores were 8.18±1.30 sec and 7.17±1.02 sec, reported studies done in Turkey (19.3±12.3)[21], while respectively (P <.001). We observed that fine hand it was less than those reported from United States of dexterity and balance functions were affected America (34.9 in the group with chronic migraine) in the participants with migraine in our study [22], Ethiopia (46.7±30)[23] and Korea (24.1±26.9)[24]. (P=.000), but their lower extremity muscle strength The reason for the differences may depend on our and endurance score was not different from the homogeneous sample, because all our participants migraine-free individuals’ (P >.05, Table 4). were migraine sufferers without aura. The other reasons could be ethnicity and cultural characteristics. DISCUSSION It is reported that depression occurs more often Migraine is a primary neurological disease, in migraine patients in comparison with the general particularly in individuals younger than 50 years, population[21,23,25,26]. Considerable evidence confirms and leads to substantial incapacitation. Migraine is that it is bidirectional in nature, unique to migraine identified as a leading cause of disability worldwide headache and significant relationship between according to the ongoing Global Burden of Diseases, depression and migraine, particularly migraine with Injuries and Risk Factors Study[17]. The effect of migraine aura. Especially, depression could be seen in 30% of is not only felt during attacks, but also between attacks, the young and adult migraine patients. Baldacci et al and it takes a toll on the patient’s emotional as well stated that 40% of migraineurs had non-depression as physical well-being[18]. Although some disability symptoms, 42.5% mild, 12.5% moderate and 5% had parameters were handled in migraineurs, differential severe depression symptoms in their study[27]. When effects of migraine on hand dexterity, dynamic balance we compared the migraineurs with migraine-free and balance-related lower extremity muscle strength individuals’ distributions according to the emotional and endurance have not been reported yet. As such, status levels, a statistically significant difference was this study aimed to explore the disability in migraine recorded (P=.005, Table 3), while the mean scores of the patients without aura, hypothesizing that patients BDI was not different in total (P >.05, Table 1). 17.5% with migraine exhibit functional disabilities according of individuals diagnosed with migraine and 50% of to the age-gender matched migraine-free individuals. the migraine-free individuals had normal emotional This study also investigated the functionality from status, while 35% of the individuals diagnosed with different aspects such as the emotional status, fine migraine and 10% of the migraine-free individuals hand dexterity, dynamic balance, balance-related had medium level depression (Table 3). It appears lower extremity muscle strength and endurance. that more migraineurs have depressive symptoms, Migraine headache often leads to disability by especially for the medium level. Additionally, the preventing social activities and work productivity[19]. high prevalence of depression symptoms (82.5% of Although all of the individuals who participated in cases) in our sample confirmed the broad existent our study were migraine patients without aura and literature data about the comorbidity of migraine with they were taken into consideration at least three days depressive symptoms. From a clinical point of view, after the attack, it was observed that their daily life clinicians and physiotherapists have to be aware that was affected almost severely. Disability due to severe in the presence of anxiety and depression, symptoms headache and frequency of pain may lead to physical may not only influence the pain perception but also be weakness, which may pose a barrier to normal physical associated with an enhanced general sensation during March 2021 KUWAIT MEDICAL JOURNAL 60 the migraine attack[27]. Therefore, emotional status diagnosed with migraine according to the controls[17]. screening should be mandatory for migraine patients It has been determined that balance functions are for functionality. negatively affected from migraine, same as in fine Migraine can appear together with different hand dexterity. The migraine patients’ 4SST mean diseases[28]. Afferent inputs in the cervical structures scores were significantly higher than the migraine- can facilitate cranio-cervical pain, which is associated free individuals’ (P=.000, Table 4). While the migraine with migraine. Pain in migraine is perceived in patients were without aura and in their pain free term, the upper cervical (C2-3) and the trigeminal nerve finding deterioration in balance is an evidence for us to dermatomes which were required for the activation focus on balance from the early stage. of trigemino-vascular nucleus[29]. It was recorded that We could not find a study focusing on the 16 of our participants with migraine had cervical disk strength. Meanwhile, studies focusing on fatigue herniation, while just seven migraine-free individuals prevalence in patients with migraine are few and due had cervical disk herniation (P <.05, Table 2). Therefore, to heterogeneous samples of headache patients, reveal it was thought that physiotherapy and rehabilitation conflicting results. It was stated that fatigue is likely approaches regarding migraine should be considered to be a migraine specific symptom and is one of the both with cervical disc herniation and migraine. commonly reported headache triggers[24]. We did not use In the latest studies concerning migraine without a specific fatigue questionnaire; instead we preferred aura in children, it has been observed that migraine to use 11SSCT to evaluate both strength and endurance without aura has an inclination to damage cognitive of balance-related lower extremity muscles at once. functions such as attention, memory, learning speed as Additionally, this test was a functional test based on a well as understanding. Esposito et al[9] observed that skill that we have to do every day. We determined that there was a significant difference in balance and fine the participants with migraine were not different from hand dexterity between the children with migraine the migraine-free individuals from the aspect of lower without aura and healthy children. Clinical studies extremity muscle strength and endurance. Depression, reported that in most migraine patients, vertigo, age, insomnia and headache intensity were major balance problems, posture dysfunction, dysarthria and factors for fatigue[24]. It is well known that there was dysmetria risks are high. It was demonstrated that most a vicious circle between muscle strength, endurance of these symptoms have a central base, but it could not with depression, fatigue and inactivity from the be exactly demonstrated yet that aura has an effect on perspective of health, well-being and quality of life. symptoms[1,4-9,30]. The assessment of cognitive functions As like this, fatigue may cause an additional impact on had not been involved in this present study’s protocol, daily life activities in migraineurs who were suffering but we observed the hand dexterity with NHPT. The from severe headache. In consideration of our clinical migraine patients’ NHPT scores for left side ranges experiences, we estimated that potential decrement between 14.84-23.63 seconds, while the migraine-free could exist in time with the direct effects of migraine individuals’ ranged between 13.54-20.18 seconds. and indirect effects of depression and fatigue. Hence, There was a significant difference for right side NHPT fatigue could be assessed with impact scales and scores, too. Therefore, it could be clearly seen that the potential muscle strength and endurance decrement NHPT scores’ ranges were wide for both sides. These in time could be analyzed with follow-up studies. results were important and showed that the migraine Additionally, chronic migraine and/or migraine with patients’ hand dexterity was significantly worse aura patients should be considered in the analysis, not than the migraine-free individuals’ (P=.000, Table 4). just the migraine patients without aura. Cognition, dysmetria and coordination could be taken It has been observed that cervical disk herniation’s into consideration with different test protocols in the effects may trigger migraine and 40% of our future studies. participants had reported that they have a diagnosis Previous studies have reported that patients with of cervical disk hernia. Thus, this has been accepted as migraine experience changes in balance, including a limitation of our study. The other limitations were deficits in static balance control and a reduction in the relatively small number of migraine population stability limits and gait velocity[4-8]. These impairments included and that all participants included were have been reported to exacerbate over a 1-year migraine patients without aura. For these reasons, the period. However, the clinical consequence to these results may have been underestimated, and further changes have not been investigated specifically. Rossi investigation in a wider population without cervical et al found increased postural releases in migraine disk herniation and with aura is needed. Despite these patients[8]. Carvalho et al stated that the results of limitations, this study has an important contribution their study showed a higher prevalence of falls and to the literature in showing the negative effects of self-reported impairment in balance in patients migraine on the sufferers’ functionality level, even 61 Preliminary findings: Functionality in patients with migraine March 2021 when the patients had migraine without aura and in All authors designed the study protocol and pain-free term. These results highlight an important substantial contributions to the conception or functional consequence of manual dexterity and the design of the work. PT. Kirteke and Dr. Cetisli- dynamic balance impairments observed in this cohort Korkmaz had full access to all the data in the suggest that these alterations are not subclinical. study and takes responsibility for the integrity Prevalence of deterioration could increase with time, of the data and the accuracy of the data analysis. as has been anticipated, so the clinical impact on They both have substantial contributions for the health and daily life would increase. Thus, more and acquisition, analysis and interpretation of data for intensive negative effects would be on functionality in the work. They have agreed to be accountable for patients with migraine. all aspects of the work in ensuring that questions Our patients with migraine were generally related to the accuracy or integrity of any part of the unaware of and/or underestimated the deterioration in work are appropriately investigated and resolved. their functionality. First of all, migraine pain is a very Dr. Duman had diagnosis and consultation of the disabling condition in its own right, therefore, all effort patients who participated in the study. Kirteke may be put into pain and symptom management. managed the first drafting of the manuscript. Dr. Secondly, functional declination that occurs in our Cetisli-Korkmaz provided revision, critically for migraine population may not cause significant important intellectual content and final approval of disability and/or injuries, so patients may ignore and/or the manuscript to be published. omit to report them. The mechanisms in relation with the inflammation during the attack occurs repeatedly, Conflict of Interest so these losses in functionality can become worse and The authors declare no conflicts of interest. lead to peripheral and central disorders[17]. Therefore, None of the authors of the manuscript received any while planning and configuring the assessment and remuneration. Further, the authors have not received treatment approaches for migraine patients, the most any reimbursement or honorarium in any other suitable perspective is taking into consideration the manner. functionality of the migraineurs in a multidisciplinary Presented as “Oral Presentation” in 3rd European manner from the early stages. Moreover, special Congress of NeuroRehabilitation 2015, Hofburg attention must be paid to investigate the functionality Congress Center Vienna, Austria. Titled as of migraine patients who were with aura and chronic “Functionality in patients with migraine” (F. Kirteke, and in attack term, through future studies. N. Cetisli Korkmaz, T. Duman; Hatay, TR)
CONCLUSION REFERENCES This study gives us evidence about the implications regarding functionality in migraine patients and 1. Kros L, Angueyra Aristizábal CA, Khodakhah K. informs us that migraine is associated with a risk of Cerebellar involvement in migraine. Cephalalgia deterioration in functionality, especially in manual 2018; 38(11):1782-1791. dexterity and dynamic balance in addition to the 2. Headache Classification Committee of the International Headache Society (IHS). The emotional status, while all participants were without International Classification of Headache Disorders, aura and in pain-free term. It was concluded that the 3rd edition. Cephalalgia 2018; 38(1):1-211. migraine patients’ needs and preferences regarding 3. Silberstein SD, Olesen J, Bousser MG, Diener functionality should be taken into consideration by HC, Dodick D, First M, et al. The International neurologists and physiotherapists while planning and Classification of Headache Disorders, (ICHD- deciding on the parameters according to the desired II)—revision of criteria for 8.2 Medication-overuse goals. By this paradigm, the most effective results could headache. Cephalalgia 2005; 25(6):460-465. be gained in overcoming the disability in patients with 4. Akdal G, Balcı BD, Angın S, Öztürk V, Halmagyı GM. migraine. A longitudinal study of balance in migraineurs. Acta Oto-Laryngologica 2012; 132(1):27-32. 5. Ongun N, Atalay NS, Degirmenci E, Sahin F, Bir LS. ACKNOWLEDGMENT Tetra-ataxiometric posturography in patients with We would like to thank Canan Altunisik for her migrainous vertigo. Pain Physician 2016; 19(1):E87- precious contributions in consulting the migraine 95. patients who participated in the study. Special thanks 6. Panichi R, Cipriani L, Sarchielli P, Di Mauro go to the all participants for their kind assistance with M, Pettorossi VE, Ricci G, et al. Balance control collecting their data. impairment induced after OKS in patients with Author contributions vestibular migraine: an intercritical marker. Eur Arch Otorhinolaryngol 2015; 272(9):2275-2282. March 2021 KUWAIT MEDICAL JOURNAL 62
7. Carvalho GF, Chaves TC, Dach F, Pinheiro CF, 19. Téllez-Zenteno JF, García-Ramos G, Zermeño-Pöhls Gonçalves MC, Florencio LL, et al. Influence of migraine F, Velazquez A, GGSM. Demographic, clinical and and of migraine aura on balance and mobility–a comorbidity data in a large sample of 1147 patients controlled study. Headache 2013; 53(7):1116-1122. with migraine in Mexico City. J Headache Pain 2005; 8. Rossi C, Alberti A, Sarchielli P, Mazzotta G, Capocchi G, 6(3):128-134. Faralli M, et al. Balance disorders in headache patients: 20. Shaik MM, Hassan NB, Tan HL, Gan SH. Quality of evaluation by computerized static stabilometry. Acta life and migraine disability among female migraine Neurologica Scandinavica 2005; 111(6):407-413. patients in a tertiary hospital in Malaysia. Biomed Res 9. Esposito M, Verrotti A, Gimigliano F, Ruberto M, Int 2015; 2015:523717. Agostinelli S, Scuccimarra G, et al. Motor coordination 21. Eraslan D, Dikmen PY, Aydınlar EI, İncesu C. The impairment and migraine in children: a new relation of sexual function to migraine-related comorbidity? European Journal of Pediatrics 2012; disability, depression and anxiety in patients with 171(11):1599-1604. migraine. J Headache Pain 2014; 15(1):32. 10. Dikmen PY, Aysevener EO, Kosak S, Aydınlar 22. Bigal M, Rapoport AM, Lipton RB, Tepper SJ, Sheftell EI, Kocaman AS. Relationship between MIDAS, FD. Assessment of migraine disability using the depression, anxiety and alexithymia in migraine migraine disability assessment (MIDAS) questionnaire: patients. Acta Neurol Belg 2020; 120(4):837-844. a comparison of chronic migraine with episodic 11. Özdemir G, Aygül R, Demir R, Özel L, Ertekin migraine. Headachen 2003; 43(4):336-342. A, Ulvi H. Migraine prevalence, disability, and 23. Ayele BA, Yifru YM. Migraine-related disability and co- sociodemographic properties in the eastern region of morbid depression among migraineurs in Ethiopia: a Turkey: A population-based door-to-door survey. Turk cross-sectional study. BMC Neurology 2018; 18(1):95. J Med Sci 2014; 44(4):624-629. 24. Seo JG, Park SP. Significance of fatigue in patients with 12. Grice Ko, Vogel KA, Le V, Mitchell A, Muniz S, Vollmer migraine. J Clin Neurosci 2018; 50:69-73. MA. Adult norms for a commercially available Nine 25. Antonaci F, Nappi G, Galli F, Manzoni GC, Calabresi Hole Peg Test for finger dexterity. Am J Occup Ther P, Costa A. Migraine and psychiatric comorbidity: 2003; 57(5):570-573. a review of clinical findings. J Headache Pain 2011; 13. Bennell K, Dobson F, Hinman R. Measures of physical 12(2):115-125. performance assessments: Self Paced Walk Test (SPWT), 26. Lee SH, Kang Y, Cho SJ. Subjective cognitive decline Stair Climb Test (SCT), Six Minute Walk Test (6MWT), in patients with migraine and its relationship with Chair Stand Test (CST), Timed Up & Go (TUG), Sock depression, anxiety, and sleep quality. J Headache Pain Test, Lift and Carry Test (LCT), and Car Task. Arthritis 2017; 18(1):77. Care Res (Hoboken) 2011; 63(S11):S350–S370. 27. Baldacci F, Lucchesi C, Cafalli M, Poletti M, Ulivi M, 14. Erdoğan Z, Atalay F. Romatoid Artritte Elektrik Vedovello M, et al. Migraine features in migraineurs Stimulasyonu Uygulamalarının Kas Kuvveti ve with and without anxiety–depression symptoms: A Fonksiyonellik Üzerine Etkisi. JPMR Sci 2011; 14:68-74. hospital-based study. Clin Neurol Neurosurg 2015; [Article in Turkish] 132:74-78. 15. Dite W, Temple VA. A clinical test of stepping and 28. İncekara Aydın F, Kutluhan S, Yürekli VA, Demirci change of direction to identify multiple falling older K, Akdağ C, Zengin E. Neurological and Psychiatric adults. Arch Phys Med Rehabil 2002; 83(11):1566-1571. Comorbidity in Migraine Patients. Turkiye Klinikleri 16. Wagner JM, Norris RA, Van Dillen LR, Thomas FP, Journal of Medical Sciences 2013; 33(1):59-66. Naismith RT. Four Square Step Test in ambulant 29. Robertson BA, Morris ME. The role of cervical persons with multiple sclerosis: validity, reliability, and dysfunction in migraine: a systematic review. responsiveness. Int J Rehabil Res 2013; 36(3):253-259. Cephalalgia 2008; 28(5):474-483. 17. Carvalho GF, Almeida CS, Florencio LL, Pinheiro CF, 30. Koppen H, Boele HJ, Palm-Meinders IH, Koutstaal BJ, Dach F, Bigal ME, et al. Do patients with migraine Horlings CG, Koekkoek BK, et al. Cerebellar function experience an increased prevalence of falls and fear of and ischemic brain lesions in migraine patients from falling? A cross-sectional study. Physiotherapy 2018; the general population. Cephalalgia 2017; 37(2):177- 104(4):424-429. 190. 18. Bryson J, Buse DC, Lipton RB. Assessment and treatment of the burden of migraine: a case series. Neurologist 2010; 16(4):254-261. 63 KUWAIT MEDICAL JOURNAL March 2021
Original Article Molecular epidemiology of Mycobacterium tuberculosis and rifampicin resistance among pulmonary tuberculosis patients in Erbil City, Kurdistan Region, Iraq
Fairuz H Abdullah Tawgozy, Bushra K Qarasnji Department of Biology, College of Science, Salahaddin University- Erbil, Kurdistan Region, Iraq
Kuwait Medical Journal 2021; 53 (1): 63 - 68
ABSTRACT
Objective: To evaluate the performance of Xpert were also positive by AFB smear microscopy. The sensitivity, Mycobacterium tuberculosis (MTB)/rifampicin (RIF) (Xpert specificity, positive and negative predictive values were MTB/RIF) assay for early diagnosis of pulmonary tuberculosis 96.26%, 90.86%, 33.97%, and 99.81% respectively. Fifty-six and detection of rifampicin resistance simultaneously, and samples out of 78 (71.79%) were positive by Xpert MTB/RIF compare the efficiency of Xpert MTB/RIF assay, acid-fast assay and negative by AFB smear microscopy. Similarly, bacilli (AFB) smear microscopy and culture techniques forty-seven (60.25%) cases were negative by culture but gave Design: Retrospective study positive result by Xpert MTB/RIF assay. The Xpert/MTBF Setting: Erbil Chest and Respiratory Diseases Center, Erbil, assay detected eleven (11/78, 14.10%) isolates as resistant to Iraq rifampicin, whereas by the proportion method, 40.62% of Subjects: Patients admitted between April 2016 and April isolates (13/32) were resistant to rifampicin. 2017 Conclusion: Xpert MTB/RIF is an efficient, rapid and reliable Intervention: Sputum samples obtained from 591 assay for diagnosis of MTB with higher sensitivity and consecutively recruited patients with signs and symptoms of specificity when culture or smear is negative. It provides tuberculosis (308 males (52.11%) and 283 females (47.88%)). enough information to start treatment as it is able to Main outcome measures: Sex, age, AFB smear, Lowenstein- detect rifampicin resistance MTB. It becomes clear that the Jensen culture grade and Xpert MTB/RIF assay proportion method of drug susceptibility testing is more Results: Seventy-eight of 591 samples (13.19%) were positive sensitive than Genexpert MTB/RIF assay in detecting RIF for MTB by Xpert MTB/ RIF’s assay, 22 (28.95%) of which resistant isolates.
KEY WORDS: AFB, culture, multidrug-resistant TB, Mycobacterium tuberculosis, Xpert MTB/RIF assay
INTRODUCTION Iraq occupies the 108th rank globally and the seventh Mycobacterium tuberculosis (MTB) is the principal position among the Eastern Mediterranean Region causative agent of tuberculosis (TB), an infectious countries with a high TB burden. About 3% of the total bacterial disease, in humans[1]. MTB alone is cases of TB exist in Iraq. In 2014, WHO estimated that responsible for over 90% of all cases of TB. It primarily there were 20,000 TB patients in Iraq, and deaths due affects the lungs (pulmonary TB), but more advanced to TB exceed 4000 annually. Estimated TB incidence forms of the disease can affect other organs and tissues rate was 45/100,000[4]. According to the survey of 2014, (extrapulmonary TB)[2]. Tuberculosis has a worldwide levels of drug resistance in Iraq was low (1.1%)[5]. distribution. The World Health Organization (WHO) Among methods of MTB diagnosis, acid-fast bacilli estimated that 10 million people had TB all over the (AFB) smear is the simplest one and gives quick results. world in 2017. TB occupies the ninth position among It has poor sensitivity and inability to differentiate leading causes of death, and about 1.4 million people rapid growers from slow growers (MTB). Although died of TB in 2017[3]. culture is slow and may take about eight weeks, it
Address correspondence to: Fairuz H Abdullah Tawgozy, Department of Biology, College of Science, Salahaddin University, Erbil, Kurdistan Region, Iraq. Tel: +964 7504899361; E-mail address: [email protected]. ORCID: https://orcid.org/0000-0001-6922-449X March 2021 KUWAIT MEDICAL JOURNAL 64 remains as the gold standard for diagnosing TB due to to the criteria of the WHO/International Union of its higher sensitivity and specificity compared to AFB Tuberculosis and Lung Diseases. smear[6]. Petroff’s method was used for digestion and Early diagnosis of TB is an essential step in taking decontamination of sputum samples. The sputum effective health measures. As a result, the techniques samples were mixed with an equal volume of 4% which depend on amplification of nucleic acids NaOH (Merk, USA) and vortex (IKA, Germany) for 20 have been developed for detection of MTB and drug seconds for homogenization[11]. The aliquot was used resistance. Early detection of multidrug-resistant TB to inoculate LJ slants. (MDR-TB, resistant to at least rifampicin (RIF) and The LJ slants were inoculated and incubated in a isoniazid) helps in preventing the spread of MDR- slant position for 48 hours at 37 °C; then the tubes were TB[7]. made to stand in an upright position. The slants were In 2010, the WHO approved the Xpert MTB/RIF test monitored daily during the first week for observation for simultaneous detection of TB as well as resistance of growth and then weekly for about eight weeks. The to RIF. Xpert MTB/RIF is a new cartridge based, positive cultures were subjected to Z-N staining for automated and rapid molecular diagnostic device. It confirmation of the presence of AFB. They were further performs sample processing and hemi-nested real- identified as M. tuberculosis by growth rate, pigment time PCR analysis in a single, hands-free step for production, colony morphology (small, whitish or identifying MTB and rapid detection of RIF resistance buff-coloured, dry, friable and rough), niacin test and in sputum samples. RIF is one of the critical first-line nitrate reduction. The absence of growth at the end of anti-TB drugs and is a reliable marker of MDR-TB. the 8th week was regarded as a negative culture[11]. All This test gives results within two hours[8-9]. culture positive isolates underwent drug susceptibility The present study aimed to evaluate the testing by proportional method on LJ according to the performance of Xpert MTB/RIF assay for early diagnosis standard instructions. LJ medium contained 0.25 μg/ of pulmonary TB and detection of RIF resistance ml rifampicin and 40μg/ml isoniazid. The slants were simultaneously as well as comparing its results with incubated at 37 °C and results were read at 28 days AFB smear microscopy and culture techniques. It also and up to 42 days, depending on control growth[12]. aimed at determination of the operational feasibility Drug susceptibility testing by proportion method is of Xpert MTB/RIF assay in detecting RIF-resistant TB considered as the gold standard. comparable to proportional method on Löwenstein– All the sputum samples were tested for the Jensen (LJ) medium. presence of MTB and RIF resistance by Xpert MTB/ RIF, the version G4 according to the manufacturer’s MATERIALS AND METHODS instructions. After labelling the Xpert MTB/RIF This study was done at Chest and Respiratory cartridge, the reagent was mixed with the collected Diseases Centre, Ministry of Health, Erbil, Iraq from sputum sample at a ratio of 2:1 (v/v) and shaken April 2016 to April 2017. Five-hundred and ninety- vigorously 10-20 times. The mixture was incubated for one suspected pulmonary TB patients with a cough 15 minutes at room temperature and shaken vigorously for more than two weeks, fever, weight and appetite 10-20 times every 5 minutes during the incubation. loss or positive chest X-ray were enrolled in this study Then, 2 ml of the decontaminated sputum sample was regardless of their age and sex. transferred into the open port of the Xpert MTB/RIF About 5-10 ml sputum samples (two deep cough cartridge slowly to prevent the formation of aerosol sputum samples, on-the-spot and early morning) and the cartridge lid closed. The cartridge was loaded were collected from each suspected pulmonary TB into the Xpert MTB/RIF instrument, and an automatic patient in sterile plastic cups. All sputum samples process completes the remaining assay steps. were submitted for Ziehl-Neelsen (Z-N) staining by ZN Stain Kit (Methylene Blue Counterstain) (Atom Statistical analysis Scientific, UK), culture on LJ (BBL™ Lowenstein- The sensitivity, specificity, positive predictive Jensen Medium Slants/USA) and Xpert MTB/RIF value and negative predictive value at 95% confidence Assay (Cepheid, Sunnyvale, CA, USA). interval level of significance were performed using Z-N staining method was performed for staining of MedCalc which is available online at (https://www. the sputum smears according to Sharma et al[10]. After medcalc.org/calc/diagnostic_test.php). the collection of two deep cough sputum samples, on- the-spot and early morning specimens, smears were Ethics approval prepared and stained using the standard method for Ethics approval was obtained from the ethical Z-N by Z-N Stain Kit (Methylene Blue Counterstain) board of the Chest and Respiratory Diseases Center, AFB smear microscopy technique. The results of smear Ministry of Health, Erbil, Iraq before the start of the microscopy were graded and reported according study. 65 Molecular epidemiology of Mycobacterium tuberculosis and rifampicin resistance among pulmonary ... March 2021
RESULTS Table 3: Two-by-two contingency tables comparing AFB smear and Five-hundred and ninety-one sputum samples the LJ culture (the gold standard) were collected from suspected pulmonary TB patients at Chest and Respiratory Diseases Center, Ministry Xpert MTB/ AFB smear results Performance Total of Health in Erbil, Iraq between April 2016 and April RIF results Positive Negative relative to culture 2017. Negative 19 10 29 PPV=65.52% Positive 3 559 562 NPV=99.47% Total 22 568 591 Sensitivity: 86.36% Table 1: Sensitivity and specificity of Xpert MTB/RIF assay Specificity: 98.24% compared to AFB smear results PPV: Positive predictive value; NPV: Negative predictive value; LJ: Xpert assay AFB smear results Performance Löwenstein–Jensen; AFB: acid-fast bacilli Total results Positive Negative relative to smear M. tuberculosis has distinctive biochemical MTB properties, some of which are utilised for identification detected 22 56 78 PPV=28.21% of various species. All of the M. tuberculosis MTB not isolates were positive for niacin, nitrate reduction, detected 1 512 513 NPV=99.81% Total 23 568 591 Sensitivity: 95.65% nicotinamidase, pyrazinamidase and binding of Specificity: 90.14% neutral red tests. They were catalase negative at room temperature and at 68 oC[11]. The identity of the isolates PPV: Positive predictive value; NPV: Negative predictive value; was confirmed by using the Xpert MTB/RIF assay. MTB: Mycobacterium tuberculosis; AFB: acid-fast bacilli The sheet of the results of identification by Xpert/MTB Twenty-two isolates were microscopically positive RIF system shows that the isolates were identified as (all positive by Xpert MTB/RIF assay). Among AFB Mycobacterium tuberculosis and sensitive or resistant to negative samples, 56 were positive by Xpert MTB/ RIF. RIF assay. Only one of the AFB positive isolates was Table 4: Sensitivity and specificity of LJ proportion method of drug negative by Xpert MTB/RIF assay as shown in Table susceptibility testing and GeneXpert MTB/ RIF assay for detection 1. That sample gave growth on LJ and was further of rifampicin resistance identified as Mycobacterium bovis by biochemical Genexpert MTB/ LJ tests. Out of 32 culture positive isolates, 31 gave a RIF assay Performance proportion Total positive Xpert MTB/RIF result and only one isolate relative to smear method RIF RIF was negative. Conversely, 47 culture negative results resistant sensitive were positive by Xpert MTB/RIF assay (Table 2). The RIF resistant 11 2 13 PPV=81.82% identity of the isolates was confirmed by cultural, RIF sensitive 0 65 65 NPV=100% morphological and biochemical characteristics. Total 11 67 78 Sensitivity: 100% Specificity: 97.01%
Table 2: Sensitivity and specificity of Xpert MTB/RIF assay PPV: Positive predictive value; NPV: Negative predictive value; compared to LJ culture LJ: Löwenstein–Jensen; RIF: rifampicin Among the 591 sputum samples which gave valid AFB smear results Performance LJ culture Total Positive Negative relative to smear results, MTB was detected in 78 samples by Xpert/ MTBF assay (Figure 1), and eleven of them were MTB detected 31 47 78 PPV=39.74% resistant to RIF. The proportion method detected 13 MTB not isolates as resistant to RIF, all of which were isoniazid detected 1 512 513 NPV=99.81% resistant, and hence considered as MDR-TB (Table 4). Total 32 559 591 Sensitivity: 96.88% Specificity: 91.59% DISCUSSION Since tuberculosis has a worldwide distribution, PPV: Positive predictive value; NPV: Negative predictive value; MTB: Mycobacterium tuberculosis; LJ: Löwenstein–Jensen early and accurate diagnosis is necessary for its control and treatment. In order to end TB by Out of 591 sputum samples cultured on LJ slant, 2030, WHO TB policies and guidelines should be 32 samples gave rise to discrete, raised, irregular, dry, followed[13]. However, until recently, diagnosis of wrinkled colonies which are creamy white and then TB had been through microscopy. Molecular-based develop buff colour. These are the characteristics of methods including GeneXpert assay are now used human type tubercle bacilli (MTB) colonies[11]. Among in the detection of MTB[1]. Thus, this study aimed at culture positive MTB isolates, 19 isolates were also investigating the performance of Xpert MTB/RIF assay positive by AFB smear microscopy while three AFB in the diagnosis of TB and RIF resistance TB at the positive isolates did not give growth on LJ (Table 3). Chest and Lung Diseases Center in Erbil, Iraq. March 2021 KUWAIT MEDICAL JOURNAL 66
the false positivity of microscopy or bacilli other than members of the Mycobacterium tuberculosis complex. One of the currently available molecular techniques that detect MTB and RIF resistance-conferring mutations simultaneously is the Xpert MTB/RIF assay. It has a unique sample processing within 15 minutes and comprises a real-time polymerase chain reaction- based detection system. It gives the results within two hours and has a detection limit of 131 CFU/ml[17]. The Xpert MTB/RIF is a useful tool for the early diagnosis of pulmonary TB. Currently, it is recommended by WHO as an initial diagnostic test in suspected MDR- TB patients or HIV-associated TB[6]. Fig. 1: Detection results of MTB by different diagnostic methods The Xpert MTB/RIF detected MTB in 13.19% Nowadays, the results of conventional diagnostic (78/591) of sputum samples. Among these, 56 were methods of TB are not acceptable as a stand-alone AFB negative and 47 were culture negative. One test to decide whether a patient has TB or not. Also, sample gave a negative result in Xpert MTB/RIF but these methods are time-consuming and not as efficient was positive by both AFB smear and culture. Since as newer methods of TB diagnosis. These drawbacks the Xpert MTB/RIF assay only detects DNA from resulted in the emergence of novel diagnostic MTB bacilli, these Xpert negative results suggest the technologies with higher capacity in the detection of presence of non-tuberculous mycobacteria in that TB within a few hours[14]. The Xpert MTB/RIF was sample. Additionally, the number of bacteria present the most thriving among these technologies and is in the sputum sample could be below the detection endorsed by the WHO. limit of GeneXpert, which is about 4.5 genomes per [18] According to the WHO recommendations reaction or 131 CFU/ml . Also, some bacilli are killed regarding TB control, for anyone who presented with during decontamination of the sputum sample and [19] a cough for more than three weeks, a direct sputum cannot give rise to visible colonies . smear examination for M. tuberculosis should be The overall sensitivity of Xpert MTB/RIF in the performed for observation of tubercle bacilli. Thus, current study was 96.26%, which is in concordance [10] [17] the diagnosis of M. tuberculosis is primarily based with the studies of Sharma et al , Suzana et al , [20] [21] [22] on the presence of tubercle bacilli in the sputum or Williamson et al , Rachow et al and Pandey et al . its detection by culture. Due to the smear positivity In their studies, the sensitivity of Xpert MTB/RIF were relation with infectiousness and a greater possibility of 96.7%, 96.9%, 97.6%, 98% and 98.6% respectively. This [23] disease transmission, smear-positive sputum samples result is higher than that of Shrestha et al and Geleta [16] are worth great consideration[15]. et al , which are 65.5% and 85.4%, respectively. This In the present study, out of 591 sputum samples relatively low sensitivity could be due to a low number collected from suspected pulmonary TB patients, 22 of patients in those studies. isolates were microscopically positive (3.72%). This The results of Xpert MTB/RIF specificity was result is near that of Geleta et al[16], who detected 9.3% 90.86%, which is in agreement with those of Rachow [21] [6] [10], (21/227) of cases with smear microscopy. This low et al , Pereira et al and Sharma et al which were level of detection with Z-N sputum smear microscopy 90.9%, 90.1% and 90%. related to the fact that Z-N stain usually detects bacilli Drug-resistant TB is one of the most serious public that reached an abundance of 105/ml of the sputum health issues worldwide. The primary reasons for sample. Moreover, much of the transmission occurs the increasing number of drug-resistant TB are that before the level of bacilli reaches 105/ml[15]. some techniques need special equipment, and many Out of 591 samples included in this study, 32 techniques are expensive and time-consuming. (5.41%) gave growth on LJ slant. This result is in Due to the high-risk of health problems associated contrast to the studies of Agrawal et al and Raj et al, who with the emergence of MDR-TB, rapid diagnosis demonstrated higher positive rates of 25% and 51.7% and detection of RIF resistance is recommended respectively. The higher positivity of their studies by the WHO for diagnosis of TB and MDR-TB in could be attributed to the lower prevalence of TB in Iraq developing countries. Xpert MTB/RIF amplifies a in comparison to India. Among these culture positive specific sequence of rpoB gene in MTB and detects samples, 19 were also AFB positive and 13 were AFB RIF resistance mutations as a marker for MDR-TB. The negative. Three AFB positive samples were negative sensitivity of Xpert MTB/RIF is closely related to the [6,24] by culture. The culture negativity was attributed to bacilli concentration in the specimen . 67 Molecular epidemiology of Mycobacterium tuberculosis and rifampicin resistance among pulmonary ... March 2021
Out of the 78 samples detected by Xpert MTB/RIF, 6. Pereira GR, Barbosa MS, Dias NJ, de Almeida CP, RIF resistance was detected in 11 samples (14.1%). Silva DR. Impact of introduction of Xpert MTB/RIF This result is higher than that of Lombardi et al[25] and test on tuberculosis (TB) diagnosis in a city with high Okonkwo et al[26], which were 4.1% and 6.9% of their TB incidence in Brazil. PloS one 2018; 13(3):e0193988. 7. Nurwidya F, Handayani D, Burhan E, Yunus F. isolates. The proportion method of drug susceptibility Molecular diagnosis of tuberculosis. Chonnam Med J testing identified 13 isolates as RIF resistant. This 2018; 54(1):1-9. [27] does not disagree with the study of Muia et al . This 8. Ramzan M, Saeed H, Zahra Z. Role of using Genexpert higher detection rate in comparison to Genexpert MTB/RIF assay in detection of Mycobacterium MTB/RIF assay could be attributed to the fact that the Tuberculosis. Journal of Medicine, Physiology and latter only identifies mutations within the rifampicin Biophysics 2018; 41. resistance determining region of the rpoB gene. The 9. Mohammed SH, Ahmed MM, Al Mousawi AM. higher resistance rate by the proportion method may Evaluation of case detection rates of pulmonary be due to mutations outside the rifampicin resistance tuberculosis before and after adoption of GeneXpert MTB/RIF. Iraqi Journal of Science 2018; 59(2C):1019- determining region or rpoA and rpoC which have 1025. been associated with RIF resistance previously. 10. Sharma SK, Kohli M, Yadav RN, Chaubey J, Bhasin D, Sreenivas V, et al. Evaluating the diagnostic accuracy CONCLUSION of Xpert MTB/RIF assay in pulmonary tuberculosis. The study results demonstrate that Xpert is PloS one 2015; 10(10):e0141011. sensitive and specific in the diagnosis of MTB. It shows 11. Bhatia R, Ichhpujani RL. Essentials of Medical higher sensitivity and specificity when culture or Microbiology. 4th ed. New Delhi: Jaypee Brothers smear is negative. It provides enough information in Medical Publishers; 2008. order to start treatment because of its ability to detect 12. Banu S, Rahman SM, Khan MS, Ferdous SS, Ahmed S, Gratz J, et al. Discordance across several methods rifampicin resistance. for drug susceptibility testing of drug-resistant Mycobacterium tuberculosis isolates in a single ACKNOWLEDGMENTS laboratory. J Clin Microbiol 2014; 52(1):156-163. We would like to express our gratitude and 13. Chiang TY, Fan SY, Jou R. Performance of an Xpert- appreciation to the staff of Biology Department, based diagnostic algorithm for the rapid detection College of Science, Salahaddin University, Erbil and of drug-resistant tuberculosis among high-risk Chest and Respiratory Diseases Center, Ministry of populations in a low-incidence setting. PloS one 2018; Health in Erbil city for their help throughout the study 13(7):e0200755. period. We value the participation of the suspected TB 14. Dai Z, Liu Z, Xiu B, Yang X, Zhao P, Zhang X, et al. A multiple-antigen detection assay for tuberculosis patients and thank them for their assistance. diagnosis based on broadly reactive polyclonal Author Contributions: Fairuz H Abdullah Tawgozy antibodies. Iranan J Basic Med Sci 2017; 20(4):360-367. did all the practical parts of the research and writing. 15. Bhatt CP, Timalsina B, Bidur K, Pradhan R, Maharjan Bushra K Qarasnji designed the study and supervised B, Shrestha B, et al. A comparision of laboratory the overall work. diagnostic methods of tuberculosis and aetiology of Financial support: None suspected cases of pulmonary tuberculosis. SAARC Conflicts of interest: There are no conflicts of interest Journal of Tuberculosis, Lung Diseases and HIV/ AIDS 2015; 11(2):1-6. REFERENCES 16. Geleta DA, Megerssa YC, Gudeta AN, Akalu GT, Debele MT, Tulu KD. Xpert MTB/RIF assay for diagnosis of pulmonary tuberculosis in sputum 1. Wokem GN, Azuonwu O, Applollus JN. Evidence- specimens in remote health care facility. BMC based comparison of molecular-genexpert and Microbiol 2015; 15:220. microscopic method in the diagnosis of mycobacterium 17. Suzana S, Ninan MM, Gowri M, Venkatesh K, Rupali tuberculosis among subjects in the limited resource P, Michael JS. Xpert MTB/Rif for the diagnosis of setting of Niger delta. J Microbiol Exp 2018; 6(2):98-102. extrapulmonary tuberculosis–an experience from 2. Gupta S, Kajal NC, Shukla AM, Shukla AK, Singh A, a tertiary care centre in South India. Trop Med Int Neki S. Role of Gene Xpert MTB/RIF in diagnosis of Health 2016; 21(3):385-392. tuberculous pus. Int J Curr Res Med Sci 2018; 4(2):81-85. 18. Helb D, Jones M, Story E, Boehme C, Wallace E, Ho K, 3. World Health Organization. Global tuberculosis report et al. Rapid detection of Mycobacterium tuberculosis 2018. 2018. and rifampin resistance by use of on-demand, near- 4. Durib AK. Prevalence of Tuberculosis in Baghdad, patient technology. J Clin Microbiol 2010; 48(1):229- Iraq 2012-2016. International Journal of Scientific and 237. Research Publications 2018; 8(2):565-570. 19. Tang T, Liu F, Lu X, Huang Q. Evaluation of GeneXpert 5. World Health Organization. Tuberculosis, Iraq. Available MTB/RIF for detecting Mycobacterium tuberculosis from: http://www.emro.who.int/irq/programmes/ in a hospital in China. J Int Med Res 2017; 45(2):816- tuberculosis.html. 822. March 2021 KUWAIT MEDICAL JOURNAL 68
20. Williamson DA, Basu I, Bower J, Freeman JT, Henderson 24. Dhanya PR, Shilpa K, Manjesh M. Study of GeneXpert G, Roberts SA. An evaluation of the Xpert MTB/ MTB/RIF for detecting mycobacterium tuberculosis RIF assay and detection of false-positive rifampicin along with analysis of rifampicin resistance from resistance in Mycobacterium tuberculosis. Diagn pulmonary and extrapulmonary specimens. Int J Microbiol Infect Dis 2012; 74(2):207-209. Med Res 2018; 3(2):1-5. 21. Rachow A, Zumla A, Heinrich N, Rojas-Ponce G, 25. Lombardi G, Di Gregori V, Girometti N, Tadolini Mtafya B, Reither K, et al. Rapid and accurate detection M, Bisognin F, Dal Monte P. Diagnosis of smear- of Mycobacterium tuberculosis in sputum samples by negative tuberculosis is greatly improved by Xpert Cepheid Xpert MTB/RIF assay—a clinical validation MTB/RIF. PloS one 2017; 12(4):e0176186. study. PloS one 2011; 6(6):e20458. 26. Okonkwo R, Onwunzo MC, Chukwuka CP, Ele PU, 22. Pandey P, Pant ND, Rijal KR, Shrestha B, Kattel S, Anyabolu AE, Onwurah CA, et al. The use of the Banjara MR, et al. Diagnostic accuracy of GeneXpert Gene Xpert Mycobacterium tuberculosis/Rifampicin MTB/RIF assay in comparison to conventional drug (MTB/Rif) assay in detection of multi-drug resistant susceptibility testing method for the diagnosis of tuberculosis (MDRTB) in Nnamdi Azikiwe multidrug-resistant tuberculosis. PloS one 2017; University Teaching Hospital, Nnewi, Nigeria. J HIV 12(1):e0169798. Retrovirus 2017; 3:1. 23. Shrestha P, Khanal H, Dahal P, Dongol P. Programmatic 27. Muia PK, Ngugi MP, Mburu DN. Performance impact of implementing GeneXpert MTB/RIF assay of GeneXpert assay in detecting pulmonary for the detection of Mycobacterium tuberculosis in tuberculosis and rifampicin resistance in patients respiratory specimens from pulmonary tuberculosis attending Kitui County Hospital, Kenya. J Trop Dis suspected patients in resource limited laboratory 2017; 5:4. settings of Eastern Nepal. Open Microbiol J 2018; 12:9- 17. 69 KUWAIT MEDICAL JOURNAL March 2021
Original Article Gamma-glutamyltransferase and lactic acid as markers of oxidative stress in carbon monoxide poisoning
Ibrahim Caltekin1, Emre Gokcen1, Atakan Savrun2, Hilal Korkmaz3, Levent Albayrak1, Bilgehan Demir4 1Department of Emergency Medicine, Bozok University Faculty of Medicine, Yozgat, Turkey 2Department of Emergency Medicine, Ordu University Faculty of Medicine, Ordu, Turkey 3Department of Physiology, Gazi University Faculty of Medicine, Ankara, Turkey 4Department of Emergency Medicine, Malatya Research and Training Hospital, Malatya, Turkey
Kuwait Medical Journal 2021; 53 (1): 69 - 73
ABSTRACT
Objectives: The aim of this study was to evaluate the Results: The difference between GGT levels in the changes in gamma-glutamyltransferase (GGT), lactate levels, three groups was significant (P<.001): in Group 1 with blood hematological values and end-organ damage, and the carboxyhemoglobin (COHb) <10, GGT was 11.5 U/L (6-34); in association of all these parameters with the clinical status of Group 2 with COHb between 10-25, GGT was 19 U/L (8-34); the patients in carbon monoxide (CO) poisoning cases. and in Group 3 with COHb >25, GGT was 20 U/L (9-92). The Design: Retrospective study difference between lactate levels in the three groups was also Setting: Malatya Training and Research Hospital, Malatya, significant (P<.001): in Group 1 with COHb <10, lactate level Turkey was 0.8 mmol/L (0.08-2.9); in Group 2 with COHb between Subjects: All patients presenting to the Emergency 10-25, lactate level was 1.3 mmol/L (0.1-3.4); and in Group 3 Department with T58 codes (toxic effect of CO), classified with COHb >25, lactate level was 2.1 mmol/L (0.3-13.7). according to the International Classification of Disease-10, Conclusion: The potential interaction between serum GGT between the dates of 1/9/2015 and 1/9/2016 were evaluated. and CO poisoning has not previously been evaluated with Intervention: None oxidative status. GGT and lactate levels can be used as Main outcome measure: Oxidative status in CO poisoning surrogate markers rather than definitive diagnostic markers evaluated by the results of GGT and lactate levels of oxidative stress in CO poisoning.
KEY WORDS: carbon monoxide poisoning, gamma-glutamyltransferase, lactic acid, oxidative stress
INTRODUCTION release in the tissues[4]. This results in an increase in the Carbon monoxide (CO) is an odorless, tasteless and production of lactate, associated with hypoxia, ischemia non-irritant gas resulting from the combustion of any and tissue necrosis[5]. Lactate is an important indicator carbonaceous compound and causes cellular damage of tissue hypoxia that results from the anaerobic to vital organs such as the heart and brain by hypoxia, glycolysis mechanism and releases some inflammatory potentially resulting in death[1,2]. mediators[6]. Gamma-glutamyltransferase (GGT), Humans usually have <5% CO in their blood; widely used in clinical practice mainly for the however, levels in heavy smokers and those in certain diagnosis of liver injury, is a marker of excessive occupations, such as diesel engine operators, forklift alcohol consumption, and is an important indicator operators, welders, police officers, industrial painters, of oxidative stress because it plays an important role firefighters and warehouse workers may reach 10% in the extracellular catabolism of glutathione[7]. GGT CO[3]. plays a role in the formation of reactive oxygen species CO binds strongly to hemoglobin, which carries and consistent evidence supports the role of systemic oxygen to the tissues, reducing the oxygen transport oxidative stress as a sign[8]. capacity of hemoglobin and subsequently, oxygen In this study, we aimed to evaluate the changes
Address correspondence to: Ibrahim Caltekin, Department of Emergency Medicine, Bozok University Faculty of Medicine, Yozgat, Turkey. E-mail: [email protected] March 2021 KUWAIT MEDICAL JOURNAL 70 in GGT levels causing oxidative stress, lactate levels, were examined. COHb (%) and lactate (mmol/L) blood hematological values and end-organ damage, levels in blood gas analysis; GGT (U/L) levels in and the association of all these parameters with the biochemical analysis; hemoglobin (Hb) (g/dL), white clinical status of the patients in CO poisoning cases. blood cell (WBC) (x103/µL), hematocrit (HCT) (%), neutrophil (x103/µL), mean platelet volume (MPV) SUBJECTS AND METHODS (fL) and mean corpuscular volume (MCV) (fL) Study design and population levels in the analysis of hematological parameters We conducted a retrospective cohort study, were determined. The heparinized blood samples conducted in line with the Declaration of Helsinki. This were measured using Siemens Rapidlab 1265 blood study was carried out retrospectively in the Emergency gas analyzer (Siemens Healthcare Diagnostics, Department of Malatya Research and Training Hospital Medfield, MA, USA). Biochemical analysis and was approved by the institutional review board results were obtained by centrifuging the blood of Malatya İnönü University. All patients presenting samples with serum separator tubes and using to the Emergency Department with T58 codes (toxic chemistry analyzer Architect c8000 System (Abbot effect of CO), classified according to the International Laboratories, Abbot Park, IL, USA). Laser-based Classification of Disease-10, between the dates of flow cytometric impedance, using an automated 1/9/2015 and 1/9/2016 were evaluated. hematology analyzer (Mindray BC-6800, Shenzen, There were 167 patients admitted with a T58 code China), was used to obtain blood hematological during the study period. The following patients (n=64) parameters from blood samples collected in were excluded: those under the age of 18, patients ethylenediaminetetraacetic acid. that had consumed alcohol, those with chronic liver function test impairment or chronic liver disease, those Statistical analysis admitted with trauma and patients with inadequate Statistical analysis was performed using SPSS data. The remaining patients (n=103; 69 females, 34 software version 22. The variables were investigated males) were included in the study. The included visually (histograms, probability plots) and analytical patients were divided into three groups according to methods (Kolmogorov–Smirnov/Shapiro–Wilk) were their carboxyhemoglobin (COHb) level at admission. used to determine whether the results were normally Group 1 included 38 patients with COHb level <10; distributed. Descriptive analyses were presented using Group 2 included 29 patients with COHb levels of 10- medians for the non-normally distributed variables. 25; and Group 3 included 36 patients with COHb level For comparison of non-normally distributed variables, >25. The patients’ records and epicrises were examined. the Kruskal–Wallis test was used. The Mann–Whitney A diagnosis of CO poisoning was made according to U test was performed to test the significance of the medical history at admission and a COHb level pairwise differences using Bonferroni correction to greater than 10%. In addition, the occurrence of end- adjust for multiple comparisons. Categorical data organ damage was divided into systemic groups; were compared using the chi-squared test. While respiratory, cardiac and central nervous system. investigating the associations between non-normally distributed variables, the correlation coefficients and Blood gas, biochemical and hematological assessment their significances were calculated using the Spearman The results of venous blood gas, biochemical and test. The significance level was set at 5% (P <.05) for a hematological analysis of CO poisoning patients type-I error.
Table 1: Comparison of clinical and laboratory parameters according to COHb levels
Clinical and laboratory Group 1 (COHb<10) Group 2 (COHb=10-25) Group 3 (COHb>25) P parameters (n=38) (n=29) (n=36) Age 28 (18-86) 34 (18-85) 38 (18-80) .167 Hemoglobin(g/dL) 13.4 (10.2-16.7) 13.5 (7.7-17.4) 14 (7.4-17) .991 White blood cell (10^3/uL) 7.9 (5-15.6) 8.8 (4.9-13.4) 9 (4.4-21.6) .424 Hematocrit(%) 41.3 (31.7-48.1) 39.7 (26.2-49.7) 40.8 (21.9-52.8) .509 Neutrophil(10^3/uL) 5.2 (2.7-13.6) 5.2 (2.1-9.7) 4.8 (2.6-18) .299 MPV(fL) 9.9 (7.3-11.7) 9.8 (6.5-11.8) 9.1 (6.8-12.5) .231 MCV(fL) 84.1 (64.4-98.3) 84.3 (67.1-94.4) 85.4 (52.1-98) .660 GGT(U/L) 11.5 (6-34)a 19 (8-34)b 20 (9-92)b <.001 Lactate(mmol/L) 0.8 (0.08-2.9)a 1.3 (0.1-3.4)b 2.1 (0.3-13.7)c <.001
MPV: mean platelet volume; MCV: mean corpuscular volume; GGT: gamma-glutamyl transferase a, b, cGroups with different letters are significantly different from each other. 71 Gamma-glutamyltransferase and lactic acid as markers of oxidative stress in carbon monoxide poisoning March 2021
speech impairment and psychiatric complaints and the other had disorientation (Table 2).
Table 2: Distribution of end organ damage
Patients Respiratory Cardiac Central Nervous System Patient 1 X X Patient 2 X Patient 3 X Patient 4 X Patient 5 X X
When we compared the three groups in terms of end-organ damage, all five patients with end-organ damage were in Group 3. When the end-organ damage was examined in terms of development in Group 3, these levels were found to be statistically significant Fig. 1: Comparison of groups in terms of GGT levels (P=.008). When the patients with end-organ damage were compared with patients without end-organ RESULTS damage, lactate and GGT levels were significantly Comparison of the groups higher in the group with end-organ damage (P <.05, The difference between GGT levels in the three Figure 3). groups were significant (P <.001). Group 1 was 11.5 U/L (6-34); Group 2 was 19 U/L (8-34) and Group 3 was 20 U/L (9-92) (Table 1, Figure 1). Similarly, the lactate levels were also significantly different (P <.001): Group 1 was 0.8 mmol/L (0.08-2.9); Group 2 was 1.3 mmol/L (0.1-3.4); and Group 3 was 2.1 mmol/L (0.3-13.7) (Table 1, Figure 2). The P-values in Table 1 are the result of comparison between all three groups. When all three groups were compared in terms of Hb, WBC, HCT, neutrophil, MPV and MCV levels, no statistically significant differences were found (Table 1). End-organ damage was reported in a total of five patients, with more than one system simultaneously affected in some cases. Two patients had non-ST- elevated myocardial infarction, three patients required mechanical ventilation, one of these patients had
Fig. 3: Comparison of lactate and GGT levels in patients with and without end organ damage
Correlations There was a positive correlation between COHb level and lactate level (r=0.680, P <.001), and between COHb level and GGT level (r=0.364, P <.001).
DISCUSSION Our study results indicate that serum lactate and GGT levels were associated with systemic oxidative stress in CO poisoning patients. End-organ damage is an important situation in CO poisoning and it was investigated in this study. Worldwide, CO is thought to have caused more Fig. 2: Comparison of groups in terms of lactate levels than half of the fatal poisonings reported in many March 2021 KUWAIT MEDICAL JOURNAL 72 countries[9]. CO binds to Hb and produces COHb, such as Hb, HCT and WBC count, and that platelet and which causes displacement of oxygen and then reduces MPV counts were significantly higher in patients with the oxygen supply to the tissues of the body. When CO poisoning than in the control group[24]. However, ischemia and hypoxia occur, the structure and function in our study, there were no statistically significant of certain vital organs undoubtedly deteriorate[10]. results in Hb, WBC, HCT, neutrophil, MPV or MCV The non-specific symptoms of CO exposure include levels across all three groups. headache, nausea, vomiting, palpitations, dizziness, confusion and early signs of damage due to high Limitations metabolic rates in oxygen-dependent organs such as There are some limitations of this study. Our the brain and heart. CO poisoning results in acute study was retrospective and based on patient records and delayed neuropsychological disorders and may and epicrises; therefore, the number of patients was ultimately result in heart and respiratory arrest[1,3]. restricted. Transportation of the patients and the When patients with end-organ damage were compared duration of admission to the Emergency Department with patients without end-organ damage, lactate and might influence our results. The authors suggest GGT levels were significantly higher in the group with that these findings must be confirmed via long-term end-organ damage. prospective studies with larger populations. In CO Oxidative stress is defined as an excess production poisoning, end organ structures like brain cells are of reactive oxygen species relative to antioxidant also affected at the cellular level. In our study, the levels, which enhances oxidative damage by creating damage levels of end organs such as brain cells were an imbalance between pro-and antioxidant factors in not specifically investigated. However, despite this favor of prooxidants[11]. Many studies recommend GGT limitation, our perceptible findings like GGT and as a marker of oxidative status[12-14]. However, previous lactate levels can be used as markers of oxidative studies have not examined GGT levels and oxidative status. stress in patients with CO poisoning. GGT levels have a positive relationship with stroke[15], contrast-induced CONCLUSION nephropathy[16], cardiovascular diseases[17], pulmonary The potential interaction between serums GGT and function and chronic obstructive pulmonary disease[18]. CO poisoning has not previously been evaluated and In our study, increased COHb levels were statistically the present study shows that GGT and lactate levels significant in terms of increased GGT levels and we might indicate increased oxidative status in patients showed that GGT levels have a positive relationship with CO poisoning. GGT and lactate levels can be used with COHb levels. as surrogate markers rather than definitive diagnostic In a study carried out by Doğan et al, lactate levels markers of oxidative stress in CO poisoning. were increased in cases of CO poisoning[19]. Moon et al suggested that a single lactate measurement ACKNOWLEDGMENT on admission could potentially be used to improve Declaration of interest: The authors report no conflicts outcomes in CO poisoning patients[20]. Icme et al stated of interest. that high lactate levels were found to be statistically Financial disclosure : This was not an industry significant in CO poisoning victims with Glasgow supported study. The authors declare that this study coma score <15[5]. In our study, increased COHb levels has received no financial support. were statistically significant in terms of increased Author contribution: Designed the study protocol: lactate levels. Caltekin I, Gokcen E, Savrun A. Prepared the It must be noted that transportation of the patient manuscript: Caltekin I, Gokcen E, Albayrak L. can affect the CO levels, resulting in CO levels Collected and analysed the data: Caltekin I, Gokcen measuring lower at first admission to the clinic[21]. E, Korkmaz H. Assisted preparing the manuscript: Identifying patients with CO poisoning can be difficult, Savrun A, Korkmaz H, Albayrak L, Demir B. Read and especially in asymptomatic patients[22]. In our study, approved the final manuscript: Caltekin I, Gokcen E, patients were divided into three groups according to Savrun A, Korkmaz H, Albayrak L, Demir B. their COHb levels at admission and this allowed us to evaluate COHb levels in patients with silent and noisy REFERENCES clinical situations. The role of platelet function in CO poisoning is not 1. Zengin S, Behcet A, Karta S, Can B, Orkmez M, Taskin completely clear, but increased platelet activation and A, et al. An assessment of antioxidant status in patients aggregation is not reflected in the current literature[23]. with carbon monoxide poisoning. World J Emerg Med Karabacak et al reported in their study that there was 2014; 5(2):91-95. 2. Smollin C, Olson K. Carbon monoxide poisoning no difference between the hematological parameters (acute). BMJ Clin Evid 2010; 2010:2103. 73 Gamma-glutamyltransferase and lactic acid as markers of oxidative stress in carbon monoxide poisoning March 2021
3. Akyol S, Erdogan S, Idiz N, Celik S, Kaya M, Ucar F, level and risk of stroke: A systematic review and meta- et al. The role of reactive oxygen species and oxidative analysis of prospective studies. J Stroke Cerebrovasc stress in carbon monoxide toxicity: an in-depth analysis. Dis 2015; 24(12):2816-2823. Redox Rep 2014; 19(5):180-189. 16. Oksuz F, Yarlioglues M, Cay S, Celik IE, Mendi MA, 4. Hampson NB. Pulse oximetry in severe carbon Kurtul A, et al. Predictive value of gamma-glutamyl monoxide poisoning. Chest 1998; 114(4):1036-1041. transferase levels for contrast-induced nephropathy 5. Icme F, Kozaci N, Ay MO, Avci A, Gumusay U, Yilmaz in patients with ST-segment elevation myocardial M, et al. The relationship between blood lactate, carboxy infarction who underwent primary percutaneous hemoglobin and clinical status in CO poisoning. Eur coronary intervention. Am J Cardiol 2015; 116:711- Rev Med Pharmacol Sci 2014; 18(3):393-397. 716. 6. Revelly JP, Tappy L, Martinez A, Bollmann M, Cayeux 17. Kunutsor SK, Bakker SJ, Kootstra-Ros JE, MC, Berger MM, et al. Lactate and glucose metabolism Gansevoort RT, Dullaart RP. Circulating gamma in severe sepsis and cardiogenic shock. Crit Care Med glutamyltransferase and prediction of cardiovascular 2005; 33(10):2235-2240. disease. Atherosclerosis 2015; 238(2):356-364. 7. Park WY, Kim SH, Kim YO, Jin DC, Song HC, Choi EJ, 18. Kim HW, Lee SH, Lee DH. Relationship of serum et al. Serum gamma-glutamyltransferase levels predict gamma-glutamyltransferase levels with pulmonary mortality in patients with peritoneal dialysis. Medicine function and chronic obstructive pulmonary disease. (Baltimore) 2015; 94(31):e1249. Lung 2014; 192(5):719-727. 8. Lee DH, Blomhoff R, Jacobs Jr DR. Is serum 19. Doğan NÖ, Savrun A, Levent S, Günaydın GP, gammaglutamyltransferase a marker of oxidative Çelik GK, Akküçük H, et al. Can initial lactate levels stress? Free Radic Res 2004; 38(6):535-539. predict the severity of unintentional carbon monoxide 9. Raub JA, Mathieu-Nolf M, Hampson NB, Thom poisoning? Hum Exp Toxicol 2015; 34(3):324-329. SR. Carbon monoxide poisoning-a public health 20. Moon JM, Shin MH, Chun BJ. The value of initial perspective. Toxicology 2000; 145(1):1-14. lactate in patients with carbon monoxide intoxication: 10. Li Q, Bi MJ, Bi WK, Kang H, Yan LJ, Guo YL. Edaravone in the emergency department. Hum Exp Toxicol 2011; attenuates brain damage in rats after acute CO 30(8):836-843. poisoning through inhibiting apoptosis and oxidative 21. Hampson NB, Dunn SL, Yip FY, Clower JH, Weaver stress. Environ Toxicol 2016; 31(3):372-379. LK. The UHMS/CDC carbon monoxide poisoning 11. Sies H. Oxidative stress: oxidants and antioxidants. Exp surveillance program: three-year data. Undersea Physiol 1997; 82(2):291-295. Hyperb Med 2012; 39(2):667-685. 12. Mason JE, Starke RD, Van Kirk JE. Gamma-glutamyl 22. Akilli NB, Akinci E, Akilli H, Dundar ZD, Koylu R, transferase: a novel cardiovascular risk biomarker. Prev Polat M, et al. A new marker for myocardial injury Cardiol 2010; 13(1):36-41. in carbon monoxide poisoning: T peak-T end. Am J 13. Emdin M, Pompella A, Paolicchi A. Gamma- Emerg Med 2013; 31(12):1651-1655. glutamyltransferase, atherosclerosis, and cardiovascular 23. Beyan C, Beyan E. Mean platelet volume and platelet disease: triggering oxidative stress within the plaque. count values in patients with carbon monoxide Circulation 2005; 112(14):2078-2080. poisoning. Angiology 2014; 65(3):257-258. 14. Karabacak M, Dogan A, Tayyar S, Bas HA. Oxidative 24. Karabacak M, Varol E, Turkdogan KA, Duman A, stress status increase in patients with nonischemic Akpinar O, Karabacak P. Response to letter to the heart failure. Med Princ Pract 2014; 23:532-537. editor: mean platelet volume and platelet count 15. Zhang XW, Li M, Hou WS, Li K, Zhou JR, Tang ZY. values in patients with carbon monoxide poisoning. Association between gamma-glutamyltransferase Angiology 2014; 65(3):259-260. March 2021 KUWAIT MEDICAL JOURNAL 74
Original Article The relationship between nutritional status and Fetuin-A in Inflammatory Bowel Disease patients
Burcu Barutcuoglu1, Nalan Gulsen Unal2, Gunes Ak1, Zuhal Parildar2, Nevin Oruc2, Ahmet Omer Ozutemiz2 1Department of Clinical Biochemistry, Ege University School of Medicine, Bornova, 35100, Izmir, Turkey 2Department of Gastroenterology, Ege University School of Medicine, Bornova, 35100, Izmir, Turkey
Kuwait Medical Journal 2021; 53 (1): 74 - 80
ABSTRACT
Objective: To investigate the relationship between Main outcome measures: Fasting serum levels of fetuin-A and nutritional index parameters body mass albumin, glucose, total cholesterol, triglyceride, C-reactive index (BMI), fat mass (FM), fat free mass (FFM) and mini protein (CRP), vitamin B12, folic acid, ferritin, fetuin-A, nutritional assessment (MNA®) in inflammatory bowel hemoglobin and white blood cell count were measured. disease (IBD) patients. Results: The level of CRP was significantly higher and Design: Randomized, prospective study fetuin-A was significantly lower (both P<.001) in IBD Setting: Department of Clinical Biochemistry and patients than in healthy subjects. Age (P<.001), MNA® total Gastroenterolgy, Medical School, Ege University, Izmir, score (P=.001), FM (P<.001), FFM (P=.003) and fetuin-A Turkey (P=.012) were significantly different between the BMI Subjects: Seventy-six consecutive IBD out-patients groups. There was a significant difference in BMI (P<.001), and 24 healthy volunteers were enrolled in this study. FM (P<.001), FFM (P<.001), levels of Fetuin-A (P=.030) and IBD patients were grouped into: 1. BMI<18.5 kg/m2; 2. CRP (P=.030) between MNA® groups. There was a weak BMI=18.5-24.9 kg/m2; and 3. BMI≥25 kg/m2 and according correlation between fetuin-A and BMI (r=0.249,P=.030). to MNA® score as: 1. MNA® <17, 2. MNA®=17.5-23.5 and Conclusion: In this study, fetuin-A, a negative acute phase 3. MNA® ≥24. protein is shown to be related to BMI in IBD patients. Interventions: Demographical data and nutritional index Serum fetuin-A levels were the lowest both in MNA<17 parameters (BMI, FM, FFM) were evaluated. MNA was and BMI<18.5 kg/m2, which showed us that it can predict assessed by a questionnaire. nutritional status in IBD patients.
KEY WORDS: chronic inflammation, fetuin-A, inflammatory bowel disease, malnutrition
INTRODUCTION as a negative acute phase reactant and is inversely Fetuin-A (Alpha 2-Heremans Schmid Glycoprotein) correlated with serum C-reactive protein (CRP) is a glycoprotein with a molecular mass of 60 kDa. It is levels[1,5]. The plasma protein and hepatic mRNA levels synthesized mainly by hepatocytes and is a potential for fetuin-A transiently fall during the acute phase of biomarker for estimating liver dysfunction[1]. Fetuin-A a systemic inflammation[6]. This event mainly results is an inhibitor of insulin receptor tyrosine kinase, and from an IL-1β induced down-regulation of its hepatic is increased in insulin resistance, diabetes mellitus and mRNA level[7]. metabolic syndrome[2-4]. Malnutrition and resultant chronic weight loss are The proinflammatory cytokines such as the major complications of inflammatory bowel disease interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour (IBD)[8]. The evaluation of nutritional status in IBD is necrosis factor-α (TNF-α) inhibit the synthesis of the first step to identify malnutrition in order to get the fetuin-A in hepatocytes. Therefore, it is considered adequate nutrients and therapeutics. Full nutritional
Address correspondence to: Burcu Barutcuoglu, MD, Associate Professor, Department of Clinical Biochemistry, Ege University, School of Medicine, Bornova, 35100, Izmir, Turkey. Tel: +90 232 3904316; E-mail: [email protected] 75 The relationship between nutritional status and Fetuin-A in Inflammatory Bowel Disease patients March 2021 status assessment needs a number of detailed wide BMI. Group 1: BMI <18.5 kg/m2, group 2: BMI=18.5- range of tests such as body mass index (BMI), arm and 24.9 kg/m2 and group 3: BMI ≥25 kg/m2. calf circumferences, dual-energy X-ray absorptiometry (DEXA), bioimpedentiometry (BIA), mini nutritional Mini Nutritional Assessment (MNA®) questionnaire assessment (MNA®) and many others. BIA and DEXA All patients took the MNA® questionnaire. The are considered to be gold standards for malnutritional same investigator did all the interviews to minimize assessment. However, since BMI is easy to perform, interobserver bias. The complete MNA® consisted of it is the most widely used assessment of nutritional screening phase (or short form) and assessment phase. status. BMI <18.8 kg/m2 is considered malnutrition. In Both were administered to all patients. The screening clinical practice, BMI is practical to measure weight phase (used as a short form to identify patients at risk loss, but early parameters to predict malnutrition in of malnutrition) consists of six items: a food intake IBD patients are needed[9]. item, two anthropometric parameters (recent weight MNA® is a widely used, 10 minute screening test loss and BMI), and three general parameters (mobility, for malnutrition which includes the assessments of physical and emotional, and neuropsychological). The life style, physical activity, medication, food intake assessment phase had twelve items: anthropometric analysis (meals, dysphagia, etc), subjective symptoms (calf and upper arm circumference), general (six (patient’s perception of health and nutrition), reduction questions on life style, medication and mobility), of weight, BMI and skinfolds. A total score of less than dietary (eight questions related to number of meals, 17 indicates malnutrition[10]. food and fluid intake), and subjective assessment Since a unique marker is still not available, an (personal view of health and nutritional status). The accurate assessment of nutritional status can be done sum of the MNA® scores of both phases distinguishes by a number of different methods and diagnostic patients with adequate nutrition, MNA® score ≥ 24; risk indicators. A correct assessment of nutritional status of malnutrition, MNA® score 17.5-23.5; and protein- provides quantitative and qualitative evaluations, calorie malnutrition, MNA® <17[10]. According to MNA® so that effectiveness of nutritional support could scores, patients were grouped into three groups. be measured and evaluated. On the other hand, The subjects were all informed about the protocol IBD patients have chronic inflammation, which is a and their informed consents were obtained. The study devastating process. Both chronic inflammation and was apporoved by the local ethical commitee (decision malnutrition affect IBD patient’s morbidity[11], so #:16-9.1/12) assessment of nutritional status alone is not enough. An ideal unique marker reflecting both nutritional and Blood sampling inflammatory status at a glance is needed. Patients Blood samples were withdrawn into gel tubes for with IBD should be followed-up closely, so the each patient following an overnight fast of 12 hours. inflammatory and nutritional status in IBD should be Venous blood samples were centrifuged at 3000 g for assessed. 10 minutes at room temperature (Thermo Scientific The aim of this study was to investigate a relationship Heraeus Labofuge 200 Centrifuge). between an inflammation related biomarker, fetuin-A, and nutritional index parameters like BMI, fat mass Laboratory investigation (FM), fat free mass (FFM) and MNA®. Serum fasting levels of albumin, glucose, total cholesterol, triglyceride, CRP, vitamin B12, folic SUBJECTS AND METHODS acid and ferritin levels were measured on the Roche Patients Cobas 8000 modular chemistry analyzer and Cobas Twenty-four healthy volunteers and seventy-six 6000 immunoassay analyzer (Roche Diagnostics consecutive outpatients with an established diagnosis International Ltd, Switzerland). White blood cell and of IBD who visited the Gastroenterology-IBD outpatient hemoglobin (Hb) count were performed using the clinics and evaluated as IBD (Crohn’s disease or Colitis Sysmex XN-2000 Automated Blood Cell Analyzer ulcerosa) were enrolled in this study. Patients with any (Sysmex, Kobe, Japan) other acute/chronic inflammation, infection, acute / chronic liver disease, diabetes, metabolic syndrome or Fetuin-A dyslipidemia disease were excluded. Serum feutin-A was measured in duplicate by sandwich enzyme-linked immunosorbent assay kit BMI (Biovendor, Human and Diagnostic Products, Cat no: The patients’ height and weight were measured. RD191037100, Czech Republic). The manufacturer BMI was calculated as body weight/height2 (kg/m2). declared the within-run and between-run coefficient IBD patients were grouped into 3 according to their of variations as 2.9% and 4.7%, respectively, with limit March 2021 KUWAIT MEDICAL JOURNAL 76 of detection of 0.104 ng/mL and linearity of 100 ng/ml. Thermo Multiscan EX microplate ELISA reader was Table 1: Demographic data used to record the readings. Inflammatory Bowel Demographic variables Disease patients Statistics Number of IBD patients 76 For each variable, Kolmogorov–Simirnov test was Gender (Female / Male) 34/42 applied to determine the concordance to a Gaussian Age (years mean ± SD) 44.8±12.7 Number of CD / Ulcerative Colitis 44/32 distribution. Variables with a Gaussian distribution BMI (kg/m2) 24.3±4.9 were expressed as mean±SD, whereas variables MNA® screening phase score 10.4±2.8 without a Gaussian distribution were expressed as MNA® assessment phase score 12.6±2 ® median (min-max). MNA total score 22.5±4.2 Smoking (+ / %) 12/15.8 One-way analysis of variance for parametric Alcohol (+ / %) 3/3.9 multiple comparison procedures and Student t test for two independent group comparisons were used for IBD: inflammatory bowel disease; CD: Crohn’s disease; BMI: body variables with a Gaussian distribution. For variables mass index; MNA: mini nutritional assessment with a non-Gaussian distribution, Kruskal–Wallis and Mann Whitney U tests were used. Dunnett’s C and female. The overall demographics of the IBD patients Bonferroni corrections were used where appropriate. are given in Table 1. Correlation coefficients were calculated either by In the healthy volunteer group, 24 patients (11 Pearson’s for parametric or by Spearman’s for non- female, 13 male) were enrolled in this study with an parametric data. Stepwise multiple linear regression average age of 69 (66-78) years, BMI of 24.3 (19-26.1) analysis was used to identify those variables with the kg/m2, CRP of 2 (0.4-4) mg/L and fetuin-A of 321.76 strongest associative influence on fetuin-A. (141.7-570.6) µg/mL and they were given in median The level of difference was accepted as statistically (min-max). Serum CRP levels were significantly significant at P-value <.05. Data management was higher and fetuin-A levels were significantly lower carried out with the statistical package program SPSS (both P <.001) in IBD patients than in healthy subjects. (Statistical Package Social Sciences Inc. Chicago IL, IBD patients were grouped into three according to USA) version 17 for Windows. their BMI (Table 2). There were statistically significant differences in age (P <.001), MNA® total score (P=.001), RESULTS FM (P <.001), FFM (P=.003) and fetuin-A (P=.012) levels Seventy-six IBD patients (44 with Crohn’s disease between the three groups. On the basis of the above and 32 with ulcerative colitis) were enrolled in this statistics, significantly different parameters were once study. Their age mean was 44.8 years and 44.7% were more compared in group pairs (BMI group pairs 1-2,1-
Table 2: Data from the three BMI groups Group 1 Group 2 Group 3 Variables (BMI <18.5 kg/m2) (BMI=18.5-24.9 kg/m2) (BMI ≥25 kg/m2) Number of patients 21 30 25 Age (years mean ± SD)**# 32.5±8.2 46.4±11.1 48.1±13.5 MNA® total score** φα 19(13-26.5) 22(11-28.5) 26 (20.5-29) FM** ## φφ αα 6.8(3-14) 14.2(6.9-24.7) 26.5(18.4-49) FFM* # φ 40.2(33-55) 43.7(36.9-56.2) 45.7(29.1-55.2) CRP (mg/L) 3(0.3-38.4) 3.5(0.4-69.7) 1.8(0.5-58.3) ESR (mm/hr) 15(4-42) 18(2-53) 17(2-56) Hb (g/dL) 11.5(9.2-14.3) 12.8(9.6-15.6) 12.7(5.4-14.6) Hct (%) 35.2(32.7-40.9) 38.2(30.9-45.1) 38.8(20.2-43.5) Ferritin (ng/mL) 12(4.3-197.6) 27.9(0.39-76.8) 24.2(1.97-171.7) Protein,Total (g/dL) 7.5(6-8.3) 7.3(5.1-8.8) 7.4(6.6-8.0) Albumin (g/dL) 4.4(2.8-5.1) 4.5(2.6-5.1) 4.6(3.7-4.9) Vitamin B12 (pg/mL) 394(222-1640) 326(172-1489) 295(140-722) Folic acid (ng/mL) 7.46(5.69-12.42) 7.93(4.26-20) 9(2.2-20) Fetuin-A (µg/mL) * # φ 30.3(21.24-35.38) 39.4(18.66-119.7) 39.7(22.78-62.09)
Three group comparison (Kruskal-Wallis test) statistically significant *: P<.050, **:P<.001. Group 1-2 comparison (Mann-Whitney test) statistically significant #: P<.050, ##:P<.001. Group 1-3 comparison (Mann-Whitney test) statistically significant φ: P<.050, φφ:P<.001. Group 2-3 comparison (Mann-Whitney test) statistically significant α: P<.050 BMI: body mass index; MNA: mini nutritional assessment; FM: fat mass; FFM: fat free mass; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; Hb: hemoglobin; Hct: hematocrit 77 The relationship between nutritional status and Fetuin-A in Inflammatory Bowel Disease patients March 2021
Table 3: Data from the three MNA groups Group 1 Group 2 Group 3 Variables MNA® <17 MNA®= 17-23.5 MNA®=24-30 Number of patients 15 17 28 BMI (kg/m2)** ## φφ 20.3(15.4-25) 23.9(17.5-34.1) 25.35(18.6-44.4) FM** ## φφ 10.2(3.2-18.6) 16.9(6-39.1) 22.3(6.4-49) FFM** # φφ α 39.5(33-56.2) 43.3(29.1-56) 46(40.5-55.2) CRP (mg/L)* φ α 5.5(0.3-38.4) 6.3(0.5-24.5) 1.55(0.4-69.7) ESR (mm/hr) 22(5-48) 22(4-48) 12(2-56) Hb (g/dL)* φ α 11.5(9.5-13.3) 11.9(5.4-14.2) 13.1(7.4-15.6) Hct (%)*φ α 37.5(32.7-39.9) 36(20.2-43.1) 39.5(25.9-45.1) Ferritin (ng/mL) 30.6(3.9-768.9) 22.56(1.97-306.4) 24.2(3.25-1717) Protein,Total (g/dL) 7.2(6.0-8.8) 7.1(5.1-8.2) 7.4(6.4-8.3) Albumin (g/dL)* φ 4.3(2.8-5.0) 4.4(2.6-5.1) 4.7(3.3-5.1) Vitamin B12 (pg/mL)* φ 425(197-1640) 314(181-917) 294(140-1002) Folic acid (ng/mL)* α 7.79(4.4-20) 6.58(2.2-17.33) 9.24(4.14-20) Fetuin-A (µg/mL) * φ 36.47(18.66-86.1) 37.34(17.4-62.9) 39.99(21.24-119.68)
Three group comparison (Kruskal-Wallis test) statistically significant *: P<.050, **:P<.001. Group 1-2 comparison (Mann-Whitney test) statistically significant #: P<.050, ##:P<.001. Group 1-3 comparison (Mann-Whitney test) statistically significant φ: P<.050, φφ:P<.001. Group 2-3 comparison (Mann-Whitney test) statistically significant α: P<.050. BMI: body mass index; MNA: mini nutritional assessment; FM: fat mass; FFM: fat free mass; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; Hb: hemoglobin; Hct: hematocrit
3 and 2-3). FM (P ≤.001), FFM (P=.007) and fetuin-A 7 male) with a mean age of 47.7±12.8 years, BMI was (P=.022) were significantly lower in group 1 than 23 (15.5-34.2) kg/m2, FM was 15.4 (3.2-35.7), FFM was in group 2. FM (P ≤.001), FFM (P=.001) and fetuin-A 43.4 (33-56), fetuin-A was 37.1 (21.24-95.61) µg/mL, (P=.003) were significantly lower in group 1 than CRP was 3.5 (0.3-69.7) mg/L, albumin was 4.4 (2.8-5.1) in group 3. MNA® (P ≤.001) and FM (P ≤.001) ) were g/dL, Hb was 11.9 (9.5-14.6) g/dL, Hct was 37.4% (31.4- significantly lower in group 2 than in group 3 (Table 2). 43.7%), ferritin 28.3 (4.27-768.9) ng/mL, vitamin B12 On the other hand, all patients were also grouped was 392 (162-1640) pg/mL and folic acid was 6.8 (2.2- into three according to their MNA® total score (Table 20.0) ng/mL. These data were given in median (min- 3). There were statistically significant difference in max). There were no significant differences between BMI (P <.001), FM (P <.001), FFM (P <.001), fetuin-A ulcerative colitis and Crohn’s disease patient groups (P=.030), CRP (P=.030), Hb (P=.003), hematocrit (Hct, at any variables. P=.002), vitamin B12 (P=.040) and folic acid (P=.024) There was a weak correlation between fetuin-A between the three groups. On the basis of above and BMI (correlation coefficient (r)= 0.249, P=.030) and statistics, significantly different parameters were also between fetuin-A and age (r=0.251, P=.029). Significant compared in group pairs (MNA® group pairs 1-2, 1-3 positive correlations were revealed between BMI and and 2-3). BMI (P <.001), FM (P=.002) and FFM (P=.033) FM (r=0.872, P <.001), BMI and FFM (r=0.474, P <.001), were significantly lower in group 1 than in group 2. BMI and MNA® (r=0.511, P <0.001). MNA® and FM BMI (P <.001), FM (P <.001), FFM (P <.001), Hb (P=.004), (r=0.486, P <.001), MNA® and FFM (r=0.492, P <.001), Hct (P=.002), albumin (P=.01) and fetuin-A (P=.043) MNA® and albumin (r=0.402, P=.001). A significant were significantly lower and CRP (P=.021) and vitamin negative correlation was revealed between MNA® and B12 (P=.013) were significantly higher in group 1 than Vitamin B12 (r=-0.353, P=.007), FFM and Vitamin B12 in group 3. FFM (P=.016), Hb (P=.006), Hct (P=.006) and (r=-0.381, P=.003). The highest correlation was shown folic acid (P=.003) were significantly lower and CRP with BMI and other nutritional parameters in IBD, (P=.04) was significantly higher in group 2 than group so BMI is the strongest predictor of malnutrition. On 3 (Table 3). the other hand, the weak correlation shown between Among the ulcerative colitis patients (35 female, 9 BMI and fetuin-A has supported the link between male) with a mean age of 43±12 years, BMI was 24.45 malnutrition and inflammation in IBD patients and (17-44.4) kg/m2, FM was 16.55 (6-49), FFM was 44.25 fetuin-A reflects both nutritional and inflammatory (29.1-56.2), fetuin-A was 36.75 (17.40-119.68) µg/mL, status. CRP was 1.7 (0.4-22.3) mg/L, albumin was 4.6 (2.6-5.1) A multiple stepwise regression was performed g/dL, Hb was 12.8 (5.4-15.6) g/dL, Hct was 38.8% (20.2- to determine which variables had the strongest 45.1%), ferritin was 20.3 (1.97-768.9) ng/mL, vitamin association with fetuin-A concentration. Age, gender, B12 was 300 (140-581) pg/mL and folic acid was 9.1 (5.5- total protein, albumin, ferritin, Hb, Hct and erythrocyte 14.8) ng/mL. In the Crohn’s disease group (25 female, sedimentation rate were the independent variables. March 2021 KUWAIT MEDICAL JOURNAL 78
All variables except BMI and CRP were excluded. The showed that since fetuin-A is significantly the lowest R’s for regression (0.430 and 0.389 respectively) were in the BMI <18.5 kg/m2 group, it may have a great significantly different from zero; (P=.005) with R2 at contribution in assessing both the inflammatory and 0.177 for BMI and R2 at 0.148 for CRP. This indicated the nutritional status. In our study, the reflection of the that approximately 18% of the variability in fetuin-A relationship between inflammation and malnutrition is predicted by BMI and approximately 15% of the is shown by the significantly low levels of fetuin-A and variability in fetuin-A is predicted by CRP. the high levels of CRP in both MNA® <17 group and in BMI <18.5 kg/m2 group. In chronic inflammation, DISCUSSION increase of skeletal muscle protein degradation and In this study, serum fetuin-A concentrations were reduction of myofibrillar proteins can be observed and significantly lower in IBD patients than in the healthy result in loss of muscle mass. In inflammatory chronic participants, which support the previous findings[12,13]. diseases, muscle protein degradation seems to depend The low levels of fetuin-A in Crohn’s disease, ulcerative on a coordinated network of signaling pathways colitis and chronic obstructive pulmonary disease were regulated by hormones and cytokines, which reduce found to be a predictor of poor outcome[13,14]. In our synthesis and increase protein degradation[9,19]. The study, there was no significant difference in CRP and most important pathway involved in muscle growth is fetuin-A levels between Crohn’s disease and ulcerative insulin, growth hormone and insulin like growth factor colitis patients similar to Manolakis et al’s study[13], 1. In IBD, as in chronic inflammatory conditions, a which suggested that fetuin-A supports the prediction significant reduction in plasma and muscle insulin like of chronic inflammatory responses in both Crohn’s growth factor 1 can be seen in response to the elevated disease and ulcerative colitis. Triggering innate concentrations of TNF-α and IL-6, cytokines that cause immune cells lead to the induction of pro-inflammatory growth hormone resistance in liver and muscles. In cytokines such as TNF-α, IFγ and IL-6, which suppress chronic inflammatory conditions, acute phase proteins the hepatic synthesis of fetuin-A[15,16]. Assessing and cytokines as TNF-α, IFN-γ, and IL-6 exert a direct the inflammatory conditions by biomarkers in IBD role in muscle wasting. We think that fetuin-A can patients helps clinicians to predict disease severity, strengthen the data related to malnutrition, and at the complicated disease behavior and decide on advanced same time monitor inflammatory status and will help treatment strategies[13]. Malnutrition is the major in introducing a strong nutritional support in order to complication and cause of weight loss in IBD patients. reduce morbidity. Definition and follow up of impaired nutritional If the relationship between BMI and inflammation status is essential, since malnutrition contributes to is put aside, visceral fat should also be discussed poor disease prognosis. The aim of this study was in IBD patients. Especially in Crohn’s disease, a to investigate a relationship between fetuin-A, an significant increase in visceral adiposity, in particular inflammation related biomarker with nutritional index mesenteric fat, can be observed. Mesenteric fat seems parameters like BMI, FM, FFM and MNA®. In our to be involved in the pathogenesis of Crohn’s disease. study, fetuin-A is significantly lowest in the BMI <18.5 Adipocytes in mesenteric fat can produce inflammatory kg/m2 IBD patient group. During active and remission cytokines such as TNF-α, IFN-γ, IL-6, and IL-1 phases of Crohn’s disease and ulcerative colitis, and other adipokines as leptin and resistin. These inflammatory cytokines released from the immune cells molecules demonstrate a strong proinflammatory in gut mucosa have been shown to be highly related effect, activating immune response and deregulating to malnutrition. Malnutrition mechanisms are related intestinal homeostasis. In our study, low fetuin-A to impaired epithelial transport, loss of epithelial levels were related to low FM, FFM and BMI, integrity and disease activity. Nutrition loss mostly suggesting that fetuin-A reflects both inflammation takes place in active phases by inflammatory diarrhea. and nutritional status. Olivier et al showed that in Inflammation may lead to ulcerative lesions in the Crohn’s disease patients, increased mesenteric fat is bowel surface which causes chronic blood loss, protein an important indicator of disease activity[22]. Gambero loss and malnutrition[17,18]. Chronic inflammation and et al showed that adipocyte mass correlated with the malnutrition together effect IBD patient morbidity[11]. degree of expression of inflammatory cytokines and In this context, our data supported that fetuin-A may disease activity[23]. be a new marker predicting both nutritional status MNA screening phase and assessment phase both and inflammation at a glance and gives additonal estimate life style, food intake, nutritional status, information about IBD patient morbidity. medication, weight loss, BMI, mobility, physical, IBD can alter the homeostasis of muscle, fat and emotional and neurophychological state of the bone, so it is crucial to analyze a relationship between patient[11]. It is widely used to distinguish adequate chronic inflammation and malnutrition[19-21]. We nutritional status and malnutrition in IBD patients that 79 The relationship between nutritional status and Fetuin-A in Inflammatory Bowel Disease patients March 2021 truly depends on investigators subjective assessment (AHSG) concentration in serum with cardiovascular which helps to make crucial decision in IBD patients. mortality in patients on dialysis: a cross-sectional Thus, fetuin-A can be a necessary marker for assessing study. Lancet 2003; 361(9360):827-833. nutritional status in IBD patients. 6. Daveau M, Christian-Davrinche, Julen N, Hiron M, Arnaud P, Lebreton JP. The synthesis of human alpha- The limitation of our study is that fetuin-A and 2-HS glycoprotein is down-regulated by cytokines in CRP should also be compared with gold standard hepatoma HepG2 cells. FEBS Lett 1988; 241(1-2):191- malnutritional assessment tests like BIA and DEXA. 194. Also, the three subgroups of BMI and MNA had a low 7. Akhoundi C, Amiot M, Auberger P, Le Cam A, Rossi number of patients. B. Insulin and interleukin-1 differentially regulate pp63, an acute phase phosphoprotein in hepatoma CONCLUSION cell line. The Journal of Biological Chemistry 1994; This study showed that fetuin-A is a negative 269(22):15925-15930. acute phase protein and it is also related to BMI in IBD 8. Weisshof R, Chermesh I. Micronutrient deficiencies in inflammatory bowel disease. Curr Opin Clin Nutr patients. Serum fetuin-A levels were the lowest both in ® 2 Metab Care 2015; 18(6):576-581. MNA <17 and BMI <18.5 kg/m , which are predictors 9. Scaldaferri F, Pizzoferrato M, Lopetuso LR, Musca T, of nutritional status. Ingravalle F, Sicignano LL, et al. Nutrition and IBD: Malnutrition and/or Sarcopenia? A Practical Guide. ACKNOWLEDGMENTS Gastroenterol Res Pract 2017; 2017: Article ID:8646495. Author contributions: Burcu Barutcuoglu: 10. Vellas B, Villars H, Abellan G, Soto ME, Rolland Y, conduct and design of the study, data interpretation, Guigoz Y, et al. Overview of the MNA--Its history and manuscript writing, final approval. Nalan Gulsen challenges. J Nutr Health Aging 2006; 10(6):456-463. Unal: Inflammatory bowel disease patient evaluations 11. Beck AM, Ovesen L, Osler M. The ‘Mini Nutritional Assessment’ (MNA) and the ‘Determine Your and patient recruitment; conduct and design of the Nutritional Health’Checklist (NSI Checklist) as study and final approval. Gunes Ak: data collection, predictors of morbidity and mortality in an elderly data interpretation and statistical analysis. Zuhal Danish population. Br J Nutr 1999; 81(1):31-36. Parildar: data interpretation, and manuscript writing. 12. Ma P, Feng YC. Decreased serum fetuin-A levels and Nevin Oruc: Inflammatory bowel disease patient active inflammatory bowel disease. Am J Med Sci 2014; evaluations and patient recruitment. Omer Ozutemiz: 348(1):47-51. Conduct and design of the study. 13. Manolakis AC, Christodoulidis G, Kapsoritakis Disclaimers: None. AN, Georgoulias P, Tiaka EK, Oikonomou K, et Funding: This study was supported by the Ege al. a2-Heremans-Schmid Glycoprotein (Fetuin A) downregulation and its utility in inflammatory bowel University Research Projects, Izmir, Turkey. disease. World J Gastroenterol 2017; 23(3):437-446. Conflict of interest: The authors declare no conflicts 14. Minas M, Mystridou P, Georgoulias P, Pournaras S, of interest. Kostikas K, Gourgoulianis K. Fetuin-A is associated with disease severity and exacerbation frequency REFERENCES in patients with COPD. COPD: Journal of Chronic Obstructive Pulmonary Disease 2013; 10(1):28-34. 1. Dabrowska AM, Tarach JS, Duma BW, Duma D. 15. Li W, Zhu S, Li J, Huang Y, Zhou R, Fan X, et al. A Fetuin-A (AHSG) and its usefulness in clinical practice. hepatic protein, fetuin-A, occupies a protective role Review of the literature. Biomed Pap Med Fac Univ in lethal systemic inflammation. PloS One 2011; Palacky Olomouc Czech Repub 2015; 159(3):352-359. 6(2):e16945. 2. Stefan N, Hennige AM, Staiger H, Machann J, Schick F, 16. Sindhu S, Akhter N, Ahmed R. Fetuin A (AHSG) in Krober SM, et al. α2-Heremans-Schimid Glycoprotein/ metabolic and inflammatory diseases: A foe or a friend. Fetuin-A is associated with insulin resistance and fat Diabetes Obes Intl J 2016; 1(5):000127. accumulation in the liver in humans. Diabetes Care 17. Ghishan FK, Kiela PR. Epithelial transport in 2006; 29(4):853-857. inflammatory bowel diseases. Inflamm Bowel Dis 3. Brix JM, Stingl H, Hollerl F, Schernthaner GH, Kopp 2014; 20(6):1099-1109. HP, Schernthaner G. Elevated fetuin-A concentrations 18. Urbano APS, Sassaki LY, Dorna MS, Carvalhaes MABL, in morbid obesity decrease after dramatic weight loss. J Martini LA, Ferreira ALA. Nutritional intake according Clin Endocrinol Metab 2010; 95(11):4877-4881. to injury extent in ulserative colitis patients. Journal of 4. Ou HY, Yang YC, Wu HT, Wu JS, Lu FH, Chang Human Nutrition and Dietetics 2013; 26(5):445-451. CJ. Increased Fetuin-A concentrations in impaired 19. Costamagna D, Costelli P, Sampaolesi M, Penna F. glucose tolerance with or without nonalcoholic fatty Role of inflammation in muscle homeostasis and liver disease, but not impaired fasting glucose. J Clin myogenesis. Mediators Inflamm 2015; 2015:805172. Endocrinol Metab 2012; 97(12):4717-4723. 20. Terzoudis S, Zavos C, Koutroubakis IE. The bone 5. Kettler M, Bongartz P, Westenfeld R, Wildberger JE, and fat connection in inflammatory bowel diseases. Mahnken AH, Bohm R, et al. Association of low fetuin-A Inflamm Bowel Dis 2014; 20(11):2207-2217. March 2021 KUWAIT MEDICAL JOURNAL 80
21. Gonçalves P, Magro F, Martel F. Metabolic inflammation creeping fat an adipose tissue? Inflamm Bowel Dis in inflammatory bowel disease: crosstalk between 2011; 17(3):747-757. adipose tissue and bowel. Inflamm Bowel Dis 2015; 23. Gambero A, Marostica M, Saad MJA, Pedrazzoli Jr J. 21(2):453-467. Mesenteric adipose tissue alterations resulting from 22. Olivier I, Théodorou V, Valet P, Castan-Laurell experimental reactivated colitis. Inflamm Bowel Dis I, Guillou H, Bertrand-Michel J, et al. Is Crohn’s 2007; 13(11):1357-1364. 81 KUWAIT MEDICAL JOURNAL March 2021
Case Report
Fusariosis as a cause of subcutaneous infection in immune-compromised patient
Khaled Alobaid1, Deepthi Nair2, Socrates Mathew Parayil3 1Mycology Reference Laboratory, Medical Laboratory Department, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait 2Microbiology unit, Department of Laboratories, Al-Amiri Hospital, Sharq, Kuwait 3Histopathology unit, Department of Laboratories, Al-Amiri Hospital, Sharq, Kuwait
Kuwait Medical Journal 2021; 53 (1): 81 - 83
ABSTRACT
Objective: To report, for the first time in Kuwait, a case of Intervention: Liposomal amphotericin B was used, but subcutaneous infection due to Fusarium solani complex and clinical response was suboptimal and the patient died highlight the important diagnostic features and therapeutic eventually. challenges. Conclusion: Treatment of such infections in the context Clinical Presentation: A patient who had rheumatoid of limited effective antifungal agents and susceptible host arthritis presented with Fusarium related subcutaneous is difficult. To improve clinical outcome, early antifungal infection, diagnosed by direct microscopy, culture and gene therapy, reversal of immune suppression and surgical sequencing. debridement are all necessary.
KEY WORDS: Fusarium, Kuwait, mycoses, soft tissue
INTRODUCTION once daily and hydroxychloroquine as a treatment Invasive fungal infections have evolved in the for rheumatoid arthritis. In April 2017, she presented last few decades. New pathogenic species have with left lower limb pain, redness and swelling. The been discovered, new susceptible hosts have been patient was normotensive and afebrile, but her lower recognized and the incidence of fungal infections limb exam showed left leg cellulitis associated with an continues to rise. Fusarium species are one of the main ulcer in the anterior aspect, with a wound diameter fungal causes of opportunistic infections in immune of 15x6 cm. Laboratory investigations revealed a compromised patients[1]. It can lead to life threatening total white blood cell count of 16.6×109/L, erythrocyte infections and is characterized by intrinsic resistance sedimentation rate of 22 mm/hr, and C-reactive to various antifungal agents[1]. In Kuwait, it hasn’t been protein of 115 mg/L. An ultrasound image of the described before, so the true burden of such infection affected leg revealed interstitial edema and swelling in is not known. Also, many clinicians are unfamiliar the subcutaneous tissue. She was treated initially with with it. The current report describes a case of locally ceftriaxone, then switched to piperacillin/tazobactam invasive soft tissue infection due to Fusarium solani due to lack of response. Despite broad spectrum complex and highlights the important aspects in the coverage, the infected site was progressing and the management of these infections. pain was severe, so pregabalin dose was increased and morphine was started to control her pain. A CASE REPORT wound swab was collected for culture which grew We report the case of a 56-year-old lady who Pseudomonas aeruginosa. In addition, a growth of white was known to have diabetes mellitus, hypertension, fluffy fungus was noted in several culture media.A ischemic heart disease and rheumatoid arthritis. Her lactophenol cotton blue mount of the fungus revealed home medications included prednisolone 7.5 mg septate hyphae and sickle shaped macroconidia.
Address correspondence to: Khaled A Alobaid, FRCPath, Mubarak Al-Kabeer Hospital, Medical Laboratory Department, Mycology Reference Laboratory, Jabriya, Kuwait. Tel: 965- 66602933; E-mail: [email protected] March 2021 KUWAIT MEDICAL JOURNAL 82
Fig. 1: H&E stain showing areas of necrosis, acute inflammatory Fig. 2: Gomori methenamine silver stain showing septate branching cells, branching hyphae, and spores. hyphae.
A presumptive identification of Fusarium species had received liposomal amphotericin B, 3 mg/kg once was made. A wound biopsy was taken and sent for daily. Tissue debridement and tapering of steroids microbiological and histopathological investigations. was recommended by the medical microbiologist. The biopsy culture also grew Fusarium species. However, steroids were not tapered because of her Histopathologic examination showed evidence of rheumatoid active disease and debridement was tissue damage with necrosis, acute inflammatory refused by the patient. She improved initially and cell infiltrates and incorporated fungal elements the pain became less severe, however, her repeated comprising of septate acute angle branching hyphae wound cultures were persistently growing Fusarium. and spores (Figures 1,2). Blood cultures were negative Liposomal amphotericin B was continued for five and serum galactomanan antigen was also negative weeks. Few weeks later, the patient developed septic by ELISA. The fungal isolate was sent to mycology shock and died eventually. reference laboratory. Gene sequencing of the internal transcribed spacer and D1/D2 domains of ribosomal DISCUSSION DNA revealed Fusarium solani complex. Antifungal This is the first reported case of Fusarium infection susceptibility testing was done by E test (bioMérieux, in Kuwait. Fusarium species is an environmental Marcy l’Etoile, France). The isolate was found to be saprophyte, which is distributed in soil, plants and resistant to caspofungin >32 µg/mL, voriconazole 12 water[1]. Around 70 species of Fusarium have been µg/mL and itraconazole >32 µg/mL, but susceptible to implicated in human and animal infections and amphotericin B 0.125 µg/mL. Accordingly, the patient most of them are grouped into different species
Fig. 3: Wound specimen examined by fluorescent microscope using Calcoflour white stainA: septate hyphae and conidia, B: septate hyphae branching at acute angles, C: crescent shaped macroconidia 83 Fusariosis as a cause of subcutaneous infection in immune-compromised patient March 2021 complexes. Fusarium solani species complex appears ACKNOWLEDGMENT to be the most common etiologic agent, followed by F. Technical assistance from Soumya Varghese and oxysporum species complex[2]. Surprisingly, Fusarium Leena Josef is thankfully acknowledged. related human infections have been rarely reported The patient was treated in the Surgical Department in the GCC region. In a study by Taj-Aldeen and of Al-Amiri Hospital. Histopathology and initial colleagues, where burden of fungal diseases have microbiology examination were carried out in Medical been studied[3], several cases have been documented Laboratory Department of Al-Amiri hospital. Further in both immune suppressed and immune competent mycology workup was carried out in Mycology individuals. Fusarium species causes a wide range Reference Lab, Mubarak Al-Kabeer Hospital. of diseases with varying severity such as keratitis, Funding Sources: Study was not funded. onychomycoses, sinusitis and fungemia[1]. In addition, Disclosure Statement: The authors have no conflicts of it can result in skin disease that manifests as either interest to declare. primary single skin lesion or metastatic multiple Statement of Ethics: The case report was approved by lesions. While the former presentation usually the ethical committee in Ministry of Health. happens after skin breakdown, the metastatic lesions are due to hematogenous spread from a different site. Author Contributions: Skin involvement is the most common presentation Khaled A Alobaid: Abstract, introduction, case of fusariosis, especially in patients with suppressed report, discussion, figure 3. Deepthi Nair: case report immunity[4,5]. The laboratory diagnosis of Fusarium and discussion. Socrates Mathew Parayil: Discussion, infections is based on direct microscopic findings, histopathology findings with microscopic figures 1 & histopathologic examination and culture result. 2. All read and approved final manuscript. Direct microscopy is a useful tool for rapid diagnosis of invasive fungal infections. Although it has low REFERENCES sensitivity, the use of optical brighteners such as calcoflour white stain improves the performance[6] 1. Nucci M, E Anaissie E. Fusarium infections in (Figure 3). Histopathologic examination can provide immunocompromised patients. Clin Microbiol Rev a presumptive diagnosis of invasive fungal infections. 2007; 20(4):695-704. In light microscopy, using Hematoxylin & eosin stain, 2. Guarro J. Fusariosis, a complex infection caused by a high diversity of fungal species refractory to treatment. Fusarium appears as hyaline (transparent) septate Eur J Clin Microbiol Infect Dis 2013; 32(12):1491-1500. hyphae, similar to Aspergillus and Scedocsporium. 3. Taj-Aldeen SJ, Chandra P, Denning DW. Burden of However, Fusarium fungi hyphae are 3-8 micrometer fungal infections in Qatar. Mycoses 2015; 58 Suppl 5:51- in diameter and they can sporulate in tissue, and hence 57. both yeast-like structures and hyphae can be present 4. Nucci M, Anaissie E. Cutaneous infection by Fusarium (as was seen in our case)[7]. The presence of hyphae and species in healthy and immunocompromised hosts: yeast-like structures together is indicative of fusariosis implications for diagnosis and management. Clin Infect in high-risk patients[1]. Our patient developed severe Dis 2002; 35(8):909-920. subcutaneous infection in the absence of classic risk 5. Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten factors such as hematologic malignancies, prolonged years’ experience at a cancer center and implications for neutropenia or organ transplantation. In addition, management. Blood 1997; 90(3):999-1008. the etiologic agent was multidrug resistant. Despite 6. Schelenz S, Barnes RA, Barton RC, Cleverly JR, Lucas receiving prolonged course of amphotericin B, the SB, Kibbler CC, et al. British Society for Medical clinical response was suboptimal and the patient died Mycology best practice recommendations for the later. The report emphasizes the important role of diagnosis of serious fungal diseases. Lancet Infect Dis adequate surgical debridement and reversal of immune 2015; 15(4):461-474. suppression in optimizing the clinical outcome[8]. 7. Guarner J, Brandt ME. Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiol Rev 2011; 24(2):247-280. CONCLUSION 8. Tortorano AM, Richardson M, Roilides E, van Fusarium infections are associated with significant Diepeningen A, Caira M, Munoz P, et al. ESCMID and morbidity and mortality among patients with ECMM joint guidelines on diagnosis and management suppressed immunity. Outcome could be improved by of hyalohyphomycosis: Fusarium spp., Scedosporium early diagnosis and involvement of multidisciplinary spp. and others. Clin Microbiol Infect 2014; 20 Suppl team. 3:27-46. March 2021 KUWAIT MEDICAL JOURNAL 84
Case Report
Robotic radical prostatectomy in patients with cerebrovascular disease history: safe but epilepsy
Bahri Gok1, Abdullah Erdem Canda2, Erem Asil3 1Yildirim Beyazit University, School of Medicine affiliated with Department of Urology, Ankara Ataturk Training and Research Hospital, Ankara, Turkey 2Department of Urology, Koc University, School of Medicine, Istanbul, Turkey 3Department of Urology, Ankara Ataturk Training and ResearchHospital, Ankara, Turkey
Kuwait Medical Journal 2021; 53 (1): 84 - 86
ABSTRACT
Among 1250 robotic radical prostatectomy procedures meningioma developed urge urinary incontinence and that were performed at our department, we identified trigerring of epilepsy in the perioperative follow-up, three patients with previous cerebrovascular disease two months after the robot-assisted laparoscopic radical history. Of those, postoperative follow-up was uneventful prostatectomy procedure. Medical management resolved for two patients. One patient who had a history of cranial the symptoms.
KEY WORDS: epilepsy, robotic radical prostatectomy, Trendelenburg
INTRODUCTION might have a significant impact on the patients with Radical prostatectomy provides long-term previous central nervous system (CNS) comorbidity. cancer control in patients with localized prostate Between February 2009 and October 2017, 1250 cancer (PCa)[1]. Robot-assisted laparoscopic radical RARP procedures were performed at our department. prostatectomy (RARP) has increasingly become a Among them, three patients were identified who had preferred treatment of choice both by patients and a history of CNS comorbidity and who underwent urologists since its introduction in 2001[2]. RARP procedure at our department. In the present We previously published our surgical technique study, we presented the characteristics, outcome and of RARP[3]. We use a transperitoneal approach patient follow-up of these three patients. in the steep (30°) Trendelenburg position. A total of 5 ports are placed, including four ports for the robotic CASE REPORT arms and camera and a 12-mm port for bedside Case 1: assistance. A 68-year-old male patient was referred for a RARP Safety of a RARP procedure in patients with procedure. He had a serum prostate specific antigen previous known cerebrovascular disease is not certain (PSA) of 7 ng/mL and a transrectal ultrasound guided yet. It was reported before that prolongation of steep prostate biopsies (TRUS-Bx) revealed PCa in three (30°) Trendelenburg position may lead to serious cores with Gleason score 4+4. Patient did not have any hemodynamic, respiratory and cerebrovascular co-morbidity. He had a history of head trauma on the adverse effects[4]. Intracranial pressure (ICP) was right side due to a car accident 30 years ago that healed suggested to increase depending on the increase with conservative management. He did not have any of venous pressure as a result of continuation of neurologic symptoms or sequels. He did not use any Trendelenburg position[5]. Therefore, increase in ICP anti-coagulant agent.
Address correspondence to: Bahri Gok, Department of Urology, Yildirim Beyazit University, School of Medicine, Ankara Ataturk Training and Research Hospital, Bilkent, Ankara 06800, Turkey. Tel: +90 5062856839; Fax: +90 3122912715; E-mail: [email protected] 85 Robotic radical prostatectomy in patients with cerebrovascular disease history: safe but epilepsy March 2021
Contrast enhanced abdomino-pelvic Case 2: computerized tomography (CT) was within normal A 68-year-old male patient was referred for a limits. A Ga-68 PSMA positron emission tomography RARP procedure who had serum PSA of 6.6 ng/ scan was carried out that showed increased ml and who underwent TRUS-Bx. PCa, Gleason expression in the prostate suggesting prostate 3+3 in six cores were detected. Abdomino-pelvic CT cancer and increased expression in right cranial area was within normal limits. He had diabetes mellitus suggesting metastasis. A neurosurgery consultation that was controlled with oral anti-diabetic drugs was carried out and a cranial magnetic resonance and was a cigarette smoker (20 packs/year). He had imaging (MRI) was requested in order to demonstrate a cerebrovascular accident seven years before and the right cranial lesion that showed a large calcified did not have any neurologic sequelea. Preoperative meningioma located in the right fronto-parietal area cranial MRI demonstrated an infarct area on the left involving the dura that opacify following iv Gad occipital and parietal areas. Patient was consulted injection (Figure 1). with neurology department and had approval for the RARP procedure. Preoperatively, patient was using acetyl salicilic acid 100 mg/day. A RARP procedure was performed and console time was 125 minutes and estimated blood loss was 50 cc. Postoperative follow-up was uneventful and patient was discharged on postoperative day 2. On postoperative 5-year follow-up, he did not have any additional neurologic complaint or complication.
Case 3: A 66-year-old male patient was referred for a RARP procedure who had serum PSA of 17 ng/ml and who underwent TRUS-Bx. PCa, Gleason 3+3 in one core was detected. Abdomino-pelvic CT and nuclear bone scan were within normal limits. He had diabetes mellitus that was controlled with oral anti-diabetic drugs. He had a cerebrovascular accident two years before and did not have any neurologic sequelea. Fig 1: Cranial MRI showing a calcified meningioma located in the right Preoperative cranial MRI showed a 3.5 mm sized fronto-parietal area involving the dura. infarct area involving pons and left paramedial areas. Patient was consulted with neurology department and A RARP procedure with bilateral extended pelvic had approval for the RARP procedure. Preoperatively, lymph node dissection was performed. Operation patient was using acetyl salicilic acid 100 mg/day. time was 2.5 hours. Estimated blood loss was 150 A RARP procedure with bilateral extended pelvic cc. Intra-operative and post-operative follow-up lymph node dissection was performed and console was uneventful and patient was discharged on post- time was 180 minutes with an estimated blood loss of operative day 3. On postoperative 2nd month follow- 100 cc. Postoperative follow-up was uneventful and up, his serum PSA was 0.0001 and he was using 1 patient was discharged on postoperative day 2. On safety pad/day with almost no urinary incontinence postoperative 1-year follow-up, he did not have any (only few drops of urine leakage during coughing). additional neurologic complaint or complication. Following the 2nd month follow-up, a temporary speech disorder with left hemiparesis occured and DISCUSSION neurology consultation suggested a transient ischemic RARP is increasingly being applied in the attack that resolved spontaneously. Patient was surgical management of localized PCa. However, discharged using clopidogrel and acetyl salicylic acid. transperitoneal RARP requires steep (30°) One month after epileptic attacks started to occur, Trendelenburg patient position in order to obtain MRI and electroencephalography tests suggested new a clear and accessible surgical open window for the onset epileptic activity triggered due to right parietal operating console surgeon. Prolongation of this meningioma. During the epileptic attacts, urinary position contributes to increase in perioperative CNS incontinence mainly as urge urinary incontinence complications depending on changes in ICP[4,6,7]. developed. Patient’s symptoms resolved following Published literature on the impact of steep (30°) initiation of antiepileptic drugs, including urge Trendelenburg patient position on cardiovascular and urinary incontinence. neurophysiological systems of the patients suggested March 2021 KUWAIT MEDICAL JOURNAL 86 that it may lead to ICP increase and this may contribute Support: None to CNS-related complications[6,8]. Increased ICP and increased ultrasonographic measurement of optic Author Contribution nerve sheath diameter in patients who underwent Writing – original draft: Bahri Gok RARP was shown by Kim et al[5]. It was also shown that Writing – review&editing: Abdullah Erdem Canda middle ear pressure significantly increased in patients Language correction: Erem Asil who underwent RARP and the authors stated that this may cause problems in patients with pre-existing ear REFERENCES disease[9]. Chalmers et al had a series of 1868 patients who 1. Roehl KA, Han M, Ramos CG, Antenor JA, Catalona underwent RARP[6]. Of those, 40 (2.1%) had retinal or WJ. Cancer progression and survival rates following CNS-related comorbidities, of which 15 had a history of anatomic radical retropubic prostatectomy in 3,478 retinal surgery and 24 had a history of cerebrovascular consecutive patients: long-term results. J Urol 2004; 172(3):910-914. accident, aneurysm and/or neurosurgery. Blood loss 2. Badani KK, Kaul S, Menon M. Evolution of robotic and surgical duration were similar in both groups. In radical prostatectomy: assessment after 2766 their series, no retinal or CNS complications occurred procedures. Cancer 2007; 110(9):1951-1958. in either group and they concluded that retinal and 3. Canda AE, Atmaca AF, Akbulut Z, et al. Results of CNS pathology present no greater risk of suffering robotic radical prostatectomy in the hands of surgeons from perioperative complications following RARP[6]. without previous laparoscopic radical prostatectomy In our series of three patients with known experience. Turk J Med Sci 2012; 42 (Suppl 1):1338-1346. preoperative CNS comorbidity, operation time was 2.5 4. Hirvonen EA, Nuutinen LS, Kauko M. Hemodynamic hours, 2 hours and 3 hours, respectively. Although no changes due to Trendelenburg positioning and pneumoperitoneum during laparoscopic hysterectomy. postoperative neurologic complication developed in Acta Anaesthesiol Scand 1995; 39(7):949-955. two of the patients who had sufficient postoperative 5. Kim MS, Bai SJ, Lee JR, Choi YD, Kim YJ, Choi SH. follow-up, an unexpected epilepsy occurred in patient Increase in intracranial pressure during carbon number 1 due to the presence of the meningioma dioxide pneumoperitoneum with steep trendelenburg located in the right fronto-parietal area involving the positioning proven by ultrasonographic measurement dura. To the best of our knowledge, this neurologic of optic nerve sheath diameter. J Endourol 2014; complication is reported for the first time in the 28(7):801-806. literature that developed in the perioperative period 6. Chalmers D, Cusano A, Haddock P, Staff I, Wagner J. Are following the RARP procedure. The degree of the preexisting retinal and central nervous system-related comorbidities risk factors for complications following Trendelenburg position and operation time might be robotic-assisted laparoscopic prostatectomy? Int Braz J factors that have an impact on ICP. Urol 2015; 41(4):661-668. In case 2, preoperative cranial MRI showed an 7. Ackerman RS, Cohen JB, Getting REG, Patel SY. Are infarct area on the left occipital and parietal areas. In you seeing this: the impact of steep Trendelenburg case 2, cranial MRI showed a 3.5 mm sized infarct area position during robot-assisted laparoscopic radical involving pons and left paramedial areas. Although no prostatectomy on intraocular pressure: a brief review neurologic problems developed in the postoperative of the literature. J Robot Surg 2019; 13(1):35-40. period in both patients, close follow-up is mandatory. 8. Mavrocordatos P, Bissonnette B, Ravussin P. Effects As no large data is available about this issue in the of neck position and head elevation on intracranial pressure in anesthetized neurosurgical patients: published literature, no strict conclusion could be preliminary results. J Neurosurg Anesthiol 2000; made. There are few reports that state no problems in 12(1):10-14. [10,11] postoperative follow-up . 9. Bozkirli F, Bedirli N, Akçabay M. Effects of step Trendelenburg position and pneumoperitoneum on CONCLUSION middle ear pressure in patients undergoing robotic Although RARP can be safely performed in patients radical prostatectomy. Turk J Med Sci 2017; 47(1):295- with CNS-related comorbidities, post-operative 299. epilepsy development due to the presence of an 10. Verdonck P, Kalmar AF, Suy K, Geeraerts T, Vercauteren existing meningioma might occur in the postoperative M, Mottrie A,et al. Optic nerve sheath diameter remains constant during robot assisted laparoscopic radical follow-up. prostatectomy. PLoS One 2014; 9(11):e111916. 11. Park EY, Koo BN, Min KT, Nam SH. The effect of ACKNOWLEDGMENT pneumoperitoneum in the steep Trendelenburg None position on cerebral oxygenation. Acta Anaesthesiol Disclosure: The authors have no potential conflicts of Scand 2009; 53(7):895-899. interest to disclose. 87 KUWAIT MEDICAL JOURNAL March 2021
Case Report
A total hip arthroplasty practice in a coxarthrosis case with hereditary multiple exostoses
Koray Basdelioglu1 , Aziz Atik2, Serdar Sargin2 1Istanbul Oncology Hospital, Istanbul, Turkey 2Department of Orthopaedics and Traumatology, Balikesir University, Medical Faculty, Balikesir, Turkey
Kuwait Medical Journal 2021; 53 (1): 87 - 89
ABSTRACT
Hereditary multiple exostoses (HME) is a skeletal Proximal femur is seen affected in 30-90% of patients with dysplasia characterised by the presence of multiple benign HME. Severe joint pain and gait abnormalities can be present osteocartilaginous masses. The incidence of HME is 1 in in these disorders affecting the daily life of patients. In this 50,000 individuals and the patients with this disease can be case report, we demonstrate total hip arthroplasty in a patient diagnosed early due to autosomal dominant inheritance. with a coxarthrosis and acetabular defect due to HME.
KEY WORDS: acetabulum, arthroplasty, defect, exostoses, hip
INTRODUCTION knees, ankles and arms. She didn’t have any family Hereditary multiple exostosis (HME) is an history of similar symptoms. There was no additional autosomal dominant inherited familial neoplasm associated comorbidity. syndrome. The syndrome shows itself as a result of On examination, the patient’s BMI was 27.5. The point mutations in the human EXT tumor suppressor patient walked with a slightly waddling gait and gene[1]. HMEs are also known as osteochondromas, could not walk for a long time. There was concentric osteocartilaginous exostoses and exostoses[2], and limitation of hip movements with flexion 80 degree, the incidence is 1 in 50,000 individuals[3]. Exocytoses rotations 15 degree each and fixed flexion deformity 20 are usually caused by outward growth from the degree. At the same time, bony swellings on both knees, metaphyses region of long bones[4]. Proximal femur ankles and lumbar region were noted in the general is seen affected in 30-90% of patients with HME[3,5]. In examination of the patient (Figure 1). Radiological this case report, we demonstrate treatment of severe examinations revealed that the patient had HME. On secondary coxarthrosis in a patient with HME by the left hip radiographs, intra-articular narrowing was difficult total hip arthroplasty. We justify our report by observed at an advanced stage and the femur head and rare presentation of such cases in the literature. neck were surrounded by exostoses (Figure 2). There was significant acetabular bone loss and upper femur CASE REPORT deformity. A 46-year-old female patient presented to our The patient was informed about the necessary clinic with a five-year history of left hip pain with surgical treatment that was total hip replacement and difficulty in walking that exacerbated within the last consent was signed by the patient. The hip joint was year. The pain was severe enough to prevent her from approached by posterolateral incision. Significant walking and performing everyday activities. She also bone defect of the acetabular roof due to pressure from complained of night pain and swellings over her hip, protruding upper femoral exostosis was found and
Address correspondence to: Koray Basdelioglu, Istanbul Oncology Hospital Cevizli Mah. Toros Cad. N : 86 34846, Maltepe, Istanbul, Turkey. Tel: +90 5534045337; E-mail: [email protected] March 2021 KUWAIT MEDICAL JOURNAL 88
Fig. 1: Exostoses seen in different parts of the skeleton in X-ray image necessitated bone grafting. The defect was repaired with the graft prepared from the healthy bone tissue of the removed femur head and the graft was fixed with two screws. Subsequently, a total hip arthroplasty (THA) operation was performed (Figure 3). The hip arthroplasty was made with CORAIL® Total Hip System [Depuy Synthes Companies, USA]. The acetabular component was cementless with a diameter of 58 mm. Two screws (25 mm and 30 mm) were used for fixation of acetabular cup. Ceramic-on-ceramic bearing was used with a head diameter of 36 mm and 13 mm femoral stem. The total skin-to-skin operation time was 65 minutes. The patient was not allowed full weight-bearing for three weeks due to the acetabulum defect and graft Fig. 3: Postoperative X-ray image of the hip repair. Partial weight-bearing was allowed at the end had healed and she had no pain complaints. Patient’s of the third week. Transition to full weight-bearing Harris hip score was 31 at the preoperative stage and it happened at the end of the fifth week. At follow-up improved to 83 at the end of the second year of follow- after 24 months, the hip was stable, the patient’s gait up.
Fig. 2: Preoperative X-ray image of the hip 89 A total hip arthroplasty practice in a coxarthrosis case with hereditary multiple exostoses March 2021
DISCUSSION literature. HME is a skeletal dysplasia characterised by ACKNOWLEDGMENT the presence of multiple exostoses[6]. The incidence Authors declare that there is no conflict of interest. is 1/50,000 and the patients with this disease can Author contribution: be diagnosed early due to autosomal dominant Koray Basdelioglu: Author and Surgeon inheritance[7,8]. Exostoses often occur near the physis Aziz Atik: Surgeon on the metaphysis of long bones[6]. Most common Serdar Sargin: English editing and surgeon localizations are distal femur, proximal tibia and proximal humerus. Exostoses of the pelvis and REFERENCES proximal femur are more difficult to diagnose because they rarely manifest symptoms[8]. 1. Porter DE, Simpson AH. The neoplastic pathogenesis of Localization of exostoses in the proximal femur solitary and multiple osteochondromas. J Pathol 1999; indicates the patient’s complaint[9]. Exostoses in the 188(2):119-125. medial of proximal femur and periacetabular region 2. Kaissi AA, Ganger R, Klaushofer K, Grill F. Spinal exostosis in a boy with multiple hereditary exostoses. may cause severe painful symptoms in the patient. Case Rep Orthop 2013; 2013:758168. Concurrently, these exostoses alter the anatomy of 3. Schmale GA, Conrad EU III, Raskind WH. The natural the hip, disrupt the acetabulum structure and cause history of hereditary multiple exostoses. J Bone Joint acetabular dysplasia and coxa valga[5,10]. Acetabular Surg Am 1994; 76(7):986-992. dysplasia and coxa valga can be found in 25% of 4. Solomon L. Hereditary multiple exostosis. Am J Hum patients with HME[5]. Exocytoses in the lateral proximal Genet 1964; 16(3):351-363. femoral regions compared to the medial proximal 5. Shapiro F, Simon S, Glimcher MJ. Hereditary Multiple femur and periacetabular exostoses cause less pain in Exostosis. Anthropometric, roentgenographic and patients and lead to less anatomical changes[9]. clinical aspects. J Bone Joint Surg Am 1979; 61(6A):815- 824. Arthroplasty operations in HME patients are 6. Heck RK. Benign bone tumors and nonneoplastic difficult and challenging procedures in consequence of conditions simulating bone tumors. In: Heck RK, complex and variable anatomic structures caused by Jr. Campbell Operative Orthopaedics. 11th ed. exocytoses in the joint circumference, accompanying Philadelphia, PA: Mosby/Elsevier; 2008. p. 860-862 . coxa valga, acetabular dysplasia, limb length differences 7. Makhdom AM, Jiang F, Hamdy RC, Benaroch TE, and defects in bone structures[11]. In the literature, Lavigne M, Saran N. Hip joint osteochondroma: there are few published reports about arthroplasty systemic review of literature and report of further three operations on osteoarthritis patients with HME[11-14]. cases. Adv Orthop 2014; 2014:180254. Vaishya et al reported a bilateral hip arthroplasty 8. Porter DE, Benson MK, Hosney GA. The hip in hereditary multiple exostoses. J Bone Joint Surgery Br which they performed on a 27-year-old patient with 2001; 83(7):988-995. [11] HME . Mesfin et al reported two patients with HME 9. El-Fiky TA, Chow W, Li YH, To M. Herditary multiple [14] who underwent THA and total knee arthoplasty . exostoses of the hip. J Orthop Surg (Hong Kong) 2009; Unlike other publications in the literature, there was an 17(2):161-165. acetabular defect in our patient. We solved the defect 10. Malagon V. Development of hip dysplasia in hereditary problem in the acetabulum with an autograft that we multiple exostoses. J Pediatr Orthop 2001; 21(2):205- formed and shaped from the patient’s femur head. We 211. fixed this graft to the defect area with one screw. We 11. Vaishya R, Swami S, Vijay V, Vaish A. Bilateral total hip performed the reaming after fixation of the autograft. arthroplasty in young man with hereditary multiple exostoses. BMJ Case Rep 2015; 2015:bcr2014207853. THA is a treatment method that provides 12. Moran M, Kreig AH, Boyle RA, Stalley PD. Bilateral symptomatic relief, functional improvement and more total hip arthroplasty in severe hereditary multiple comfortable and convenient daily life, even though exostoses: a report of two cases. Hip Int 2009; 19:279- the procedure may be difficult because of distorted 282. anatomy and accompanying anomalies in HME 13. Annapureddy SR, Chapman TWL, Charnley GJ. Dual patients. aetiology hip pain requiring total hip arthroplasty in hereditary multiple exostoses: a case report and review CONCLUSION of the literature. Hip Int 2002; 12(4):397-399. Coxarthrosis due to HME is a very difficult 14. Mesfin A, Goddard MS, Tuakli-Wosornu YA, Khanuja HS. Total hip and knee arthroplasty in patients with condition to manage hip arthroplasty. Patient groups hereditary multiple exostoses. Orthopedics 2012; with long-term follow-ups are needed to evaluate the 35(12):e1807-10. anatomical and functional outcomes of THA in HME patients due to the small number of studies in the March 2021 KUWAIT MEDICAL JOURNAL 90
Case Report
Patellar tendon ganglion cyst with Osgood Schlatter disease: A rare coexistence
Nilufer Aylanc, Nebil Eker, Mustafa Resorlu Department of Radiology, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale, Turkey
Kuwait Medical Journal 2021; 53 (1): 90 - 92
ABSTRACT
Patellar tendinopathy is one of the causes of anterior findings, there was bone irregularities and bone marrow knee pain. Osgood Schlatter disease (OSD) is another edema on the tibial tuberosity and osseous fragment reason for pain in this location, occasionally accompaning neighboring these structures with surrounding soft tissue patellar tendinopathy. We present magnetic resonance edema. imaging and radiographic findings in a case of OSD with Patellar tendinopathy is a pathophysiological process incidentally diagnosed patellar intratendinous ganglion that can be seen in people with knee pain and can occur that is a rare coexistence. We report a case of a 30-year-old due to recurrent trauma. Radiological findings can be male who presented with anterior knee pain, prolonged encountered in a wide range from mild structural changes for 20 years. In radiologic evaluation, there was opacity in in the tendon due to degeneration to intratendinous the patellar tendon and there was osseous fragment near lesions and adjacent bone pathologies such as OSD. the tibial tuberosity on lateral radiographic image. Except Therefore, there is a relationship between two pathologies for this lesion, patellar tendon had the signal intensity and magnetic resonance imaging plays an important role changes indicating patellar tendinopathy. Besides these in the radiological diagnosis of these two entities.
KEY WORDS: ganglia, pain, patella, tendinopathy, tibia
INTRODUCTION findings, patellar tendinopathy is also seen at the same Ganglion cysts are benign lesions that can be time in different forms[3]. We report a case where these seen in any part of the body, but frequently seen in two entities were seen, both patellar ganglion cyst hand, wrist, foot, ankle and knee side. They can be and tibial apophysitis, presenting with anterior knee seen in bones, joints, tendon sheaths or in soft tissues. pain. Both pathologies are the result of exposure of the Intratendinous ganglia are rare lesions, while patellar knee to chronic micro traumatic processes and their tendon replacement is almost rare[1]. Ganglion cysts coexistence is very rare. placed on knee side may be one of the symptoms of anterior knee pain. Unlike synovial cysts, these lesions CASE REPORT have no synovial epithelial and occur secondary to A 30-year-old man was referred to the Department mucoid degeneration of connective tissue because of Orthopedic Clinic with an increasing prevalence of occasionally chronic irritation and repetitive of anterior knee pain prolonged for 20 years. On traumas[2]. Osgood Schlatter disease (OSD) is also conventional radiography, there was slight opacity one of the causes of anterior knee pain, caused by in the patellar tendon tract on lateral radiograph repetitive microtraumas to anterior aspect of the tibia, and mild irregularity on tibial tuberosity contour leading to processes from tibial tuberosity edema to where the patellar tendon inserts (Figure 1). On bone fragmentation at this side. With all the osseous magnetic resonance images, there was a lesion slightly
Address correspondence to: Nilufer Aylanc, Associate Professor, Department of Radiology, School of Medicine,Canakkale 18 Mart University, 17100 Canakkale, Turkey. Tel: +90 2862635950; +90 5058569606; E-mail: [email protected] 91 Patellar tendon ganglion cyst with Osgood Schlatter disease: A rare coexistence March 2021
diameter of 7.9 mm. Mild bone marrow edema were also seen in soft tissues adjacent to the bone fragment and in adjacent tibial tuberosity, clearly seen on fat saturated images (Figure 2). An informed consent form was taken from the patient for case presentation.
DISCUSSION OSD and ganglion cysts are rare diseases on their own, and it is very rare to see both in the same region. Ganglion cysts are benign lesions and can be seen in any part of the body, especially in hand, foot, wrist, ankle and knee[3]. In those anatomical localizations they can be seen in soft tissues, in tendons or tendon sheaths, in articular capsule or they can be seen in bones[4]. Histologically, with no synovial component, they have fibrotic wall and are not classified as true cysts. It is suggested that mucinous degeneration in collagen fibers and active mucinous secretion because of hypercellularity, takes a role in the occurrence of these cystic lesions[3]. Fig 1. Lateral knee radiography; mild opacity in the trace of patellar However, repetitive microtraumas take an tendon (red arrow) and a bone fragment (white arrow) superiorly important role in etiology[5]. Ischemia and chronic to tibial tuberosity. irritation of tendon resulting in degeneration can be another reason for cystic formation, or these cystic hyperintense on sagittal T1 and hyperintense on lesions may be congenital[2,3,5]. sagittal proton density sequence in the patellar tendon, Tendinous degeneration can cause ruptures in the dimensions of 20x5x5 (CCxAPxT), indicating over time. However, during degeneration, different cystic lesion. Signal changes suggesting tendinopathy histopathologic processes can occur such as hypoxia, except from this lesion were observed in tendon also. mucoid degeneration, tendolipomatosis and calcific On the distal portion of the tendon adjacent to the tendinopathy, alone or together. Hypoxia is the tibia, a slight contour irregularity on the T1 weighted most common pathology in tendon ruptures, that series and a bone fragment with a signal characteristic causes necrosis in tenositis, longitudinal detachment like that of the neighboring bones, were observed in a in collagen fibrils and structural distortion. In
Fig 2. MR images; sagittal fat saturated proton density (a) and T1 weighted fast spin echo image (b); signal changes reflecting to patellar tendinopathy and cystic lesion within the tendon (red arrow). A bony fragment (white arrow) seen superiorly to tibial tuberosity. March 2021 KUWAIT MEDICAL JOURNAL 92 tendolipomatosis, irregular destructive cavitations AKNOWLEDGMENT come to occur due to lipocytes accumulation between We want to thank Assoc. Prof. Dr. Burak Kaymaz, deep collagen and finally result in reducing in the Canakkale Onsekiz Mart University, School of tendon’s tensile strength[6,7]. Calcific tendinopathy Medicine for treatment and his kind support. with calcium accumulation in collagen fibers is seen as The authors declare no conflict of interest. a thickening in the tendon and inflammation around Funding: None calcification[6,7]. Mucoid degeneration in ligaments Contributions: Nilufer Aylanc gathered information and tendons cause detachment in collagen fibers and and wrote the article; Nebil Eker made a literature liquefaction and result in mucin accumulation[6]. survey and Mustafa Resorlu made revisions and Intratendinous ganglion cysts, especially in patellar corrections. tendon, is a very rare localization for ganglions and are seen frequently in sportsmen who also have underlying REFERENCES tendinopathy, as reported in literature[4]. OSD is another pathology that can cause chronic degenerative process 1. McCarthy CL, McNally EG. The MRI appearance of in knee and can be presented with anterior knee pain cystic lesions around the knee. Skeletal Radiol 2004; like patellar tendinopathy. OSD can also be seen with 33(4):187-209. fragmentations from tibial tuberosity that may result 2. Jose J, O’Donnell K, Lesniak B. Symptomatic intratendinous ganglion cyst of the patellar tendon. in chronic irritation resulting from chronic repetitive Orthopedics 2011; 34(2):135. traumas in anterior tibial tuberosity, with apophysitis 3. Mebis W, Jager T, Van Hedent E. Intratendinous and distal patellar tendinopathy. In etiology, jumping patellar ganglion cyst with coexistant Osgood and kicking movements in the etiology play a role and Schlatter Disease. J Belg Soc Radiol 2016; 100(1):86. OSD is more often seen in the male population. The 4. Touraine S, Lagadec M, Petrover D, Genah I, Parlier- cases clinically present with pain, swelling, tension in Cuau C, Bousson V, et al. A ganglion of the patellar the anterior knee and complaints, with aggravation of tendon in patellar tendon-lateral femoral condyle these symptoms during sports activities[8,9]. friction syndrome. Skeletal Radiol 2013; 42(9):1323- In radiographs, irregular contour and 1327. 5. Saha P, Bandyopadhyay U, Mukhopadhyay AS, fragmentation in tibial tuberosity with surrounding Kundu S, Mandal S. Ganglion cyst of knee from soft tissue swelling can be seen, especially on lateral Hoffa’s Fat Pad protruding anterolaterally through radiograph. On magnetic resonance images, patellar retinacular rent: A case report. J Orthop Case Rep tendinopathy can be detected better as increase in 2015; 5(3):69-71. tendon thickness and signal pattern and in pathologies 6. Kannus P, Józsa L. Histopathological changes in tibial tuberosity, especially in the early period[3]. In preceding spontaneous rupture of a tendon. A the differential diagnosis of OSD, separate ossification controlled study of 891 patients. J Bone Joint Surg centers, tibial tuberosity avulsion fractures, Sinding- Am 1991; 73(10):1507-1525. Larsen-Johansson syndrome and jumper’s knee can be 7. Arner O, Lindholm A, Orell SR. Histologic changes in subcutaneous rupture of the Achilles tendon: a thought. study of 74 cases. Acta Chir Scand 1959; 116(5-6):484- In Sinding-Larsen-Johansson, chronic traction 490. damage with patellar tendinopathy and bony findings, 8. Martinoli C, Valle M. Pediatric musculoskeletal like OSD, can be seen in the inferior pole of patella. In ultrasound. In: Bianchi S, Martinoli C, (eds.) jumper’s knee, patellar tendinopathy is seen frequently Ultrasound of the musculoskeletal system. Berlin, in elderly adolescents and many authors suggest that it Germany: Springer; 2007. p. 921-959. is the adult form Sinding-Larsen-Johansson disease[10]. 9. Long G. Musculoskeletal trauma. In: Carty H, Brunelle F, Stringer DA and Kao SCS. (eds.) Imaging nd CONCLUSION children. Volume 1. 2 ed. Churchill Livinstone, Edinburgh; 2005. p. 65-240. Both patellar tendon ganglion and Osgood 10. Dupuis CS, Westra SJ, Makris J, Wallace EC. Injuries Schlatter disease are not uncommon. Co-existence of and conditions of the extensor mechanism of the these two is a rare phenomenon but with no specific pediatric knee. Radiographics 2009; 29(3):877-886. clinical implications. This case is presented for its rare occurrence. 93 KUWAIT MEDICAL JOURNAL March 2021
Case Report
Unusual location of the hydatid cyst: Coexistence of serratus anterior muscle and lung
Ibrahim Ethem Ozsoy, Mehmet Akif Tezcan Department of Thoracic Surgery, University of Health Sciences, Kayseri, Turkey
Kuwait Medical Journal 2021; 53 (1): 93 - 96
ABSTRACT
Hydatid cyst, although seen less each year, is still a serious occurred concurrently on the lung and serratus anterior public health problem in countries such as Turkey where muscle. In our case, the cyst was first thought to be a mass. livestock is an important source of income and adequate When the germinative membrane was expectorated to the measures are not taken concerning protection against bronchus, the hydatid cyst was diagnosed with fiberoptic the disease. We present a rare hydatid cyst case which bronchoscopy.
KEY WORDS: germinative membrane, hydatid cyst, lung, serratus anterior
INTRODUCTION with left chest pain approaximately 8 months ago and Hydatid cyst, although seen less each year, is still a chest X-ray was taken, and an oval-shaped lesion was serious public health problem in countries such as detected in the left hilar region (Figure 1). Computerized Turkey where livestock is an important source of thoracic tomography was then performed, and a mass income and adequate measures are not taken lesion with a size of 35x55 mm, located in the concerning protection against the disease[1]. paramediastinal region of the left upper lobe (Figure Hippocrates (460-377 BC) reported the presence of 2), and a mass lesion adjacent to the serratus anterior hydatid cysts in cattle and swine and defined the muscle was seen (Figure 3). In the history of the patient, hydatid cyst that he found in the human liver as a the lesion in the lung was evaluated to be a solid lesion; ‘pouch filled with water’ (Jecur aqua repletum)[2]. It computed tomography-guided tru-cut needle biopsy can settle into almost any organ/tissue in the body. The was performed and histopathological diagnosis was most common settling organs are liver and [1]lungs . reported as a chronic inflammation in another health Hydatid cysts located in muscle or soft tissue constitute center. Approximately 8 months after the transthoracic 1-5% of all echinococcal infections in endemic areas[3]. biopsy procedure, the patient was admitted to the We present a rare hydatid cyst case which occurred chest diseases outpatient clinic with dyspnea and FOB concurrently on the lung and serratus anterior muscle. was performed. During the FOB procedure, the dirty In our case, the cyst was first thought to be a mass. white material seen in the left upper lobe entrance was When the germinative membrane was expectorated to removed with forceps (Figure 4). Pathological the bronchus, the hydatid cyst was diagnosed with examination revealed a germinative membrane and fiberoptic bronchoscopy (FOB). Echinococcus granulosus infection. The indirect hemagglutination test was negative in the patient. The CASE REPORT patient, who had complaints of hemoptysis and had A 23-year-old male patient applied to the polyclinic pneumonia after FOB, was hospitalized in the thoracic
Address correspondence to: Ibrahim Ethem Ozsoy, Assistant Professor, Department of Thoracic Surgery, University of Health Sciences, Barbaros Mh. Turgut Reis Cd. 22/26 Kocasinan, Kayseri, Turkey. Tel: +90 0352 315 77 00; +90 0506 855 29 98; E-mail: [email protected]; ORCID ID: 0000-0003-2722-5309 March 2021 KUWAIT MEDICAL JOURNAL 94
Fig. 2: Paramediastinal lesion in the left lung upper lobe on CT.
Fig. 1: Thorax graphy of the patient surgery clinic and treated with antibiotics and albendazole for about two weeks. Abdominal ultrasonography was performed and there was no pathology in the liver. The patient was then operated and left posterolateral thoracotomy was performed. First, the lesion in the serratus anterior muscle was excised (Figure 5). When the lesion was opened with a scalpel, it was seen that there was a germinative membrane and a purulent fluid in the membrane (Figure 6). Cystotomy was performed by entering the thorax and the non-expectorated part of the germinative membrane was removed, bronchial air leak was sutured and capitonnage was performed. The diagnosis of both lesions was confirmed Fig. 3: CT image of the lesion located in the serratus anterior muscle
Fig. 4: The membrane at the left upper lobe entrance on the FOB and the image in the solution of the membrane. 95 Unusual location of the hydatid cyst: Coexistence of serratus anterior muscle and lung March 2021
diseases, bronchoscopy can be performed in cases required for differential diagnosis. Endobronchial white-yellow bright cyst membrane can be seen in bronchoscopy. Considering that it may cause cyst rupture, it is not routinely recommended in the diagnosis of hydatid cyst. However, in the presence of suspicion in the diagnosis of hydatid cyst clinically and radiologically, and especially if there is suspicion of malignancy, it should be done[10,11]. In our patient too, approximately 8 months after transthoracic biopsy, since the cyst was perforated and opened into the bronchus, the diagnosis was made by membrane expectoration and removal of the membrane by FOB. The membrane was seen by the excision of the mass in Fig. 5: Operation image of the lesion in the serratus anterior muscle the serratus anterior muscle and it was histopathologically confirmed. histopathologically as hydatid cyst. The patient was Although the surgery to be performed in ruptured discharged on the postoperative fifth day. cysts may seem to be the same in technical terms, it will be necessary to consider some issues. The DISCUSSION management of ruptured hydatid cyst in the acute Hydatid cyst disease is common in the whole stage should mainly be directed to major complications world. Due to the lack of appropriate data in many resulting from the discharge of cyst content towards countries, the assessment of the current situation the pleural cavity or tracheobronchial tree. After the cannot be fully performed. High parasitic prevalence acute period, conservative treatment should be is reported in Eurasia (e.g. Mediterranean countries, performed to provide as much lung tissue as possible. Russian Federation and Turkic Republics), Africa After the infected cyst is opened and the contents are (North and Eastern regions), Australia and South evacuated, the cavity must be thoroughly cleaned. In America[4,5]. In roughly 60% of the patients, hydatid the presence of severe pericystic inflammation and cyst settles in the liver and in 30% of the patients, it severe pneumonia, lobectomy may have to be settles in the lungs; and it is usually solitary in the preferred, even if it is not desired at all[12]. In our lungs[6,7]. Parasites that cannot hold on to both organs can rarely settle into other parts of the body with systemic circulation[8]. The coexistence of the hydatid cyst of the serratus anterior muscle and the hydatid cyst of the lung is even more rare. Symptoms and findings in patients vary according to the location and size of the cyst. The most common symptoms in the literature are cough (53-62%), chest pain (49-91%), dyspnea (10-70%) and hemoptysis (12- 21%). Less frequently, weakness, nausea and vomiting can be seen[6,7]. If the cyst is located in the soft tissue or muscle, it may be seen as swelling in the settled area. In our patient, the first symptom is chest pain. The application complaint after transthoracic biopsy was shortness of breath. His complaint after FOB was hemoptysis. The most diagnostic symptom is expectoration of cyst fluid or membranes. This means that the cyst is perforated and open to the bronchus. After perforation, the general condition of the patient may be impaired and chest pain may develop with shortness of breath. Acute hypersensitivity reactions, including fever and anaphylaxis, are the most prominent findings of ruptured cyst. Very rarely, there may be deaths due to anaphylaxis[6,9]. Since it is a disease that mimics many Fig. 6: Excised specimen from the serratus anterior muscle March 2021 KUWAIT MEDICAL JOURNAL 96 patient, pneumonia and hemoptysis were treated as a 3. Tarhan NC, Tuncay IC, Barutcu O, Demirors H, result of cyst perforation and membrane expectoration. Agildere AM. Unusual presentation of an infected Then, by performing a thoracotomy, the cyst in the primary hydatid cyst of biceps femoris muscle. Skeletal serratus anterior muscle was excised and the infected Radiol 2002; 31(10):608-611. 4. Eckert J, Deplazes P. Biological, epidemiological, cyst in the lung was opened and the contents were and clinical aspects of Echinococcosis, a zoonosis of evacuated. Lastly, capitonnage was performed. ıncreasing concern. Clin Microbiol Rev 2004; 17(1):107- 135. CONCLUSION 5. Romig T. Epidemiology of echinococcosis. Langenbecks Physicians working in endemic areas should Arch Surg 2003; 388(4):209-217. consider hydatid cyst in the neoplasm evaluation 6. Kokturk O, Guruz Y, Akay H, Akhan O, Biber C, processes and determine their approach methods Cağırıcı U, ve ark. Toraks Derneği Paraziter Akciğer accordingly. Hastalıkları Tanı ve Tedavi Rehberi. Toraks Dergisi 2002; 3:1-16. 7. Çobanoğlu U, Sayır F, Mergan D. Tanısal İkilem: ACKNOWLEDGMENTS Hidatik hastalığı 11 olgunun analizi. Türkiye Parazitol Conflict of Interest:No conflict of interest was declared Derg 2011;35:164-168. by the authors. 8. Yüncü G, Sevinç S. Akciğer hidatik kistleri. Ökten İ, Financial Disclosure: This was not an industry Güngör A, editörler. Göğüs cerrahisi. Ankara: 2003: supported study. The authors declare that this study 1011-1023. has received no financial support. 9. Kuzucu A, Soysal O, Ozgel M, Yologlu S. Complicated All authors contributed to the design and hydatid cysts of the lung: clinical and therapeutic implementation of the research, to the analysis of the issues. Ann Thorac Surg 2004; 77(4):1200-1204. results and to the writing of the manuscript. All authors 10. Komurcuoglu B, Ozkaya S, Cirak AK, Yalniz E, Polat G. Pulmonary hydatid cyst: The characteristics of patients discussed the results and contributed to the final and diagnostic efficacy of bronchoscopy. Exp Lung Res manuscript. 2012; 38(6):277-280. 11. Kut A, Cakir E, Midyat L, Cakir FB, Ozaydin E. REFERENCES Endobronchial findings of hydatid cyst disease: a report of five pediatric cases. Pediatr Pulmonol 2012; 1. Yalçınkaya İ. Önsöz. In: Yalçınkaya İ. (ed.), Akciğer 47(7):706-709. Hidatik Kisti. Ankara, Türkiye Solunum Araştırmaları 12. Üçvet A, Gürsoy S. Cerrahi yaklaşım. In: Yalçınkaya İ. Derneği 2016: 9-10. (ed.), Akciğer Hidatik Kisti. Ankara, Türkiye Solunum 2. McManus DP, Zhang W, Li J, Bartley PB. Echinococcosis. Araştırmaları Derneği, 2016:51-67. Lancet 2003; 362(9392):1295-1304. 97 KUWAIT MEDICAL JOURNAL March 2021
Case Report
Invasive fungal rhinosinusitis in a chronic kidney disease patient
Lubna A Khreesha, Suhaib M Eid, Mohammad Y Ghunaim Department of Otolaryngology, Jordan University Hospital, Amman, Jordan
Kuwait Medical Journal 2021; 53 (1): 97 - 100
ABSTRACT
A rare disease in our country, invasive fungal rhinosinusitis management and a dedicated team, we have successfully (IFRS) is a fatal disease if left untreated. We have faced a managed to tackle this challenge. We present this case hoping challenging case of IFRS at our institute and with proper to provide helpful information about this disease.
KEY WORDS: amphotericin B deoxycholate, end stage renal disease, functional endoscopic sinus surgery
INTRODUCTION MRI is used to detect soft tissue abnormalities and Invasive fungal rhinosinusitis (IFRS) is a rare involvement of adjacent structures. aggressive disease, sometimes leading to death, The combined use of surgery and antifungal characterized by invasion of sinonasal tissue directly amphotericin B reduced mortality to 15-50%. With by fungi – most commonly Aspergillus and Mucor advances in endoscopic sinus procedures, the species. It occurs rapidly within hours to days and it morbidity also declined compared to traditional open may extend to surrounding tissue and organs like hard surgical debridement[8,9]. palate, orbital cavity and intracranially in advanced cases[1,2]. CASE REPORT IFRS is also called fulminant fungal rhinosinusitis[3] We report the case of a 37-year-old man with a with duration less than four weeks because of its rapid medical history significant of end stage renal disease and fatal nature[4]. It requires urgent diagnosis and due to focal segmental glomerulosclerosis, hepatitis management, otherwise mortality can reach 50-80%[5,6]. C and thrombotic thrombocytopenic purpura Facial swelling is the most common sign and who underwent three renal transplants, the last of symptom followed by fever, nasal congestion and which was six months prior to presentation. He was ophthalmoplegia, as recent studies have shown. Those on immunosuppressive treatment in the form of might also be accompanied by epistaxis, impaired mycophenolic acid, tacrolimus and prednisolone. vision and meningitis that progress within hours[7]. The patient was referred to our emergency Diagnosis is based on endoscopy, biopsy and department after he was diagnosed with invasive histopathology. Endoscopic findings include signs fungal rhinosinusitis by frozen section biopsy during a of mucosal ischemia with white or pale discoloration functional endoscopic sinus surgery (FESS) in another while necrosis presents as eschars as a result of fungal hospital. On presentation, the patient was complaining angioinvasion, black crusts or sloughing of the septum, of continuous moderate to severe dull right-sided facial which might result in perforation[5]. pain that was associated with throbbing right retro- Computed tomography (CT) and magnetic orbital pain and blurring of vision. Upon examination, resonance imaging (MRI) are the most useful during the patient was afebrile and had right facial and the evaluation of IFRS and preoperative preparations. periorbital swelling. No ulcerations were noted in
Address correspondence to: Dr. Suhaib M Eid, Otolaryngology Resident, Jordan University Hospital, Queen Rania Street, PO box: 1105, Postal code: 11910, Amman, Jordan. Tel: 00962-79623 0120 / 00962-788122286; E-mail: [email protected] March 2021 KUWAIT MEDICAL JOURNAL 98
Fig. 1: Findings in the sinus CT and MRI of the brain before surgical intervention. A) axial cut sinus CT with involvement of the orbital cavity (yellow arrow); B) coronal cut sinus CT with marked thinning of the lamina papracia (red arrow) and opacification of ethmoida air cell (white arrow) CT the hard palate and there were no signs suggestive of from which a frozen section biopsy was taken which cranial nerve involvement. Nasal examination could showed fungal hyphae and the diagnosis was finalized not be done due to anterior nasal packing. as IFRS. Revision of the patient’s old charts revealed that he Few hours after presenting to our hospital, he was admitted to our hospital multiple times, where he suffered from sudden visual loss in his right eye. was treated as a case of fever of unknown origin and Funduscopic examination revealed right central retinal cluster headache. artery occlusion as the cause. An increased intraocular In the other hospital, he presented complaining of pressure in left eye was also noted. severe headache, right clear nasal discharge that turned A new sinus CT scan and brain MRI (Figure 2) black in color, right eye epiphora and numbness over showed widening of the right osteomeatal complexes the tip of his nose that spread to the right side of his and non-visualization of superior and middle turbinate, face. A sinus CT scan and brain MRI (Figure 1) lead confirming the diagnosis of sino-orbital IFRS. to the initial diagnosis of chronic rhinosinusitis. FESS Intravenous amphotericin B deoxycholate and was done, revealing black necrotic lesions in right piperacillin/tazobactam were started, mycophenolic middle turbinate and the nasal septum posteriorly, acid was discontinued, and tacrolimus doses were
Fig. 2: Brain MRI (A) and sinus CT (B) after first surgical intervention 99 Invasive fungal rhinosinusitis in a chronic kidney disease patient March 2021
drugs in a varsity of conditions and the high incidence of diabetes mellitus associated infections[13,14]. The fungi that causes mucormycosis is related to the Zygomycete class, of the Mucorales order, represented by various genera including Mucor, Rhizopus, Rhizomucor and Absidia[14]. Patients with mucormycosis presenting clinically with an acute sinusitis picture including headache, nasal obstruction, fever, euphoria, facial swelling and in some cases ophthalmoplegia, may be present with a rapid progression to adjacent structures through vascular pathway, and in some cases, the progression can reach the brain tissue. Clinical picture of progressed disease include palate ulceration, necrotic tissue and the involvement of nasal turbinate[15,16]. The diagnosis of mucormycosis is confirmed by histology, but it could be indicated by imaging showing involvement of areas in suspicion[17]. A Fig. 3: Histopathological examination of the operation material high degree of clinical suspicion is required in the using GMS and PAS stain, aseptate hyphae typical of mucormycosis observed (arrow). diagnosis of mucormycosis and prompt medical and surgical management is to be started due to the high impact of the disease upon patient life due to extensive adjusted with monitoring of his serum glucose progression into vital structures and rapid progression, and creatinine levels. He also underwent multiple even in cases where histological confirmation is not endoscopic debridement of any necrotic lesion found obtained yet[14,15]. until healthy mucosa was seen. Microbiological The treatment of complicated mucormycosis in cultures of the debrided tissue showed the fungus to a patient with renal transplant is multidisciplinary, be of the Mucor species (Figure 3). involving surgical and medical management. The After a month of amphotericin B deoxycholate approach to this should be driven by several points. treatment, the patient’s creatinine level elevated First, an early diagnosis must be made (due to the from his baseline of 1.5 to 4.2. Hence, amphotericin B need for high degree of suspicion), followed by early deoxycholate was discontinued in favor of intravenous initiation of treatment, both surgical and medical, liposomal amphotericin B (3 mg/kg/day). preferably in the first five days. This has allowed One month later, the patient underwent another a decrease in mortality rate from 82.9% to 48.6%. FESS for follow up. No necrotic lesions were found Thirdly, all predisposing factors must be controlled and blind biopsies from the right maxilla, right orbital and removed, particularly glucocorticoid use that lamina papyracea, left maxilla, left nasal wall near the should be stopped or minimized[15,18,19]. Lastly, the most lamina papyracea and the nasal septum showed no important step in the management is the extensive evidence of mucormycosis. The patient was discharged debridement of affected tissues to prevent further with monthly follow-ups and biopsies. progression due to angioinvasion, necrosis and poor The patient was doing well after eight months drug penetration to the affected area[14,19]. of treatment with no evidence of disease activity or Medically, amphotericin B in both forms, recurrence. deoxcholate and liposomal, in combination with posaconazle have been used as antifungal drugs[14], DISCUSSION the duration of which is dependent on clinical and Mucormycosis affecting post renal transplant radiological picture. Intravenous amphotericin B patient have shown that they are uncommon with deoxycholate is associated with nephrotoxicity and an incidence of 1-14% of transplant recipients[10]. elevation of creatinine level. In contrast, liposomal Mucormycosis accounts for 0.2-1.2% of IFRS in amphotericin B and amphotericin B lipid complex are recipients of renal transplant[11,12]. Mucormycosis less harmful on the kidneys[20,21]. occupies 3rd place among its piers (candidiasis, A multi-disciplinary step-wise approach has aspergillosis). By definition, it’s an opportunistic allowed a patient who attended our hospital to be mycotic infection caused by multiple types of fungi successfully treated, despite wide involvement of worldwide[13]. Studies have shown an increased paranasal sinus and orbit, although with major incidence due to large use of immunosuppressant functional and aesthetic consequences. March 2021 KUWAIT MEDICAL JOURNAL 100
CONCLUSION 7. Turner JH, Soudry E, Nayak JV, Hwang PH. Survival Zygomycosis is a debilitating fungal disease with outcomes in acute invasive fungal sinusitis: a poor prognosis that should be suspected early in any systematic review and quantitative synthesis of immunocompromised host who presents with fever of published evidence. Laryngoscope 2013; 123(5):1112- 1118. unknown origin or persistent upper respiratory tract 8. Eliashar R, Resnick IB, Goldfarb A, Wohlgelernter J, symptoms not explained by other causes. A definitive Gross M. Endoscopic surgery for sinonasal invasive and early diagnosis of the disease by biopsy is essential aspergillosis in bone marrow transplantation patients. for prompt treatment. The mainstay treatment of Laryngoscope 2007; 117(1):78-81. the disease is the combination of endonasal surgical 9. Alobid I, Bernal M, Calvo C, Vilaseca I, Berenguer J, debridement and antifungal medications. Alos L. Treatment of rhinocerebral mucormycosis by combination of endoscopic sinus debridement and ACKNOWLEDGMENT amphotericin B. Am J Rhinol 2001; 15(5):327-331. We at the Department of Otolaryngology, Head 10. Einollahi B, Lessan-Pezeshki M, Pourfarziani V et al. Invasive fungal infections following renal and Neck in the University of Jordan acknowledge transplantation: A review of 2410 recipients. Ann the efforts of all the staff who helped in making this Transplant 2008; 13(4):55-58. a success. 11. Chkhotua A, Yussim A, Tovar A, Weinberger M, Sobolev V, Bar-Nathan N, et al. Mucormycosis of the Conflict of interest: Authors declare no conflict of renal allograft: case report and review of the literature. interest. Transpl Int 2001; 14(6):438-441. 12. Nampoory MR, Khan ZU, Johny KV, Constandi JN, Author contribution Gupta RK, Al-Muzairi I, et al. Invasive fungal infections Dr. Lubna Khreesha: Constructing an idea for in renal transplant recipients. J Infect 1996; 33(2):95- 101. manuscript; organizing and supervising the course of 13. Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh the case report; taking the responsibility and reviewing TJ, Kontoyiannis DP. Epidemiology and clinical the article before submission, not only for spelling and manifestations of mucormycosis. Clin Infect Dis 2012; grammar, but also for its intellectual content. 54 Suppl 1:S23-34. Dr. Suhaib Eid: Literature review; construction of 14. Gamaletsou MN, Sipsas NV, Roilides E, Walsh TJ. the body of the manuscript; corresponding author. Rhino-orbital-cerebral mucormycosis. Curr Infect Dis Dr. Mohammad Ghunaim: Literature review; Rep 2012; 14(4):423-434. construction of the body of the manuscript; logical 15. Wali U, Balkhair A, Al-Mujaini A. Cerebro-rhino interpretation and presentation of the case. orbital mucormycosis: An update. J Infect Public Health 2012; 5(2):116-126. 16. Almyroudis NG, Sutton DA, Linden P, Rinaldi MG, REFERENCES Fung J, Kusne S. Zygomycosis in solid organ transplant recipients in a tertiary transplant center and review of 1. Epstein VA, Kern RC. Invasive fungal sinusitis and the literature. Am J Transplant 2006; 6(10):2365-2374. complications of rhinosinusitis. Otolaryngol Clin North 17. Spellberg B, Ibrahim AS. Recent advances in the Am 2008; 41(3):497-524. treatment of mucormycosis. Curr Infect Dis Rep 2010; 2. Chakrabarti A, Denning DW, Ferguson BJ, Ponikau J, 12(6):423-429. Buzina W, Kita H, et al. Fungal rhinosinusitis: A 18. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying categorization and definitional schema addressing amphotericin B-based frontline therapy significantly current controversies. Laryngoscope 2009; 119(9):1809- increases mortality among patients with hematologic 1818. malignancy who have zygomycosis. Clin Infect Dis 3. Feurguson BJ. Fungal rhinosinusitis. In: Cummings 2008; 47(4):503-509. (eds): Otolaryngology Head and Neck Surgery, 5th ed. 19. Spellberg B, Kontoyiannis DP, Fredricks D, Morris MI, Philadelphia: Mosby Elsevier; 2010. p. 709-710. Perfect JR, Chin-Hong, PV, et al. Risk factors for 4. Ergun O, Tahir E, Kuscu O, Ozgen B, Yilmaz T. Acute mortality in patients with mucormycosis. Med Mycol invasive fungal rhinosinusitis: Presentation of 19 cases, 2012; 50(6):611-618. review of the literature, and a new classification system. 20. Ben-Ami R, Lewis RE, Kontoyiannis DP. J Oral Maxillofac Surg 2017; 75(4):767.e1-767.e9 Immunocompromised hosts: Immunopharmacology 5. Gillespie MB, O’Malley BW, Jr., Francis HW. An of modern antifungals. Clin Infect Dis 2008; 479(2):226- approach to fulminant invasive fungal rhinosinusitis 235. in the immunocompromised host. Arch Otolaryngol 21. Simitsopoulou M, Roilides E, Dotis J, Dalakiouridou Head Neck Surg 1998; 124(5):520-526. M, Dudkova F, Andreadou E, et al. Differential 6. Kennedy CA, Adams GL, Neglia JP, Giebink GS. Impact expression of cytokines and chemokines in human of surgical treatment on paranasal fungal infections in monocytes induced by lipid formulations of bone marrow transplant patients. Otolaryngol Head amphotericin B. Antimicrob Agents Chemother 2005; Neck Surg 1997; 116(6 Pt 1):610-616. 49(4): 397-1403. 101 KUWAIT MEDICAL JOURNAL March 2021
Selected Abstracts of Articles Published Elsewhere by Authors in Kuwait
Kuwait Medical Journal 2021; 53 (1): 101 - 103
Modeling the effect of lockdown timing as a COVID-19 control measure in countries with differing social contacts
Tamer Oraby1, Michael G Tyshenko2, Jose Campo Maldonado3, Kristina Vatcheva4, Susie Elsaadany5, Walid Q Alali6, Joseph C Longenecker7, Mustafa Al-Zoughool8 1School of Mathematical and Statistical Sciences, The University of Texas Rio Grande Valley, Edinburg, TX, 78539, USA. [email protected]. 2McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1N 6N5, Canada. 3School of Medicine, The University of Texas Rio Grande Valley, Edinburg, TX, 78539, USA. 4School of Mathematical and Statistical Sciences, The University of Texas Rio Grande Valley, Edinburg, TX, 78539, USA. 5Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. 6Department of Epidemiology and Biostatistics, Faculty of Public Health, Kuwait University, 13110, Safat, Kuwait. 7Department of Public Health Practice, Faculty of Public Health, Kuwait University, 13110, Safat, Kuwait. 8Department of Environmental and Occupational Health, Faculty of Public Health, Kuwait University, 13110, Safat, Kuwait.
Sci Rep. 2021 Feb 8;11(1):3354. doi: 10.1038/s41598-021-82873-2.
The application, timing, and duration of lockdown strategies during a pandemic remain poorly quantified with regards to expected public health outcomes. Previous projection models have reached conflicting conclusions about the effect of complete lockdowns on COVID-19 outcomes. We developed a stochastic continuous-time Markov chain (CTMC) model with eight states including the environment
(SEAMHQRD-V), and derived a formula for the basic reproduction number, R0, for that model. Applying the [Formula: see text] formula as a function in previously-published social contact matrices from 152 countries, we produced the distribution and four categories of possible [Formula: see text] for the 152 countries and chose one country from each quarter as a representative for four social contact categories (Canada, China, Mexico, and Niger). The model was then used to predict the effects of lockdown timing in those four categories through the representative countries. The analysis for the effect of a lockdown was performed without the influence of the other control measures, like social distancing and mask wearing, to quantify its absolute effect. Hypothetical lockdown timing was shown to be the critical parameter in ameliorating pandemic peak incidence. More importantly, we found that well-timed lockdowns can split the peak of hospitalizations into two smaller distant peaks while extending the overall pandemic duration. The timing of lockdowns reveals that a “tunneling” effect on incidence can be achieved to bypass the peak and prevent pandemic caseloads from exceeding hospital capacity. March 2021 KUWAIT MEDICAL JOURNAL 102
Associations of adiposity and parental diabetes with prediabetes among adolescents in Kuwait: A cross-sectional study
Mohammad Almari1,2, Saad Alsaedi2, Anwar Mohammad3, Ali H Ziyab1,3 1Department of Community Medicine and Behavioral Sciences, Faculty of Medicine, Kuwait University, Safat, Kuwait. 2Medical Services Directorate, Kuwait National Guard, Safat, Kuwait. 3Epidemiology and Public Health Unit, Dasman Diabetes Institute, Safat, Kuwait.
Pediatr Diabetes. 2018 Dec;19(8):1362-1369. doi: 10.1111/pedi.12780. Epub 2018 Oct 11.
BACKGROUND Prediabetes, a high-risk state for developing diabetes, has become more prevalent among children and adolescents in recent decades. This study sought to estimate the prevalence of prediabetes and assess its association with adiposity among adolescents in Kuwait. Also, to determine whether maternal and paternal history of diabetes associate with offspring prediabetes in a sex-specific manner.
METHODS A cross-sectional study was conducted by enrolling students (n = 1959; aged 14-19 years) attending high schools across Kuwait. Body mass index-for-age z-scores were estimated using the World Health Organization growth reference. Glycated hemoglobin A1c (HbA1c) was measured in capillary blood using point-of-care testing. Prediabetes was defined according to the diagnostic criteria of the American Diabetes Association (ADA; 5.7 ≤ HbA1c% ≤ 6.4) and the International Expert Committee (IEC; 6.0 ≤ HbA1c% ≤ 6.4). Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using Poisson regression with robust variance estimation.
RESULTS According to the ADA criteria, 33.3% (620/1845) of participants had prediabetes; whereas, 8.5% (157/1845) met the IEC definition for prediabetes. Subjects classified as obese had higher prevalence of prediabetes compared to children in the thinness/normal group (aPR = 1.68, 95% CI: 1.44-1.95). Analysis stratified by offspring sex showed that maternal history of diabetes is associated with prediabetes among male offspring (aPR = 1.29, 95% CI: 1.02-1.63). In contrast, paternal history of diabetes showed an association with prediabetes among female offspring (aPR = 1.22, 95% CI: 1.01-1.48).
CONCLUSIONS Prediabetes affects a substantial proportion of adolescents in Kuwait and adiposity and parental diabetes being the main associated factors with prediabetes. 103 Selected Abstracts of Articles Published Elsewhere by Authors in Kuwait March 2021
Pet-Keeping in Relation to Asthma, Rhinitis, and Eczema Symptoms Among Adolescents in Kuwait: A Cross-Sectional Study
Khadijah A AlShatti1, Ali H Ziyab2 1Faculty of Medicine, Kuwait University, Safat, Kuwait. 2Department of Community Medicine and Behavioral Sciences, Faculty of Medicine, Kuwait University, Safat, Kuwait.
Front Pediatr. 2020 Jun 23;8:331. doi: 10.3389/fped.2020.00331. eCollection 2020.
BACKGROUND Findings on the associations between household pet-keeping and allergic diseases, including asthma, rhinitis, and eczema, have been contradictory, with investigations reporting positive, negative, and null associations. This study sought to estimate the prevalence of pet-keeping among families in Kuwait and to assess the associations between pet-keeping and symptoms of allergic diseases among adolescents.
METHODS Schoolchildren aged 11-14 years (n = 3,864) were enrolled in this cross-sectional study. The children›s parents completed questionnaires regarding their child›s environmental exposures, including pet- keeping in the past 12 months, and clinical history and symptoms of allergic diseases. Associations were assessed using Poisson regression with robust variance estimation, and adjusted prevalence ratios (aPRs) and their 95% confidence intervals (CIs) were estimated.
RESULTS Pet-keeping in the past 12 months was reported by 42.8% of the participating families. Birds, cats, rabbits, fish, and dogs were kept by 28.3, 13.2, 7.8, 3.9, and 3.1% of all households, respectively. Current cat ownership was significantly associated with current wheezing (aPR 1.29, 95% CI 1.05-1.58), current rhinitis symptoms (aPR 1.18, 95% CI 1.02-1.36), and ever doctor-diagnosed eczema (aPR 1.25, 95% CI 1.03- 1.50). Current rabbit-keeping was positively associated with multiple symptoms of asthma (e.g., study- defined current asthma: aPR 1.38, 95% CI 1.04-1.82) and eczema (e.g., severe eczema: aPR 1.94, 95% CI 1.02-3.71). Similarly, current bird-keeping was associated with study-defined current rhinitis (aPR 1.19, 95% CI 1.05-1.41) and current itchy rash (aPR 1.27, 95% CI 1.10-1.46).
CONCLUSIONS Household pet-keeping is very common and diverse in Kuwait and was found to be positively associated with symptoms of allergic diseases among adolescents. The findings of associations between rabbit- keeping and symptoms of asthma and eczema add to the existing literature and further highlight the importance of considering the pet type when assessing such associations. March 2021 KUWAIT MEDICAL JOURNAL 104
Forthcoming Conferences and Meetings
Compiled and edited by Vineetha Elizabeth Mammen
Kuwait Medical Journal 2021; 53 (1): 104 - 108
Urgent Care: A Comprehensive Approach to 23rd Annual Superbugs & Super drugs 2021 Common Challenges 2021 Mar 15-16, 2021 Mar 01-04, 2021 United Kingdom / London United States / Sarasota, FL Event listing ID: 1381483 Event listing ID: 1371600 Event website: https: //www.smi-online.co.uk/ Event website: https://www. pharmaceuticals/uk/superbugs-superdrugs americanmedicalseminars.com/events/urgent-care-a- comprehensive-approach-to-common-challenges-2/ International Symposium on Intensive Care and Emergency Medicine 40th Annual Meeting 2021 UK General Internal Medicine Conference 2021 Mar 16 -19, 2021 Mar 02 -03, 2021 Belgium / Bruxelles United Kingdom / London Event listing ID: 1381430 Event listing ID: 1381279 Event website: https://www.isicem.org/1/main.asp Event website: http: //www.ukgim.com 19th European Congress of Internal Medicine 2021 Office Practice ofPrimary Care Medicine 2021 Mar 18-20, 2021 Mar 08-12, 2021 Spain / Malaga United States / Boston Event listing ID: 1381200 Event listing ID: 1381270 Event website: https: //efim.org/ecim2021/ Event website: https: //primarycare.hmscme.com
OPPCM 2021 — Office Practice ofPrimary Care NYU Langone Seminar in Advanced Rheumatology Medicine 2021 Mar 18-21, 2021 Mar 08 -13, 2021 United States / Virtual Webinar, New York United States / Boston Event listing ID: 1389144 Organizer: Harvard Medical School Event website: https://www.highmarksce.com/ Contact: Phone: 617-384-8600 nyumc/index.cfm?do=pln. viewActivity&style Email: [email protected] =2&preview=true&plannerID=1878#CourseDetails Event website: https: //primarycare.hmscme.com/ Wisconsin Rheumatology Association Annual 4th Emirates Cardiac Society Heart Failure Conference Meeting 2021 2021 Mar 19-20, 2021 Mar 11-13, 2021 United States / Kohler, WI United Arab Emirates / Dubai Event listing ID: 1389132 Event listing ID: 1387205 Event website: https: //wi-rheum.org/home.html Event website: http://emirateshf.com/ Gordon Research Seminar — Alcohol-Induced End United States and Canadian Academy of Pathology Organ Diseases 110th Annual Meeting 2021 Mar 20-21, 2021 Mar 13-18, 2021 United States / Galveston, TX United States / Virtual Conference Event listing ID: 1317997 Event listing ID: 1381457 Event website: https: //www.grc.org/find-a- Event website: https: //www.uscap.org/uscap-annual- conference/ meeting/ 105 Forthcoming Conferences and Meetings March 2021
Royal College of Physicians of Edinburgh Updates in Infectious Diseases: Adult Issues in the Outpatient Dermatology, Allergy and Immunology 2021 and Inpatient Settings 2021 Mar 23, 2021 Apr 05-08, 2021 United Kingdom / Edinburgh United States / Sarasota Event listing ID: 1381265 Event listing ID: 1381242 Event website: https: //events.rcpe.ac.uk/updates- Event website: https: //www. dermatology-allergy-and-immunology americanmedicalseminars.com/events/infectious- diseases-adult-issues-in-the-outpatient-and-inpatient- New Zealand Internal Medicine Society of Australia settings-2/ and New Zealand Scientific Meeting 2021 th Mar 24-26, 2021 12 Congress of the Vascular Access Society 2021 New Zealand / Rotarua Apr 07-10, 2021 Event listing ID: 1387787 Germany / Berlin Event listing ID: 1381484 Event website: https: //www.imsanzconference.co.nz/ Event website: http://www.vas2021.org
Principles of Medical Education: Maximizing Your 17th ECCC & 16th WFCCN World Congress 17th Teaching Skills Emirates Critical Care Conference & 16th WFCCN Mar 24 -26, 2021 World Congress United States / Boston Apr 08-10, 2021 Organizer: Harvard Medical School United Arab Emirates / Dubai Phone: 617-384-8600 Organizer: Info Plus Events Email: [email protected] Phone: 044218996 Event listing ID: 1389569 Email: [email protected] Event website: https: //medicaleducators.hmscme. Event listing ID: 1404891 com/ Event website: http://eccc-dubai.com/ Principles of Prevention in Primary Care: Pearls and Mayo Clinical Reviews 32nd Annual Family Medicine Pitfalls 2021 and Internal Medicine Update 2021 Apr 11-13, 2021 Mar 24-27, 2021 United States / Boston United States / Phoenix Event listing ID: 1381252 Event listing ID: 1387766 Event website: http: //preventionprinciples.com Event website: https: //ce.mayo.edu/family-medicine/ content/32nd-annual-clinical-reviews-family- American College of Medical Genetics and medicine-and-internal-medicine-update Genomics Annual Clinical Genetics Meeting 2021 Apr 13-17, 2021 Association for Palliative Medicine of Great Britain United States / Los Angeles and Ireland 2021 Event listing ID: 1387358 Event website: https: //www.acmg.net Mar 25-26, 2021 United Kingdom / Edinburgh ESC Preventive Cardiology 2021 Event listing ID: 1381974 Apr 15-17, 2021 Event website: https: //pccongress.org.uk Slovenia / Ljubljana Event listing ID: 1380990 Radiology for the Non-Radiologist 2021 Event website: https://www.escardio.org/Congresses- Mar 29 & Apr 01, 2021 &-Events/Preventive-Cardiology United States / Sarasota, FL Event listing ID: 1387764 SG-ANZICS Asia PacificIntensive Care Forum 2021 Event website: https: //www. Apr 15-19, 2021 americanmedicalseminars.com/events/radiology-for- Singapore / Suntec City the-non-radiologist-5/ Event listing ID: 1388157 Event website: http://sg-anzics.com March 2021 KUWAIT MEDICAL JOURNAL 106
Society of General Internal Medicine Annual ACP IM2021 — ACP Internal Medicine Meeting Meeting 2021 2021: Virtual Experience Apr 21-24, 2021 Apr 29 & May 01, 2021 United States / Virtual Conference United States / Virtual Event listing ID: 1387773 Organizer: American College of Physicians Event website: https: //connect.sgim.org/ Contact: ACP Member and Product Support annualmeeting/home Phone: 215-351*2600 Email: [email protected] ESC Frontiers in Cardiovascular Biomedicine 2021 Event listing ID: 1391187 Apr 22-25, 2021 Event website: http: //annualmeeting.acponline.org Hungary / Budapest World Congress on Osteoarthritis 2021 Event listing ID: 1387258 Apr 29 - May 02, 2021 Event website: https://www.escardio.org/Congresses- United States / Denver &-Events/Frontiers-in-Cardiovascular-Biomedicine Event listing ID: 1389152 Event website: https: //2021.oarsi.org/ British Society for Paediatric and Adolescent Rheumatology Annual Conference 2020 AATS Aortic Symposium 2021 Apr 26-28, 2021 May 01-04, 2021 United Kingdom / Manchester United States / Seattle, WA Event listing ID: 1366046 Event listing ID: 1380954 Event website: https: //www.rheumatology.org.uk/ Event website: https://www.aats.org/aatsimis/ events-learning/conferences/annual-conference AATSWeb/Association/Meetings/Annual_ Meeting/101st_Annual_Meeting/AATS_101st_ Royal College of Physicians of Edinburgh Hints on Annual_Meeting.aspx Haematology 2021 Apr 27, 2021 Mayo Clinic 41st Annual Practice of Internal Medicine United Kingdom / Edinburgh 2021 Event listing ID: 1387838 May 03-07, 2021 Event website: https: //events.rcpe.ac.uk/hints- United States / Rochester, MN 55904 haematology Event listing ID: 1381251 Event website: https: //ce.mayo.edu/internal- GPIU — General Practitioners Infertility Update medicine/content/41st-annual-practice-internal- Apr 29, 2021 medicine-2021 United Kingdom / London th Organizer: The Symposium Office-Genesis Research Euro GUCH the 12 European Meeting on Adult Trust Congenital Heart Disease 2021 May 04-05, 2021 Phone: +44 (0) 20 7594 2150 Spain / Seville Email: [email protected] Event listing ID: 1387267 Event listing ID: 1406936 Event website: https://www.escardio.org/Congresses- Event website: https: //www.symposia.org.uk/ &-Events/Working-group-events/EuroGUCH courses/general-practitioners-infertility-update/ Diabetes Update 2021 AATS Mitral Conclave 2021 May 05-08, 2021 Apr 29-30, 2021 United States / Live Streaming United States / New York, NY Organizer: Harvard Medical School Event listing ID: 1387155 Phone: 617-384-8600 Event website: https://www.aats.org/aatsimis/ Email: [email protected] AATSWeb/Association/Meetings/Mitral_ Event listing ID: 1396973 Conclave/2021/Mitral_Landing_Page.aspx Event website: https: //diabetesupdate.hmscme.com/ 107 Forthcoming Conferences and Meetings March 2021
11th Annual London Core Review Cardiothoracic Innovations and New Practices in Internal Course 2021 Medicine 2021 May 06-09, 2021 May 17-21, 2021 United Kingdom / London United States Event listing ID: 1387176 Organizer: Harvard Medical School Event website: https://assets.website-files. Phone: 617-384-8600 com/5c98d3d0f5786df983a4094d/5e74f3d Email: [email protected] d5836b8581fd56419_2021_london_core_review_ Event listing ID: 1404122 cardiothoracic_surgery_course_brochure.pdf Event website: https: //im.hmscme.com
Mayo Clinic Principles of Pain Management & Optimizing Transition from Pediatric to Adult Palliative Care: Essential Tools for the Clinician 2021 Care May 06-08, 2021 May 24 -26, 2021 United States / San Diego United States / Live streaming Event listing ID: 1381316 Organizer: Harvard Medical School Event website: https: //ce.mayo.edu/pain-medicine/ Phone: 617-384-8600 content/principles-pain-management-palliative-care- Email: [email protected] essential-tools-clinician-2021 Event listing ID: 1403943 Event website: https: //transition.hmscme.com 7th Annual Mayo Clinic Rheumatology Review for Primary Care 2021 Cardiology for Primary Care and Hospital May 06-08, 2021 Medicine 2021 United States / Virtual Conference May 24 -27, 2021 Event listing ID: 1387771 United States / Sarasota Event website: https: //ce.mayo.edu/family-medicine/ Event listing ID: 1365747 content/7th-annual-mayo-clinic-rheumatology- Event website: https: //www. review-primary-care-2021 americanmedicalseminars.com/events/cardiology- for-primary-care-and-hospital-medicine-3/ 22nd European Congress of Trauma & Emergency
Surgery College of Intensive Care Medicine of Australia May 09 -11, 2021 And New Zealand Annual Scientific Meeting 2021 Slovenia / Ljubljana Jun 01-03, 2021 Email: [email protected] Australia / Virtual Conference Event listing ID: 1306935 Event listing ID: 1408997 Event website: https://www.estes-congress.org/ Event website: https://asm.cicm.org.au/2021/ Society for Academic Emergency Medicine Annual European League against Rheumatism Congress Meeting 2021 2021 May 11-14, 2021 Jun 02-05, 2021 United States / Virtual Conference France / Virtual Conference Event listing ID: 1387505 Event website: https://www.saem.org/annual- Event listing ID: 1408030 meeting/future-and-past-meetings/future-meetings Event website: https: //congress.eular.org/
Controversies in Internal Medicine Conference 2021 ASCENT Limb Preservation Conference 2021 May 17-21, 2021 Jun 03-05, 2021 United States / Hilton Head Island United States / Stevenson Event listing ID: 1387858 Event listing ID: 1408319 Event website: https: //www.bucme.org/live/9084 Event website: https://ascentcli.com
March 2021 KUWAIT MEDICAL JOURNAL 108
IMCR — Internal Medicine Comprehensive Review AAEM21 — American Academy of Emergency and Update 2021 Medicine 27th Annual Scientific Assembly 2021 Jun 07-12, 2021 Jun 19-23, 2021 United States / Live Streaming United States / St. Louis Organizer: Harvard Medical School Organizer: American Academy of Emergency Phone: 617-384-8600 Medicine – AAEM Event listing ID: 1382412 Email: [email protected] Event website: https://www.aaem.org/aaem21 Event listing ID: 1398441 Event website: https: //internalmedicine.hmscme.com/ Rehabilitation Medicine Society of Australia and New Zealand 5th Annual Scientific Meeting 2021 Emergency Medicine Masterclass Sydney 2021 Jun 22-25, 2021 Jun 10-11, 2021 Australia / Broadbeach Australia / Sydney Event listing ID: 1408053 Event listing ID: 1387005 Event website: https: //www.dcconferences.com.au/ Event website: https://www.emcore.com.au/emcore- rmsanz2021/ sydney-2021.html Emergency Medicine Core Knowledge Conference th 9 Congress of European Microbiologists 2021 London 2021 Jun 11-15, 2021 Jun 30 – Jul 02, 2021 Germany United Kingdom / London Event listing ID: 1407977 Event listing ID: 1387514 Event website: https: //fems2021.org/ Event website: https://www.emcore.com.au/emcore- london-2021.html European Human Genetics Conference 2021 Jun 12-15, 2021 31st European Congress of Clinical Microbiology and United Kingdom Infectious Diseases 2021 Event listing ID: 1407945 Jul 09-12, 2021 Event website: https: //2021.eshg.org/ Austria / Vienna Event listing ID: 1408008 Biennial Congress of the International Organization of Event website: https: //www.eccmid.org/ Mycoplasmology 2021 Jun 15-17, 2021 Israel / Tel Aviv-Yafo Event listing ID: 1407998 Event website: https: //iom2020.org/ 109 KUWAIT MEDICAL JOURNAL March 2021
WHO-Facts Sheet
1. E.coli 2. Guillain-Barré syndrome 3. Immunization coverage 4. Newborns: improving survival and well being 5. Scabies
Compiled and edited by Vineetha E Mammen
Kuwait Medical Journal 2021; 53 (1): 109 - 116
1. E.coli temperature of 37 °C. Some STEC can grow in acidic foods, down to a pH of 4.4, and in foods with a
KEY FACTS minimum water activity (aW) of 0.95. · Escherichia coli (E. coli) is a bacteria that is STEC is destroyed by thorough cooking of foods commonly found in the lower intestine of warm- until all parts reach a temperature of 70 °C or higher. E. blooded organisms. Most E.coli strains are harmless, coli O157:H7 is the most important STEC serotype in but some can cause serious food poisoning. relation to public health; however, other serotypes · Shiga toxin-producing E. coli (STEC) is a bacterium have frequently been involved in sporadic cases and that can cause severe foodborne disease. outbreaks. · Primary sources of STEC outbreaks are raw or undercooked ground meat products, raw milk, and Symptoms faecal contamination of vegetables. Symptoms of the diseases caused by STEC include · In most cases, the illness is self-limiting, but it abdominal cramps and diarrhoea that may in some may lead to a life-threatening disease including cases progress to bloody diarrhoea (haemorrhagic haemolytic uraemic syndrome (HUS), especially in colitis). Fever and vomiting may also occur. The young children and the elderly. incubation period can range from 3 to 8 days, with a · STEC is heat-sensitive. In preparing food at home, median of 3 to 4 days. Most patients recover within 10 be sure to follow basic food hygiene practices such days, but in a small proportion of patients (particularly as “cook thoroughly”. young children and the elderly), the infection may · Following the WHO “Five keys to safer food” is a lead to a life-threatening disease, such as haemolytic key measure to prevent infections with foodborne uraemic syndrome (HUS). HUS is characterized pathogens such as STEC. by acute renal failure, haemolytic anaemia and thrombocytopenia (low blood platelets). Overview It is estimated that up to 10% of patients with Escherichia coli (E. coli) is a bacterium that STEC infection may develop HUS, with a case-fatality is commonly found in the gut of humans and rate ranging from 3 to 5%. Overall, HUS is the most warm-blooded animals. Most strains of E. coli are common cause of acute renal failure in young children. harmless. Some strains however, such as Shiga toxin- It can cause neurological complications (such as producing E. coli (STEC), can cause severe foodborne seizure, stroke and coma) in 25% of HUS patients and disease. It is transmitted to humans primarily through chronic renal sequelae, usually mild, in around 50% of consumption of contaminated foods, such as raw or survivors. undercooked ground meat products, raw milk, and Persons who experience bloody diarrhoea or contaminated raw vegetables and sprouts. severe abdominal cramps should seek medical care. STEC produces toxins, known as Shiga-toxins Antibiotics are not part of the treatment of patients because of their similarity to the toxins produced by with STEC disease and may possibly increase the risk Shigella dysenteriae. STEC can grow in temperatures of subsequent HUS. ranging from 7 °C to 50 °C, with an optimum
Address correspondence to: Office of the Spokesperson, WHO, Geneva. Tel.: (+41 22) 791 2599; Fax (+41 22) 791 4858; Email: [email protected]; Web site: http://www.who.int/ March 2021 KUWAIT MEDICAL JOURNAL 110
Sources and transmission reduce the introduction of large numbers of pathogens Most available information on STEC relates to in the slaughtering environment). Good hygienic serotype O157:H7, since it is easily differentiated slaughtering practices reduce contamination of biochemically from other E. coli strains. The reservoir carcasses by faeces, but do not guarantee the absence of this pathogen appears to be mainly cattle. In of STEC from products. addition, other ruminants such as sheep, goats, deer Education in hygienic handling of foods for are considered significant reservoirs, while other workers at farms, abattoirs and those involved in the mammals (such as pigs, horses, rabbits, dogs, and cats) food production is essential to keep microbiological and birds (such as chickens and turkeys) have been contamination to a minimum. The only effective found infected. method of eliminating STEC from foods is to introduce E. coli O157:H7 is transmitted to humans primarily a bactericidal treatment, such as heating (for example, through consumption of contaminated foods, such as cooking or pasteurization) or irradiation. raw or undercooked ground meat products and raw milk. Faecal contamination of water and other foods, as Household well as cross-contamination during food preparation Preventive measures for E. coli O157:H7 infection (with beef and other meat products, contaminated are similar to those recommended for other foodborne surfaces and kitchen utensils), will also lead to diseases. Basic good food hygiene practice, as infection. Examples of foods implicated in outbreaks described in the WHO “Five keys to safer food”, can of E. coli O157:H7 include undercooked hamburgers, prevent the transmission of pathogens responsible dried cured salami, unpasteurized fresh-pressed apple for many foodborne diseases, and also protect against cider, yogurt, and cheese made from raw milk. foodborne diseases caused by STEC. An increasing number of outbreaks are associated The five keys to safer food are: with the consumption of fruits and vegetables · Keep clean. (including sprouts, spinach, lettuce, coleslaw, and · Separate raw and cooked. salad) whereby contamination may be due to contact · Cook thoroughly. with faeces from domestic or wild animals at some · Keep food at safe temperatures. stage during cultivation or handling. STEC has also · Use safe water and raw materials. been isolated from bodies of water (such as ponds · Five keys to safer food manual and streams), wells and water troughs, and has been Such recommendations should in all cases be found to survive for months in manure and water- implemented, especially “cook thoroughly” so that trough sediments. Waterborne transmission has been the centre of the food reaches at least 70 °C. Make sure reported, both from contaminated drinking-water and to wash fruits and vegetables carefully, especially if from recreational waters. they are eaten raw. If possible, vegetables and fruits Person-to-person contact is an important mode should be peeled. Vulnerable populations (such as of transmission through the oral-faecal route. An small children and the elderly) should avoid the asymptomatic carrier state has been reported, where consumption of raw or undercooked meat products, individuals show no clinical signs of disease but are raw milk, and products made from raw milk. capable of infecting others. The duration of excretion Regular hand washing, particularly before food of STEC is about 1 week or less in adults, but can be preparation or consumption and after toilet contact, longer in children. Visiting farms and other venues is highly recommended, especially for people where the general public might come into direct who take care of small children, the elderly or contact with farm animals has also been identified as immunocompromised individuals, as the bacterium an important risk factor for STEC infection. can be passed from person to person, as well as through food, water and direct contact with animals. Prevention A number of STEC infections have been caused The prevention of infection requires control by contact with recreational water. Therefore, it is measures at all stages of the food chain, from also important to protect such water areas, as well as agricultural production on the farm to processing, drinking-water sources, from animal waste (4). manufacturing and preparation of foods in both commercial establishments and household kitchens. Producers of fruits and vegetables WHO’s “Five keys to growing safer fruits and Industry vegetables” provides rural workers who grow fresh The number of cases of disease might be reduced fruits and vegetables for themselves, their families and by various mitigation strategies for ground beef (for for sale in local markets, with key practices to prevent example, screening the animals pre-slaughter to microbial contamination of fresh produces during 111 WHO-Facts Sheet March 2021 planting, growing, harvesting and storing. temperature and touch sensations. This can result in The five keys to growing safer fruits and vegetables muscle weakness and loss of sensation in the legs and/ are: or arms. · Practice good personal hygiene. It is a rare condition, and while it is more common in · Protect fields from animal faecal contamination. adults and in males, people of all ages can be affected. · Use treated faecal waste. · Evaluate and manage risks from irrigation water. Symptoms · Keep harvest and storage equipment clean and dry. Symptoms typically last a few weeks, with most · Five keys to growing safer fruits and vegetables individuals recovering without long-term, severe neurological complications. WHO response · The first symptoms of Guillain-Barré syndrome WHO provides scientific assessments to control include weakness or tingling sensations. They STEC in food. These assessments serve as the usually start in the legs, and can spread to the arms basis for international food standards, guidelines, and face. and recommendations developed by the Codex · For some people, these symptoms can lead to Alimentarius Commission. paralysis of the legs, arms, or muscles in the face. In WHO promotes the strengthening of food 20%–30 % of people, the chest muscles are affected, safety systems by promoting good manufacturing making it hard to breathe. practices and educating retailers and consumers · The ability to speak and swallow may become about appropriate food handling and avoiding affected in severe cases of Guillain-Barré syndrome. contamination. These cases are considered life-threatening, and During E. coli outbreaks, such as the those in Europe affected individuals should be treated in intensive- in 2011, WHO supports the coordination of information care units. sharing and collaboration through International · Most people recover fully from even the most Health Regulations and the International Food Safety severe cases of Guillain-Barré syndrome, although Authorities Network (INFOSAN) worldwide. WHO some continue to experience weakness. works closely with national health authorities and · Even in the best of settings, 3%–5% of Guillain- international partners, providing technical assistance Barré syndrome patients die from complications, and the latest information on outbreaks. which can include paralysis of the muscles that control breathing, blood infection, lung clots, or cardiac arrest. 2. Guillain-Barré syndrome Causes KEY FACTS Guillain-Barré syndrome is often preceded by an · Guillain-Barré syndrome (GBS) is a rare condition infection. This could be a bacterial or viral infection. in which a person’s immune system attacks the Guillain-Barré syndrome may also be triggered by peripheral nerves. vaccine administration or surgery. · People of all ages can be affected, but it is more In the context of Zika virus infection, unexpected common in adults and in males. increase in cases of Guillain-Barré syndrome has · Most people recover fully from even the most been described in affected countries. The most likely severe cases of Guillain-Barré syndrome. explanation of available evidence from outbreaks of · Severe cases of Guillain-Barré syndrome are rare, Zika virus infection and Guillain-Barré syndrome is but can result in near-total paralysis. that Zika virus infection is a trigger of Guillain-Barré · Guillain-Barré syndrome is potentially life- syndrome. threatening. People with Guillain-Barré syndrome should be treated and monitored; some may need Diagnosis intensive care. Treatment includes supportive care Diagnosis is based on symptoms and findings on and some immunological therapies. neurological examination including diminished or loss of deep-tendon reflexes. A lumbar puncture may Introduction be done for supportive information, though should In Guillain-Barré syndrome, the body’s immune not delay treatment. Other tests, such as blood tests, system attacks part of the peripheral nervous system. to identify the underlying trigger are not required The syndrome can affect the nerves that control to make the diagnosis of GBS and should not delay muscle movement as well as those that transmit pain, treatment. March 2021 KUWAIT MEDICAL JOURNAL 112
Treatment and care should be treated and monitored; some may need The following are recommendations for treatment and intensive care. Treatment includes supportive care care of people with Guillain-Barré syndrome: and some immunological therapies. · Guillain-Barré syndrome is potentially life- threatening. GBS patients should be hospitalized Introduction so that they can be monitored closely. In Guillain-Barré syndrome, the body’s immune · Supportive care includes monitoring of breathing, system attacks part of the peripheral nervous system. heartbeat and blood pressure. In cases where a The syndrome can affect the nerves that control patient’s ability to breathe is impaired, he or she is muscle movement as well as those that transmit pain, usually put on a ventilator. All GBS patients should temperature and touch sensations. This can result in be monitored for complications, which can include muscle weakness and loss of sensation in the legs and/ abnormal heart beat, infections, blood clots, and or arms. high or low blood pressure. It is a rare condition, and while it is more common in · There is no known cure for GBS. But treatments adults and in males, people of all ages can be affected. can help improve symptoms of GBS and shorten its duration. Symptoms · Given the autoimmune nature of the disease, Symptoms typically last a few weeks, with most its acute phase is typically treated with individuals recovering without long-term, severe immunotherapy, such as plasma exchange to neurological complications. remove antibodies from the blood or intravenous · The first symptoms of Guillain-Barré syndrome immunoglobulin. It is most often beneficial when include weakness or tingling sensations. They initiated 7 to 14 days after symptoms appear. usually start in the legs, and can spread to the arms · In cases where muscle weakness persists after the and face. acute phase of the illness, patients may require · For some people, these symptoms can lead to rehabilitation services to strengthen their muscles paralysis of the legs, arms, or muscles in the face. In and restore movement. 20%–30 % of people, the chest muscles are affected, making it hard to breathe. WHO Response · The ability to speak and swallow may become WHO is supporting countries to manage GBS in affected in severe cases of Guillain-Barré syndrome. context of Zika virus infection by: These cases are considered life-threatening, and · Enhancing surveillance of GBS in Zika affected affected individuals should be treated in intensive- countries. care units. · Providing guidelines for the assessment and · Most people recover fully from even the most management of GBS. severe cases of Guillain-Barré syndrome, although · Supporting countries to implement guidelines some continue to experience weakness. and strengthen health systems to improve the · Even in the best of settings, 3%–5% of Guillain- management of GBS cases. Barré syndrome patients die from complications, · Defining the research agenda for GBS. which can include paralysis of the muscles that control breathing, blood infection, lung clots, or cardiac arrest. 3. Immunization coverage Causes KEY FACTS Guillain-Barré syndrome is often preceded by an · Guillain-Barré syndrome (GBS) is a rare condition infection. This could be a bacterial or viral infection. in which a person’s immune system attacks the Guillain-Barré syndrome may also be triggered by peripheral nerves. vaccine administration or surgery. · People of all ages can be affected, but it is more In the context of Zika virus infection, unexpected common in adults and in males. increase in cases of Guillain-Barré syndrome has · Most people recover fully from even the most been described in affected countries. The most likely severe cases of Guillain-Barré syndrome. explanation of available evidence from outbreaks of · Severe cases of Guillain-Barré syndrome are rare, Zika virus infection and Guillain-Barré syndrome is but can result in near-total paralysis. that Zika virus infection is a trigger of Guillain-Barré · Guillain-Barré syndrome is potentially life- syndrome. threatening. People with Guillain-Barré syndrome 113 WHO-Facts Sheet March 2021
Diagnosis 2019, children face the greatest risk of death in their Diagnosis is based on symptoms and findings on first 28 days. neurological examination including diminished or · In 2019, 47% of all under-5 deaths occurred in the loss of deep-tendon reflexes. A lumbar puncture may newborn period with about one third dying on be done for supportive information, though should the day of birth and close to three quarters dying not delay treatment. Other tests, such as blood tests, within the first week of life. to identify the underlying trigger are not required · Children who die within the first 28 days of birth to make the diagnosis of GBS and should not delay suffer from conditions and diseases associated treatment. with lack of quality care at birth or skilled care and treatment immediately after birth and in the first Treatment and care days of life. The following are recommendations for treatment · Preterm birth, intrapartum-related complications and care of people with Guillain-Barré syndrome: (birth asphyxia or lack of breathing at birth), · Guillain-Barré syndrome is potentially life- infections and birth defects cause most neonatal threatening. GBS patients should be hospitalized deaths. so that they can be monitored closely. · Women who receive midwife-led continuity of · Supportive care includes monitoring of breathing, care (MLCC) provided by professional midwives, heartbeat and blood pressure. In cases where a educated and regulated to internationals standards, patient’s ability to breathe is impaired, he or she is are 16% less likely to lose their baby and 24% less usually put on a ventilator. All GBS patients should likely to experience pre-term birth. be monitored for complications, which can include abnormal heart beat, infections, blood clots, and Who is most at risk? high or low blood pressure. Neonates · There is no known cure for GBS. But treatments Globally 2.4 million children died in the first month can help improve symptoms of GBS and shorten its of life in 2019. There are approximately 7 000 newborn duration. deaths every day, amounting to 47% of all child deaths · Given the autoimmune nature of the disease, under the age of 5-years, up from 40% in 1990. its acute phase is typically treated with The world has made substantial progress in child immunotherapy, such as plasma exchange to survival since 1990. Globally, the number of neonatal remove antibodies from the blood or intravenous deaths declined from 5.0 million in 1990 to 2.4 million in immunoglobulin. It is most often beneficial when 2019. However, the decline in neonatal mortality from initiated 7 to 14 days after symptoms appear. 1990 to 2019 has been slower than that of post-neonatal · In cases where muscle weakness persists after the under-5 mortality The share of neonatal deaths among acute phase of the illness, patients may require under-five deaths is still relatively low in sub-Saharan rehabilitation services to strengthen their muscles Africa (36 per cent), which remains the region with and restore movement. the highest under-five mortality rates. In Europe and Northern America, which has one of the lowest under- WHO Response five mortality rates among SDG regions, 54 per cent of WHO is supporting countries to manage GBS in all under-five deaths occur during the neonatal period. context of Zika virus infection by: An exception is Southern Asia, where the proportion · Enhancing surveillance of GBS in Zika affected of neonatal deaths is among the highest (62 per cent) countries. despite a relatively high under-five mortality rate. · Providing guidelines for the assessment and Sub-Saharan Africa had the highest neonatal management of GBS. mortality rate in 2019 at 27 deaths per 1,000 live births, · Supporting countries to implement guidelines followed by Central and Southern Asia with 24 deaths and strengthen health systems to improve the per 1,000 live births. A child born in sub-Saharan Africa management of GBS cases. or in Southern Asia is 10 times more likely to die in the · Defining the research agenda for GBS. first month than a child born in a high-income country. Top 10 countries with the highest number 4. Newborns: improving (thousands) of newborn deaths, 2019 survival and well being Causes KEY FACTS The majority of all neonatal deaths (75%) occurs · Although the global number of newborns deaths during the first week of life, and about 1 million declined from 5 million in 1990 to 2.4 million in newborns die within the first 24 hours. Preterm birth, March 2021 KUWAIT MEDICAL JOURNAL 114 intrapartum-related complications (birth asphyxia contact between mother and infant); or lack of breathing at birth), infections and birth · hygienic umbilical cord and skin care; defects cause most neonatal deaths in 2017. From the · early and exclusive breastfeeding; end of the neonatal period and through the first 5 · assessment for signs of serious health problems years of life, the main causes of death are pneumonia, or need of additional care (e.g. those that are low- diarrhoea, birth defects and malaria. Malnutrition is birth-weight, sick or have an HIV-infected mother the underlying contributing factor, making children · preventive treatment (e.g. immunization BCG and more vulnerable to severe diseases. Hepatitis B, vitamin k and ocular prophylaxis) Families should be advised to: Number of newborn · seek prompt medical care if necessary (danger Country deaths (thousands) signs include feeding problems, or if the newborn India 522 has reduced activity, difficult breathing, a fever, Nigeria 270 fits or convulsions, or feels cold); Pakistan 248 · register the birth; Ethiopia 99 Democratic Republic of the Congo 97 · bring the baby for timely vaccination according to China 64 national schedules. Indonesia 60 Some newborns require additional attention and care Bangladesh 56 during hospitalization and at home to minimize their Afghanistan 43 United Republic of Tanzania 43 health risks.
Priority Strategies Low-birth-weight and preterm babies: The vast majority of newborn deaths take place · If a low-birth weight newborn is identified at home, in low and middle-income countries. It is possible to the family should be helped in locating a hospital improve survival and health of newborns and end or facility to care for the baby. preventable stillbirths by reaching high coverage of · increased attention to keeping the newborn warm, quality antenatal care, skilled care at birth, postnatal including skin-to-skin care, unless there are care for mother and baby, and care of small and sick medically justifiable reasons for delayed contact newborns. In settings with well-functioning midwife with the mother; programmes the provision of midwife-led continuity · assistance with initiation of breastfeeding, such as of care (MLCC) can reduce preterm births by up to helping the mother express breast milk for feeding 24%. MLCC is a model of care in which a midwife the baby from a cup or other means if necessary; or a team of midwives provide care to the same · extra attention to hygiene, especially hand washing; woman throughout her pregnancy, childbirth and · extra attention to danger signs and the need for the postnatal period, calling upon medical support care; and if necessary. With the increase in facility births · additional support for breastfeeding and (almost 80% globally), there is a great opportunity for monitoring growth. providing essential newborn care and identifying and managing high risk newborns. However, few women Sick newborns and newborns stay in the facility for the recommended · Danger signs should be identified as soon as 24 hours after birth, which is the most critical time possible in health facilities or at home and the when complications can present. In addition, too many baby referred to the appropriate service for further newborns die at home because of early discharge from diagnosis and care; the hospital, barriers to access and delays in seeking · If a sick newborn is identified at home, the family care. The four recommended postnatal care contacts should be helped in locating a hospital or facility to delivered at health facility or through home visits play care for the baby. a key role to reach these newborns and their families. Newborns of HIV-infected mothers Accelerated progress for neonatal survival and · preventive antiretroviral treatment (ART) for promotion of health and wellbeing requires mothers and newborns to prevent opportunistic strengthening quality of care as well as ensuring infections; availability of quality health services or the small and · HIV testing and care for exposed infants; and sick newborn. · counselling and support to mothers for infant feeding. Community health workers should be Essential newborn care aware of the specialized issues around infant All babies should receive the following: feeding. Many HIV-infected newborns are born · thermal protection (e.g. promoting skin-to-skin prematurely and are more susceptible to infections. 115 WHO-Facts Sheet March 2021
WHO response Scabies is endemic in many resource-poor tropical WHO is working with ministries of health and settings, with an estimated average prevalence partners to: 1) strengthen and invest in care, particularly of 5–10% in children. Recurrent infestations are around the time of birth and the first week of life as most common. The sheer burden of scabies infestation and newborns are dying in this time period; 2) improve the its complications imposes a major cost on health care quality of maternal and newborn care from pregnancy systems. In high-income economies, cases are sporadic, to the entire postnatal period, including strengthening yet outbreaks in health institutions and vulnerable midwifery; 3) expand quality services for small and sick communities contribute to significant economic cost in newborns, including through strengthening neonatal national health services. nursing.; 4) reduce inequities in accordance with the Scabies occurs worldwide. However, it is the most principles of universal health coverage, including vulnerable groups – young children and the elderly addressing the needs of newborns in humanitarian in resource-poor communities – who are especially and fragile settings; 5) promote engagement of and susceptible to scabies and the secondary complications empower mothers, families and communities to of infestation. The highest rates of infestation occur participate in and demand quality newborn care; and in countries with hot, tropical climates, especially 6) strengthen measurement, programme-tracking and in communities where overcrowding and poverty accountability to count every newborn and stillbirth. coexist, and where there is limited access to treatment.
Symptoms 5. Scabies Scabies mites burrow into the top layer of the epidermis where the adult female lays eggs. The eggs KEY FACTS hatch in 3-4 days and develop into adult mites in 1–2 · An estimated 200 million people worldwide suffer weeks. After 4–6 weeks the patient develops an allergic from scabies at any one time reaction to the presence of mite proteins and faeces in · Up to 10% of children in resource-poor areas are the scabies burrow, causing intense itch and rash. Most affected by scabies individuals are infected with 10–15 mites. · Human scabies is a parasitic infestation caused by Patients typically present with severe itch, linear Sarcoptes scabiei var hominis burrows and vesicles around the finger webs, wrists, · Scabies occurs worldwide but is most common upper and lower limbs and belt area. Infants and small in hot, tropical countries and in areas of high children may have a more widespread rash, including population density involvement of the palms, soles of the feet, ankles and sometimes the scalp. Inflammatory scabies nodules Human scabies is a parasitic infestation caused may be seen, particularly on the penis and scrotum of by Sarcoptes scabiei var hominis. The microscopic adult males and around the breasts of females. Because mite burrows into the skin and lays eggs, eventually of the delay between initial infection and development triggering a host immune response that leads to of symptoms, burrows may be seen in close contacts intense itching and rash. Scabies infestation may be that have yet developed itch. complicated by bacterial infection, leading to the Individuals with crusted scabies present with development of skin sores that, in turn, may lead to thick, exfoliating crusts that may be more widespread, the development of more serious consequences such including the face. as septicaemia, heart disease and chronic kidney Immunosuppressed individuals, including people disease. In 2017, scabies and other ectoparasites were living with HIV/AIDS, may develop an uncommon included as Neglected Tropical Diseases (NTDs), manifestation called crusted (Norwegian) scabies. in response to requests from Member States and the Crusted scabies is a hyper-infestation with thousands recommendations of the WHO Strategic and Technical to millions of mites, producing widespread scale and Advisory Group for NTDs. crust, often without significant itching. This condition has a high mortality if untreated due to secondary Scope of the problem sepsis. Scabies is one of the commonest dermatological Mite effects on immunity, as well as the direct effects conditions, accounting for a substantial proportion of scratching, can lead to inoculation of the skin with of skin disease in developing countries. Globally, it bacteria, leading to the development of impetigo (skin is estimated to affect more than 200 million people at sores), especially in the tropics. Impetigo may become any time, although further efforts are needed to assess complicated by deeper skin infection such as abscesses this burden. Prevalence estimates in the recent scabies- or serious invasive disease, including septicaemia. In related literature range from 0.2% to 71%. tropical settings, scabies-associated skin infection is a March 2021 KUWAIT MEDICAL JOURNAL 116 common risk factor for kidney disease and possibly in several countries. Safety of ivermectin in pregnant rheumatic heart disease. Evidence of acute renal women or children under 15 kg body weight has not damage can be found in up to 10% of children with been established, so ivermectin should not be used in scabies infestation in resource-poor settings and, these groups until more safety data are available. Itch in many, this persists for years following infection commonly intensifies with effective treatment for 1-2 contributing to permanent kidney damage. weeks, and treated individuals should to be informed about this. Transmission Because people in the early stage of new infestation Scabies is usually transmitted person-to-person may be asymptomatic and because the treatments through close skin contact (e.g. living in the same for scabies do not kill the parasite’s eggs, best results residence) with an infested individual. The risk of are obtained by treating the whole household at the transmission increases with the level of infestations, same time and repeating treatment in the time frame with highest risk due to contact with individuals with appropriate for the chosen medication. crusted scabies. Transmission due to contact with infested personal items (e.g. clothes and bed linens) is WHO response unlikely with common scabies but may be important WHO works with Member States and partners for individuals with crusted scabies. As there is an to develop control strategies and scabies outbreak asymptomatic period of infestation, transmission may response plans. WHO recognizes that the burden occur before the initially infested person develops of disease and the risk of long-term sequelae need symptoms. to be better defined, and that control strategies must integrate with existing activities in order to facilitate Treatment rapid, cost-effective uptake of the strategy. WHO is Primary management of affected individuals working to have ivermectin added to the WHO Model involves application of a topical scabicide such as 5% List of Essentials Medicines when it is next updated. permethrin, 0.5% malathion in aqueous base, 10–25% Additionally, it is working to ensure that quality, benzyl benzoate emulsion or 5–10% sulphur ointment. effective medications will be accessible to the countries Oral ivermectin is also highly effective and is approved that need them.