VOLUME 39 NUMBER 3 SEPTEMBER 2007
KMJ K M J KUWAIT MEDICAL JOURNAL
The Official Journal of The Kuwait Medical Association
EDITORIAL Medical Education Changes Should be Evidence Based 213 Raymond M Kirk
REVIEW ARTICLE Bioecological Control of Acute and Chronic Diseases: The Role of Pro-, Pre- and Synbiotics 216 Stig Bengmark Depression in Patients with HIV/AIDS 227 Sammod Vardhana M, Bairy Laxminarayana K
ORIGINAL ARTICLES Validity and Predictive value of Exercise Induced Inverted T-wave Normalization for Diagnosis of Ischemic Heart Disease 231 Mousa AJ Akbar, Mohamad Hussain Alkandary, Bader A Abdulkader, Aly Hegazy Use of Controller Medications Among Asthmatic Patients: A Family Medicine Centre Based Study 238 Fotooh Ahmed Al-Jarky, Samia Salem Al-Musallam Changing Patterns of Cardiovascular Risk Factors in Hospitalized Patients with Acute Myocardial Infarction in Babol, Iran 243 Karim O Hajian-Tilaki, Farzad Jalali Non-cystic Fibrosis Bronchiectasis: the Experience in Saudi Arabia 248 Hanaa Hasan Banjar Predictive Value of Tests in Screening Urine Samples for Bacterial Culture 253 Prem Anand Nagaraja, El Sayed M M El Aasar Comparison of Human T- cell Leukemia Virus Type-1 (HTLV-1) Seroprevalence in High Risk Patients (Thalassemia and Hemodialysis) and Healthy Individuals from Charmahal - Bakhtiari Province, Iran 259 Ali Karimi, Mohamed-Reza Nafici, Reza Imani Haematological Changes in Malaria: Relation to Plasmodium Species 262 Khaled Taha, Soheir Zein El-Dein, Majid Idrees, Gamal Makboul, Ghassan Baidas
CASE REPORTS A Complex Atheromatous Plaque of the Thoracic Aorta: The Role of Transesophageal Echocardiography 268 Muath Alanbaei, Suzanne Morin, Thao Huynh Adult Intussusception: A Radiological Approach 271 Margaret Linny Austin, Venkatanarayana Ravi Hoisala, Majid Ali Jamal A Female Infant with Severe Combined Immunodeficiency 275 Enamul Hoque, Mona Hussain Badawi, Zahra Qabazard Neonatal Presentation of Two Siblings with Pena-Shokeir Syndrome 278 Bhaskar Ramgopal Gupta Cholestatic Jaundice Induced by Carbimazole in Grave’s Disease 281 Ahmed ALDousari, Saleh AL Enezi, Fahad ALEnezi Always Look Beyond the Stones: Hyperoxaluria Overlooked 284 Khalid Al-Ibrahim, Sherif A Sadek Severe Hypereosinophilia in an Asthmatic Young Female 287 Jehan A Qassem, Najat Ashour, Puthusseril PBoby
KU ISSN 0023-5776 Continued inside
Vol. 39 No. 3 September 2007 KUWAIT MEDICAL JOURNAL C O N T E N T S
Continued from cover
SELECTED ABSTRACTS OF ARTICLES PUBLISHED ELSEWHERE BY AUTHORS IN KUWAIT 290
FORTHCOMING CONFERENCES AND MEETINGS 292
WHO-FACTS SHEET 298 1. Recent Food Scares Prove Weaknesses in Food Safety Systems Around the World - FAO and WHO Urge for More Vigilance 2. Battle against Chagas the “Kissing Bug” Disease - Strategy Set Out to Eliminate Disease 3. Safe Blood for Safe Motherhood: Global Facts on Blood Safety and Donation 4. New WHO Online Tool to Improve Clinical Trial Transparency
ARABIC ABSTRACTS OF ARTICLES PUBLISHED IN THIS ISSUE 303
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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 Editor: Adel Khader Ayed International Editor: Pawan K Singal Associate Editors: Adel A Alzayed Mousa Khoursheed Mustafa M Ridha Nasser Behbehani Noura Al-Sweih
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September 2007 KUWAIT MEDICAL JOURNAL
Editorial
Medical Education Changes Should Be Evidence Based
Raymond M Kirk Department of Surgery, Royal Free Hospital, London, UK
Kuwait Medical Journal 2007, 39 (3): 213-215
The University of Kuwait Medical School William Withey Gull (1816-1890) physician to Guy’s retains traditional clinical teaching methods with Hospital, London, famously stated, ‘Make haste clinical examinations. They appear to me, as a and use all new remedies before they lose their visiting examiner, to be of the highest standard. The effectiveness’. Treatments can be compared by first local co-examiners have, of course, taught the narrowing differences between groups, excluding students, set the examinations and set the standards all who do not fit within narrow limits, then for success. As successful as is the present system, treating each group differently. By comparing the there is, or will be, increasing pressure for change. groups regarding success or failure of treatment, survival or death, the best treatment can usually be Pressure for change demonstrated. Sometimes the need for change is obvious. The same critical standards should be applied to American medical schools at the end of the 19th new methods of teaching and assessing medical century varied greatly. Abraham Flexner visited no students. It is, however, difficult to compare less than 167 medical schools in North America, outcomes following different methods of training and studied the methods of training in a number of and assessment, because outcome results fro m E u ropean countries. He admired the German medical teaching and assessment courses are not university-based system and his 1910 report[1] to the clear-cut. How does one compare success of a Carnegie Foundation profoundly influenced highly specialized academic working in a well- medical training in the United States of America. supported major center with that of an isolated Since his re-organization there have been continual generalist practising in a deprived community? changes in the education of medical students, not Prestigious medical schools take pride in producing always brought about in response to improving the first type - ‘high-flyers’, but a larger number of standards but from the influence of other forces. people benefit from access to the second Three powerful drivers of change can be identified. practitioner. There are financial pressures to reduce costs of training since time spent teaching medical students Examinations dominate curriculum removes clinicians from contributing to the clinical Modular methods of training have been workload. There is increasing resistance of patients adopted enthusiastically because they are highly to submit to exposure and examination except by structured. Courses are divided into units, each those responsible for treating them, and in many intended to teach an aptitude or transmit a places, increasing challenges to clinicians over component of knowledge which can be objectively treatment, often associated with litigation. There is, assessed for each component - a ‘module’. The way or will be, within all societies, increasing regulation in which components are combined in clinical of our responsibilities towards others regarding practice is, however, complex and plays a vital respect for their personal human rights, including function in the successful application of the privacy and dignity. knowledge or aptitude. The Gestalt psychologists In all fields of activity, as new methods are of Germany emphasized that you cannot judge the introduced they are often accepted uncritically as whole by merely looking at the parts - and the only be t t e r , simply because they are new. This phenomenon way to judge medical practice is to see it is well known in the treatment of disease; Sir performed, and audit the results, in the clinic, at the
Address correspondence to: Professor R M Kirk, MS FRCS, Department of Surgery, Royal Free Hospital, London NW3 2QG, UK. Tel: 0207 794 0500 ext: 35412, Home: 0208 340 8575, Fax: 0207 472 6444, E-mail: [email protected] 214 Medical Education Changes Should Be Evidence Based September 2007 bedside, and in the treatment theatre. A particularly another opinion, not an absolute diagnosis. worrying educational trend is to favour modular Increasingly, clinical skills are initially taught in content that can be objectively assessed, thus often ‘Skills laboratories’, using simulations. This is a excluding the subtler but vital aspects of medical valuable introduction and spares patients fro m training often acquired unconsciously during trainees who are performing for their first attempt. ma s t e r / a p p r entice contact. Unconsciously acquired Because it is carried out in a classroom, the teaching knowledge and skills that cannot be objectively can be structured to cover the subject in a relaxed assessed are too often rejected as ‘subjective, atmosphere. The danger is, however, that this aid to p robably biased, and cynically described as clinical instruction is replacing real contact with ‘teachers trying to create clones of themselves”. patients. In order to make assessment of candidates objectively comparable, it is necessary to exclude Subjective information is vital all subjective tests. In the United States of America The relationship between clinicians and patients clinical oral bedside examinations were abandoned is intensely subjective. A doctor unconsciously in 1964 and the current US Medical Licensing takes into account the patient’s gender, age, Examination (USMLE) is carried out in three steps; appearance, behaviour, speech, tone of voice, and apart from computer-based case simulations in step interprets what is said and found in the light of the 3, the testing is by a variety of multiple choice initial judgement, modifying it as new evidence is examinations (MCQ) [ 2 ]. In clinical practice the revealed. The process of interpreting the findings physician has to generate the diagnosis and the and offering treatment plan demands sensitivity to t reatment decision; in examinations by various the patient’s reactions as each statement is made, so MCQs the candidate is supplied with the answers that an explanation or a reassurance can be given, and merely needs to eliminate the incorrect ones. or an alternative plan can be suggested. It is inevitable that the arguments for Most human inter-relationships are not based increasingly structured teaching and objectivity in solely on rationality. Successful medical practitioners assessments of candidates will drive out methods often cannot identify the reasons for their success, of training and examination that are subjective. In or they may attribute it incorrectly. In areas where some cases objectivity is more apparent than real. practical skills are necessary, surgeons, for example, Some subjective analogue judgements by the frequently claim that a particular manoeuvre they candidates or the examiners are awarded on a have developed accounts for their good results - it numerical scale and are thereafter treated as though is sometimes obvious that it is their outstanding they are statistically valid. A British writer and decision-making and sedulous search for perfection bro a d c a s t e r , Malcolm Muggeridge, famously stated, that is responsible. This is borne out by the fact that ‘The credence which western man accords to any others who use the manoeuvre do not get numerate answer would be the envy of any African comparable results, while colleagues who use other witchdoctor’. methods but are equally talented and careful, are Students demand, and the teachers are urged to equally successful. provide, instruction that enables their students to The practice of medicine is not an explicit pass examinations. Their efforts should be directed science that can be transmitted by words or at producing good doctors, not good examination numbers in the same way as mathematics and candidates - and they are not the same. physics are sciences. Success depends on how the Access to patients is being reduced in most science is applied and this is tacit (Latin tacere = to Western countries as a result of changes within be silent), best transmitted by example from master society. Traditionally, trainees were encouraged to to apprentice. The polymath Polanyi stated that ‘By perform a complete examination on every patient watching the master and emulating his efforts in but in western countries they are incre a s i n g l y the presence of his example, the appre n t i c e permitted to examine only the affected part or unconsciously picks up the rules of the art, system and any other system that could have a including those which are not explicitly known to bearing on treatment. In consequence they do not the master himself’[3]. unconsciously acquire a vital knowledge of the Nevertheless, theoreticians continue to believe range of normality and so will in future be unable that it is possible to provide future doctors with to dismiss a patient’s anxiety and confidently state ‘routines’ such as problem-solving strategies and that all is well without ordering investigations. they reject the subtle and often subjective tacit Unnecessary and often expensive and even harmful learning acquired by experiential learning gained investigations may be a means of thro w i n g ‘on the job’[4]. It will be interesting to see how responsibility upon someone else. Investigations successful are the methods being adopted in some are often operator-dependent and interpretation is of the new medical schools in Britain and September 2007 KUWAIT MEDICAL JOURNAL 215 elsewhere; clinical contact starts almost from the objectively assessed, is far more valuable than first day. Anatomy is not taught on cadavers and encyclopedic knowledge; they are commonsense, many traditional methods are changed as in the competence, commitment, compassion and Peninsula Medical School in South West of communication. We cannot afford to ignore them. It England[5]. Only by allowing enthusiasts to test suffices to recognize them, even though we have no their theories, can we decide what is best. What we units of measurement for them. must resist is being pushed into accepting that medicine can be taught by simulations, computer- CONCLUSION driven tests, formal modular factual feeding and As calls are made for changes in medical tested and assessed by MCQs. training and practice, we must demand from those Teachers were formerly given a great deal of who propose the changes, the same standards of latitude, allowed to teach in a manner in which evidence that we as clinicians demand of each other they felt comfortable. Formal structured training when we propose a new treatment. We should be methods increasingly constrict them into set forms clear what are the justifications provided for of teaching which limit their non-verbal innovations, and how were they arrived at. communication with the audience. Moreover, as As we watch the outcomes and incorporate groups of trainees move through the steps, the beneficial methods we should not lightly abandon teachers are at risk of finding themselves repeating the tried and tested methods still valued in Kuwait a course of instruction without variation, time after - training on patients, assessed on patients. time, thus dulling their enthusiasm and desire to pass on their passion for the subject. REFERENCES The present accessibility of facts using computers makes it less important to test ability to 1. Flexner A. Medical education in the United States and recall information, allowing us to focus on the Canada: a report to the Carnegie Foundation for the Advancement of Teaching. New York: Carnegie Foundation subtleties of decision-making, the ability to for the Advancement of Teaching, 1910. recognize minor incongruities, and the instinctive 2. Melnick DE, Dillon GF, Swanson DB. Medical licensing empathy with patients, since we belatedly now examinations in the United Sates. J Dent Educ 2002; 66:595- accept that the patient’s trust, and satisfaction with 599. the outcome, depends heavily on the rapport with 3. Polanyi M. Personal Knowledge: towards a post-critical philosophy. Rouledge & Keegan Paul. London 1973, p 53. his or her clinician. We must reject the present 4. Norman G. Building on experience - the development of demands for exclusive emphasis on objectivity clinical reasoning. N Eng J Med 2006; 355:2251-2252. while almost totally excluding subjectivity. The 5. Watts G. A wind of change blowing from the West. BMJ possession of five qualities, each beginning with 2007; 334:64-65. the letter ‘C,’ none of which is capable of being KUWAIT MEDICAL JOURNAL September 2007
Review Article
Bioecological Control of Acute and Chronic Diseases: The Role of Pro-, Pre- and Synbiotics
Stig Bengmark Lund University, Lund, Sweden Departments of Hepatology and Surgery, University College London (UCL), London Medical School, United Kingdom
Kuwait Medical Journal 2007, 39 (3): 216-226
ABSTRACT The incidence of acute and chronic diseases is increasing found in the large intestine, where it also contributes to worldwide and especially in what has been called the the digestion of food ingredients and making them third world. This development is strongly associated available for absorption. The flora is significantly red u c e d with Western lifestyle: lack of physical exercise, mental among Westerners, which might contribute to the stress, use of tobacco and alcohol and consumption of reduced resistance to disease. Attempts are made to refined and calorie-condensed foods, a lifestyle, which supplement beneficial bacteria, most often lactic acid seems to “paralyze” the innate immune system and bacteria (LAB). One can expect, as LAB are depending on reduce resistance to disease. Increased level of general access to plant fibers that more pronounced effects can be inflammation in the body is common for almost all obtained by simultaneous administration of LAB and diseases, and is likely to be a result of Western lifestyle. A plant fibers, a formulation often referred to as synbiotics. microbial flora, which covers the surfaces of all living Cutting-edge results have also been obtained when they organisms, plants as well as animals, plays an important are tried both in acute conditions such as perioperative role in protecting the body surfaces and the whole body. tr eatment, in connection with larger abdominal operations, The majority of the immune system is in the gut, and liver transplantation, acute severe pancrea t i t i s , extensive flora has a profound influence on its function. The flora trauma and in chronic diseases such as liver cirrhosis and exists on all human surfaces but the majority is to be chronic colitis.
AN EPIDEMIC OF CHRONIC DISEASES morbidities. Selective bowel decontamination e.g., Despite some breath-taking advances in parallel parenteral and topical application of a medico-pharmaceutical and surgical treatment, are handful of powerful antibiotics is no longer a medical and surgical emergencies, as well as treatment option. We seem, after more than 30 advanced medical and surgical treatments, still years of dedicated efforts to combat sepsis by the affected by an by unacceptably high morbidity use of various combinations of antibiotics and more and mortality? Sepsis is the most common medical than 30 randomised clinical trials, ready to conclude and surgical complication, estimated in the US that vigorous use of antibiotics, despite some alone to annually affect as many as 751,000[1,2], and observations of a modest decrease in incidence of cause death of approximately 215, 000 patients chest infections, will not significantly re d u c e ( 2 9 % )[ 2 ], which makes sepsis the tenth most mortality in critically ill patients [ 5 ]. Two re c e n t common cause of death in the country. It is multi-center studies document no effects of especially alarming that both morbidity and antibiotic treatment when used in severe acute mortality in critical illness (CI), especially when pancreatitis[6,7]. Cytokine inhibitors have most often septic, is fast increasing and has done so for several failed when used in acute disease and critical decades. With a documented 1.5% rate of increase illness[8], but reported effects in chronic illnesses are per year it might double within the coming 50 to 60 somewhat more promising[9]. Still side-effects and years. Presently available treatment options: price constitute important obstacles, especially for antibiotics and antagonists/inhibitors of individual long-term treatments. pro-inflammatory cytokines have not met early It is well known that the majority of individuals, high expectations. Instead, these treatments have who end up in ICUs, are elderly and have one or often instituted new complications and new several chronic illnesses and other signs of reduced
Address correspondence to: Prof. Stig Bengmark, MD, PhD, FRACS (hon), FRCPS (hon), 185 Barrier Point Road, Royal Docks, London E16 2SE, United Kingdom. Tel & Fax: +44 20 7511 6841, E-mail: [email protected] September 2007 KUWAIT MEDICAL JOURNAL 217 resistance to disease. The epidemic of critical illness strong effects on both immune cells and flora, is strongly associated with an epidemic of chronic affecting homeostasis of the immune system and diseases (ChDs). World Health organization estimates resistance to disease. A series of experiment have that 46% of global disease burden and 59% of global demonstrated an upto 100, 000 times (5 logs of mortality is due to ChDs; 35 million individuals die o rder) increase in growth of Gram-negative each year from chronic diseases, and the numbers bacteria exposed to noradrenaline (see further: are steadily increasing[10]. Circumstantial evidence Lyte[18]), which explains a relatively old observation supports the association of ChDs to modern life of significantly higher blood levels of noradrenaline style, stress, lack of exercise, abuse of tobacco and and adrenaline in patients, who develop severe alcohol, and to the transition from natural septic conditions compared to patients with an unprocessed foods to processed, calorie-condensed uncomplicated postoperative course [ 1 9 ]. Luminal and heat-treated foods. release of noradrenaline is a strong inducer of increased virulence of luminal bacteria[20] and much OUTCOME ASSOCIATED WITH LIFE STYLE, suggest that PPMs, normally indolent colonizers, ESPECIALLY INTAKE OF FOODS under stress change their phenotype and become The association between ChDs, CI and reduced life-threatening pathogens[21]. intake of plant fibers, plant antioxidants together with increased consumption of industrially OUTCOME ASSOCIATED WITH IMMUNE produced and processed dairy products, refined DYSFUNCTION sugars and starch products is obvious. A s Our knowledge and understanding of function examples; the per capita consumption of refined of the innate immune system and resistance to sugar has increased from about one pound per disease has increased significantly during the last person per year in 1850 to about 100 lbs/person decade. Increasing evidence suggests that outcome /year in the year 2000 and the per cow milk after larger medical and surgical procedures and production from 2 - 50 quarts/day. Dairy products, e m e rgencies is intimately associated with pre - especially milk (mostly from pregnant cows) are morbid health and the strength of the immune rich in proinflammatory molecules: hormones such system, also reflected by the speed and depth of as estrogens and growth factors such as IGF-1. functional deterioration during the first few hours Consumption of bovine milk has been shown to after trauma. Arecent study suggests that in severe release inflammatory mediators, increase intestinal acute pancreatitis four variables: high age, chronic permeability and induce leakage of molecules such health status, need for mechanical ventilation and as albumin and hyaluronan. Heating up milk increase in serum creatinine during the first 60-72 (pasteurization), and especially production of and hrs are strongly associated with poor outcome[22]. storage of milk powder, produces large amounts of advanced glycation products (AGEs, Fig. 1) and OUTCOME ASSOCIATED WITH EXPOSURE advanced lipoxidation products (ALEs)[11], known TO CHEMICALS, INCLUDING to induce and potentiate inflammation. This PHARMACEUTICALS information is important as many enteral nutrition Homeostasis is important for bodily functions solutions are based on milk powder. B re a d , and particularly for the immune system and especially from gluten-containing grains, is also resistance to disease. Modern man is also richly rich in molecules with documented pro - exposed to chemicals. The effects on immune inflammatory effects (see further: Bengmark) [12-14]. functions of pharmaceuticals is often not known and appreciated as federal agencies do not OUTCOME ASSOCIATED WITH PREMORBID regularly require testing of immune effects of new HEALTH drugs. Evidence from experimental studies allows, Signs of a failing immune system are often however, the assumption that a large proportion of observed in those patients who later develop acute the pharmaceuticals used in medicine and critical illness. About half of the patients, who particularly in the ICUs have depressive effects on develop sepsis, are in the age group of 65 years and the immune function. Chemical substances can, above, and 48 % of the patients are neutropenic[15,16]. depending on dose, have both stimulatory and Stress and hormones play an important role, and inhibitory functions, a phenomenon given the both flora and mucosal cells have important name of chemical hormesis and re f e r red to as endocrine functions and produce as well as Arndt-Schultz law[23]. A broad range of chemicals respond to hormones. The gastrointestinal (GI) have also been shown to be immunostimulatory tract contains 100 million neurons (which is equal / p reventive of morbidity in lower doses and to the number of neurons in the spinal cord ) immunoinhibitory/disease-inducing in larger doses. distributed through all its layers[17] and they exert Several drugs have been shown to derange 218 Bioecological Control of Acute and Chronic Diseases: The Role of Pro-, Pre- and ... September 2007 m a c rophage functions, bactericidal efficacy and destructive inflammation’ more than twenty years production and secretion of cytokines. For example, a g o[ 4 5 ]. The extent of neutrophil infiltration is supply of antibiotics (150 mg/kg body weight of significantly aggravated by mechanical therapeutic Mezlocillin, Bayer) has been shown to significantly e fforts such as handling of the bowels during s u p p ress essential macrophage functions; operation[37], and ventilation of the lungs[46]. It is also chemiluminescence response, chemotactic motility, influenced by poor nutritional status, pre-existing bactericidal and cytostatic ability and lymphocyte immune deficiency, obesity, diabetes and high proliferation[24]. levels of blood sugar[47] and is strongly associated with increased expressions in the body of OUTCOME ASSOCIATED WITH PROVIDED molecules such as NF-kB, COX-2, LOX and NUTRITION iNOS[48,49]. A recent study emphasizes the role of In the past, it was largely ignored that the post- s u p p ressed apoptosis of circulating neutro p h i l s traumatic immuno-depression becomes significantly and its association to increased activation of NF-kB more pronounced when the regulatory functions of and reduced activity of caspases-9 and -3 in the gut and liver are by-passed through parenteral patients with clinical sepsis [50]. administration of nutrition. It was believed not long ago that parenteral infusion of large amounts THE LUNGS IN FOCUS of water, electrolytes, nutrients such as fat and The most frequently observed and most often s u g a r, would benefit the patient and impro v e severe clinical manifestations of organ failure are outcome. Today, however, it is well known that seen in the lungs. In severe acute pancreatitis the supply, especially parenterally, of larger amounts of organ systems most often involved in early (within fluid and electrolytes[25-27], fat[28-30], sugar[31,32] and 24 hrs) single organ failure are pulmonary (91%[51], nutrients[33,34] leads to immune dysfunction, reduces 8 1 %[ 5 2 ]), renal (4.5% [ 5 1 ], 5%[ 5 2 ]) and coagulation resistance to disease and increases morbidity. (4.5%[51], 14%[52]). Extensive neutrophil infiltration not only of the lungs but also other distant organs NEUTROPHIL FUNCTION IN FOCUS is a characteristic finding in patients dying of Severe trauma, major surgery and severe sepsis sepsis. The degree of oxidative stress and of will, parallel with a significant decrease in neutrophil activation and infiltration, especially in lymphocytes, induce a significant increase in the lungs, appears to be the main determining circulating and tissue neutrophils. factor of outcome [ 5 3 ]. The acute lung injury is A marked depression of innate cellular characterized by alveolar capillary endothelial cell immunity with persistent decline in T-4 helper i n j u r y, increased capillary permeability and lymphocytes and elevation of T-8 suppre s s o r subsequent hypoxia, and accumulation of lymphocytes is observed in patients after severe n e u t rophil-associated inflammatory pro d u c t s : t r a u m a[ 3 5 ]. It is also suggested that a T- 4 / T- 8 reactive oxygen species, proteolytic enzymes, lymphocyte cell ratio of < 1 is a reliable sign of eucosanoids and various other mediators. severe immuno-suppression and a prediction of Splanchnic hypoperfusion with endothelial cell complications such as multiple organ dysfunction i n j u r y, increased expression of interc e l l u l a r syndrome, and this has been verified in patients adhesion molecule-1 (ICAM-1)[ 5 4 ] and serine with myocardial infarction, acute pancre a t i t i s , p roteases released by the hypoxic pancre a s[ 5 5 ], multiple severe trauma and in oncology ICU mesenteric lymph, transported via the lymphatics patients[36]. Parallel to the decrease in lymphocytes a and thoracic duct rather than portal vein[54-56] are in significant increase in circulating neutrophils and addition to various cytokines[57] suggested to initiate accumulation in tissues of neutrophils will occur, neutrophil-mediated tissue injuries, particularly in often observed and reported in conditions such as the lungs. Experimental studies have also shown shock, sepsis, major trauma, major burns and that post-shock mesenteric lymph will activate the severe acute pancreatitis. Accumulating evidence mechanisms leading to acute lung injury[58], and suggest that tissue infiltration of neutrophils in that diversion of thoracic duct lymph will prevent trauma induces common post-trauma/post- trauma-hemorrhagic shock induced lung injury[59]. operative dysfunctions such as paralytic ileus[37,38], It was recently demonstrated in experimental bone marrow suppression, endothelial cell animals subjected to caecal ligation and puncture dysfunction, and results in tissue destruction and (CLP) that stress-induced neutrophil infiltration of organ failure, particularly in lungs[39-41], intestines[42], the lung and subsequent tissue destruction can be l i v e r[ 4 3 ] and kidney[ 4 4 ]. Neutrophil infiltration of effectively prevented by oral supplementation of a distant organs[45], especially of the lungs[46] are also synbiotic cocktail. Asynbiotic formulation, Synbiotic characteristic findings in patients dying of sepsis, 2000 Forte (see further below), administered orally suggested to be a consequence of ‘generalized auto- before the trauma[60] or a subcutaneous injection[61] September 2007 KUWAIT MEDICAL JOURNAL 219 of the four LAB in the cocktail prevented effectively both neutrophil accumulation and tissue destruc t i o n in the lungs (Fig. 2 A-C). The average neutrophil count in lung (average of five fields) after enteral administration of: mixture of LAB and bioactive fibers = 9.00 ± 0.44 (1), only LAB = 8.40 ± 0.42 (2), only bioactive fibers = 31.20 ± 0.98 (3) and placebo (non-fermentable fiber) 51.10 ± 0.70 (4). The corresponding values of myeloperoxidase (MPO) were 25.62 ± 2.19 (1), 26.75 ± 2.61 (2), 56.59 ± 1.73 (3) and 145.53 ± 7.53 (4). Similarly the changes in MDA were 0.22 ± 1.31 (1), 0.28 ± 3.55 (2), 0.48 ± 5.32 (3) and 0.67 ± 2.94 (4) and in nitric oxide 17.16 ± 2.03 (1), 18.91 ± 2.24 (2), 47.71 ± 3.20 (3) and 66.22 ± 5.92 (4). All differences between treatment groups and placebo were statistically significant (p > 0.05).
USE OF PRE-, PRO- AND SYNBIOTICS Fig 1: Content of AGE (furosine) in various milk- based products and soya-milk. a. Milk powder kept for two years at room temperature. b. Both prebiotic fibers and some probiotic bacteria, Milk powder kept for one year at room temperature. c. DIF with whey alone or in combination have d e m o n s t r a t e d plus casein. d. DIF with hydrolyzed whey. e. Milk powder kept for one year at 4o C. f. Fresh milk powder. g. Raw (whole) bovine milk. DIF= e x t r a o rdinary efficacy to re s t o re and maintain Dietetic Infant formulas, UHT = ultra heat treatment. (after Baptista et immunity and prevent complications. The al)11. following effects are reported after use of some specific LAB: who observed that supplemented pyruvate is an l reduce/eliminate potentially pathogenic effective scavenger of ROS and exhibits strong anti- micro- organisms (PPMs) inflammatory effects: suppresses NF-kB activation, l reduce/eliminate various toxins, mutagens reduces secretion of NO and pro i n f l a m m a t o r y and carcinogens cytokines, prevents intestinal translocation, reduces [73] l promote apoptosis cardiac ischemia and improves kidney function . l sy n t h e s i z e / r elease numerous nutrient: antioxidants, Cardioprotective effects have also been reported gr owth, coagulation and other bioactive compounds f rom intravenous administration of lyophilised [74] l modulate the innate and adaptive immune LAB . defence mechanisms (for further information - see LAB, which shows significant immunomodulatory Bengmark[62-64]) effects in vitro and in animal experiments, will More recent studies suggest that LAB sometimes fail, when it comes to clinical trials. Only l pr omote/maintain gastrointestinal (GI) motility a small minority of existing LAB have been and prevent GI paralysis and postoperative ileus[6 5 - 6 7 ] demonstrated to show strong clinical immuno- And has the ability to: modulatory abilities. Experience from clinical l inhibit NF-kB activation[68-70] studies deem to indicate that the clinical efficacy l inhibit constitutive synthesis of IL-8 and varies from none to significant as one goes from synthesis and secretion of IL-8 induced by TNF- single-strain probiotic to full flora re p l a c e m e n t a [71,72] (enemas of feces): single-strain probiotic < multi- l inhibit COX-2 expression and restore the Cox- strain probiotic < or ~ single-strain/single fiber 1/Cox-2 ratio[73] synbiotics < multi-strain/multi-fiber synbiotics Some of these effects are produced by both live < total fecal flora replacement[75,76]. and dead LAB. However, the inhibition of synthesis and secretion of IL-8 is only induced by live LAB Prebiotics: and not by bacterial lysate, heat-killed or gamma- Prebiotics are substrates to be fermented by irradiated LAB[71]. Immuno-modulatory effects are flora e.g., non-digestible food ingredients, mainly also induced by microbial products, such as plant fibers, which undigested will reach the colon butyrate, propionate, pyruvate and sometimes also and food ingredients often referred to as colonic lactate and acetate. Butyrate and proprionate for foods. Prebiotics are nutrients essential for supply example decrease COX-2 expression by 85 and 72% of substrate and energy for both flora and the host, respectively and increase COX-1 expression by 37 and essential for mucosal growth, water and and 23% re s p e c t i v e l y, effects, which cannot be e l e c t rolyte balance, and the body’s re s i s t a n c e obtained with lactate or acetate[72]. Of great interest against invading pathogens. Thus far, only one in this connection are recent observations by Fink, clinical study has tried only prebiotics in critically 220 Bioecological Control of Acute and Chronic Diseases: The Role of Pro-, Pre- and ... September 2007
Fig. 2A Fig. 2B
Fig. 2: Histological sections of rat lungs 24 hours after cecal ligation and puncture. A. After placebo treatment, B. After treatment with only bioactive fibers, C. After treatment with both bioactive fibers and live lactic acid bacteria (Synbiotic 2000) (Photo Dr Ozer Ilkgul Izmir, Turkey)
differences exist in the ability of LAB to survive the passage through the GI tract and to influence cytokine production after passage through the stomach and small intestine, as demonstrated in a study on ileostomy patients[78]. Four different LAB species were compared: Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus rhamnosus and Bifidobacter animalis. Out of the originally orally administered 108 cells/ml of each LAB, after the passage through the stomach and small in t e s t i n e , only between 107 (Lactobacillus plantarum) and 102 (Lactobacillus rhamnosus) bacterial cells remained. Most of the strains tested showed, after passage through the small intestine, a significantly red u c e d or weak (especially Lactobacillus rha m n o s u s ) ability to influence cytokine production, e.g., the state of inflammation. Also, the ability to ferment fiber is much dependent on the strain used - this is especially so for semi-resistant prebiotics such as Fig. 2C oligofructans: inulin and phleins. When the ability of 712 different LAB to ferment oligofructans was ill patients. Forty-one burn patients were randomized studied, only 16/712 were able to ferment the to receive during the first 15 days either 6 g of phleins and 8/712 the inulin type fiber[79]. Only four o l i g o f ructose/d or sucrose as placebo. No LAB species were able to ferment these fibers: difference was observed between the groups in Lactobacillus plantarum (several strains), Lactobacillus e ffect on lactulose/mannitol ratio or clinical p a r a c a s e i subspecies p a r a c a s e i, Lactobacillus bre v i s [77] outcome . and Pediococcus pe n t o s a c e u s . The ability to control various pathogens is also strain-specific and limited Probiotics to a few strains. When the ability of fifty different P robiotics are live micro o rganisms supplied LAB to control 23 different pathogenic Clostridium from outside the body, most commonly to the difficile (CD) was tested, only five proved effective digestive tract. Most probiotics supplemented to against all, eight were antagonistic to some, but 27 humans, such as those provided with dairy were totally ineffective[80]. The five most effective products or sold in health stores, are not effective strains were Lb paracasei subsp paracasei (2 strains) enough to be used in clinical medicine. Gre a t and Lb plantarum (3 strains). September 2007 KUWAIT MEDICAL JOURNAL 221
BOVINE MILK NOT IDEAL AS CARRIER OF MULTI-STRAIN/MULTI-FIBER SYNBIOTICS PROBIOTICS/SYNBIOTICS IN CLINICAL TRIALS It is important to recognize that cow’s milk is Lund University microbiologists Åsa Ljungh not an ideal carrier of probiotics, especially for and Torkel Wadström developed a multi- specific clinical use. In addition to its proposed role strain/multi-fiber synbiotic formula, which in as risk factor for increased degree of inflammation recent years has been extensively used in clinical in the body and development of ChDs[81], bovine trials. The choice of LAB for the formulation was milk: done after extensive studies of > 350 human[96] and [97] l In contrast to breast milk, does not contain any >180 plant microbial strains and especially their fibers or fiber-like molecules (only elephant milk ability to produce bioactive proteins, transcribe NF- contains as much as human milk). Complex kB, produce pro- and anti-inflammatory cytokines, fucosylated oligosacharides characteristic of human p roduce antioxidants, and most important, to milk, with structural similarities to immuno- functionally complement each other. The formulation modulating cell surface glycoconjugates, which consists of a mixture of four bioactive LABs, one e n f o rce GI immunity and stimulate growth of from each of the four main genera of lactobacillus; health-supporting gut microflora, do not exist in 1 01 0 of Pediacoccus pentosaceus 5-33:3, 101 0 o f bovine milk[82]. Leuconostoc mesenteroides 32-77:1, 1010 of Lactobacillus paracasei subsp paracasei 19 and 1010 of Lactobacillus l Cow’s milk releases inflammatory mediators, induce inflammation, and induce leakage of plantarum 2362, e.g. 40 billion LAB per dose, to molecules such as albumin/hyaluronan, increases which is added a mixture of four well studied intestinal permeability and causes translocation bioactive plant fibers: 2.5 g betaglucan, 2.5 g inulin, /leaky gut[83-88]. 2.5 g pectin and 2.5 g resistant starch, a total of 10 g plant fibers. It is produced by Medipharm, Kågeröd l Cow’s milk is rich in advanced glycation Sweden and Des Moines, Iowa, USA under the p roducts (AGEs), produced during the heating name of Synbiotic 2000™. One or two such doses up/pasteurization process (Fig. 1)[11 , 8 9 ] . It is particularly are supplemented to the patients per day. In recent so for milk powder, a common ingredient in clinical studies a Synbiotic 2000 FORTE™ and a Probiotic nutrition formulas. There is a direct association 11 2000 FORTE™ (no fiber added), containing 10 of between the dietary intake of AGEs and the level of each of the four LABs, e.g., 400 billion LAB per dose markers of systemic inflammation[90]. are tried. l Cow’s milk is rich in free poly-unsaturated fats (PUFAs), seen also, in lower concentrations than THE EFFECTS OF SYNBIOTIC 2000 THUS FAR those in fermented dairy products, to reduce the INVESTIGATED IN THE FOLLOWING ability of LAB to adhere to mucous membranes and DISEASES [91] to grow . Acute pancreatitis: l The colonization rate (ability to adhere to the Sixty-two patients with severe acute pancreatitis mucosa and replicate) of so called yoghurt bacteria (SAP) (Apache II scores: Synbiotic 2000-treated = is low (Examples: lb casei 2%, lb Reuteri 2% and lb 11.7 ± 1.9, controls = 10.4 ± 1.5) were given either acidophilus 0%)[92]. two sachets/day of Synbiotic 2000™ (2 x 40 billion l The LAB which can grow on milk substrates LAB/day and totally 20 g fibers) or the same seem to lack clinical efficacy, as demonstrated in amounts of fibers (20 g) as in Synbiotic 2000™ two recent controlled studies in postoperative and during the first 14 days after arrival to the critically ill patients re s p e c t i v e l y. A s t a n d a rd hospital[98]. 9/33 patients (27%) in the Synbiotic co m m e r cial product (TREVISÒ, Ch Hansen, Denmark) 2000-treated group and 15/29 patients (52%) in the containing Lactobacillus acidophilus LA5, Bifidobacterium fiber only-treated group developed subsequent lactis BP12, Streptococcus thermophilus, La c t o b a c i l l u s infections. 8/33 (24%) Synbiotic 2000-treated and b u l g a r i c u s, mixed with 7.5 g oligofru c t o s e w a s 14/29 (48%) of the fiber only-treated patients supplied to 45 critically ill patients and 45 control s [9 3 ] developed SIRS, MOF or both (p < 0.005)[98]. and to 72 elective abdominal surgery patients and 65 controls respectively [94]. The ICU study reported Polytrauma: significant reductions in number of PPMs in the In polytrauma patients two pro s p e c t i v e stomach of the treated patients, but no influence on randomized trials with Synbiotic 2000 and intestinal permeability nor any clinical benefits. Synbiotic 2000 Forte respectively have been The peri-operative study reported no differences in concluded. The first study compared in patients bacterial translocation, gastric colonization, or with acute extensive trauma: Synbiotic 2000 (40 systemic inflammation, or septic complications (See billion LAB/d) with a soluble fiber, a peptide diet further my commentary on the ICU study[95]). and supplementation of glutamine. Treatment with 222 Bioecological Control of Acute and Chronic Diseases: The Role of Pro-, Pre- and ... September 2007
Synbiotic 2000™ lead to a highly significant only fiber group Enterobacter cloacae (eight patients), d e c rease in number of chest infections (4/26 E n t e rococcus faecalis/faecium (seven patients), patients - 15%) as compared to peptide diet (11/26 Escherichia coli (seven patients), Klebsiella pneumoniae patients - 42%, p < 0.04), glutamine (11/32 patients (two patients), Staphylococcus aureus (two patients), - 34%, p < 0.03) and only fibers (12/29 patients- and P roteus mirabilis (one patient). Statistically 41%, p < 0.002) (Spindler- Vesel A, personal significant differences between the groups were communication). Also the total number of also observed in use of antibiotics (mean: Synbiotic infections were significantly decreased; Synbiotic 2000; 2 ± 5 days, only fibers; 10 ± 14 days). 2000ª 5/26 patients (19%), only fibers 17/29 patients (59%), peptide 13/26 patients (50%) and Chronic liver disease and liver transplantation: glutamine16/32 patients (50%). In the second study Fifty-eight patients with liver cirrhosis suffering sixty-five polytrauma patients were randomized to so called minimal encephalopathy were randomized receive once daily for 15 days Synbiotic 2000 Forte into three treatment groups: Group 1 (20 patients) (400 billion LAB + 10 gram of fibers, see above) or received Synbiotic 2000 (40 billion LAB), Group 2 maltodextrine as placebo. Significant reductions (20 patients) received the same amount of the fibers were observed in number of deaths (5/35 Vs 9/30, in Synbiotic 2000 and Group 3 (15 patients) p < 0.02), severe sepsis (6/35 Vs 13/30, p < 0.02), received placebo (non-fermentable, non-absorbable chest infections (19/35 Vs 24/30, p < 0.03), central fiber - crystalline cellulose)[101].A significant increase line infections (13/32 Vs 20/30, p < 0.02) and in intestinal LAB flora was observed after one ventilation days (average 15 Vs 26 days)[99]. month of supplementation in the Synbiotic-treated group, but not in the other two groups. Intestinal Abdominal surgery: pH was significantly reduced in both treatment In a randomized controlled study forty-five g roups but not in the placebo-treated gro u p . patients undergoing major surgery for abdominal Significant decreases in faecal counts of Escherichia cancer were divided into three treatment groups: 1) coli, Staphylococcus and Fusobacterium, but not in Enteral nutrition (EN) + Synbiotic 2000 (LEN), 2) P s e u d o m o n a s and En t e ro c o c c u s , and significant EN + only the fibers in the same amounts (20 g) as de c r eases in ammonia/s, endotoxin/s ALT/s and in Synbiotic 2000™ (FEN) and 3) a standard bilirubin/s (original level 252 ± 182) were observed parenteral nutrition (PN). All treatments lasted for in the Synbiotic 2000-treated group (84 ± 65, p < two preoperative and seven postoperative days. 0.01) and in the only fiber-treated group (110 ± 86, p The incidence of postoperative bacterial infections < 0.05) while it remained unchanged in the placebo was 47% with PN, 20% with FEN and 6.7% with group. The improvements in liver function were LEN (p < 0.05)[100]. Significant improvements were accompanied by significant improvements in also documented in prealbumin (LEN, FEN), C- psychometric tests and in the degree of reactive protein (LEN, FEN), serum cholestero l encephalopathy. Later, studies by the same group (LEN, FEN), white cell blood count (LEN), serum of investigators did also show significant endotoxin (LEN, FEN) and IgA (LEN). In another improvements in liver blood flow and indocyanine p rospective randomized double-blind trial clearance in patients supplemented for one week performed in 80 patients subjected to pyloru s - with Synbiotic 2000[102]. These results offers great pr eserving pancreatoduodenectomy (PPPD) rec e i v e d hope that synbiotic treatment to patients on a twice daily either Synbiotic 2000™ (2 x 40 billion waiting list for liver transplantation, would help LAB) or only the fibers in composition from the day prevent septic episodes, improve liver function, b e f o re surgery and during the first seven and promote an improved outcome. postoperative days. A highly significant difference Sixty-six patients were randomized to either in infection rate (p = 0.005) was observed as only receive Synbiotic 2000 or only the fibers in 5/40 patients (12.5%) in the Synbiotic 2000-treated Synbiotic 2000 in connection with human group suffered infections (four wound and one orthotopic liver transplantation. The treatment was urinary tract infection) versus 16/40 (40%) in the started on the day before surgery and continued for only fiber group (six wound infections, five 14 days after surgery. During the first postoperative peritonitis, four chest infections, two sepsis, and month only one patient in the Synbiotic 2000- one of each of urinary tract infection, cholangitis t reated group (3%) showed signs of infection and empyema) (Rayes N, et al, personal (urinary infection) compared to 17/33 (51%) in the communication). The infecting microorganism in patients supplemented with only the four fibers[103]. the Synbiotic treated group were K l e b s i e l l a The infecting organisms in the Synbiotic-treated pneumoniae (two patients), Enterobacter cloacae (two group were Enterococcus fecalis in one patient and in patients), P roteus mirabilis (one patient) and the only fiber- t reated group were E n t e ro c o c c u s Enterococcus faecalis/faecium (one patient) and in the f e c a l i s / f e c i u m - 11, Escherichia coli -3, E n t e ro b a c t e r September 2007 KUWAIT MEDICAL JOURNAL 223 cl o a c a e -2, Pseudomonas aeruginosa - 2 and St a p h y l o c o c c u s Rutgeerts’ disease scores after three months of aureus in one patient. The use of antibiotics was on treatment were 0.6 ± 0.8 in the Synbiotic-treated an average 0.1 ± 0.1 d in the synbiotic-treated group and 0.8 ± 1 in the placebo group (NS). patients and 3.8 ± 0.9 d in the only fiber-treated group. CONCLUSIONS The novel treatment of Synbiotics is still in its Inflammatory bowel disease: early infancy. It is clear that, although sometimes Daily rectal instillations with Synbiotic 2000 dramatic effects are observed after synbiotic reconstituted in saline were given to ten patients treatment, there are conditions, which do not seem with distal colitis over two weeks. One patient to respond to such treatment. A lot of evidence withdrew after one week. The remaining patients suggests that one of the main effects of synbiotic showed dramatic improvements in various disease treatment is reduction of both acute and chronic s c o res during the three weeks of observation; inflammation. However, some indications suggest episodes of diarrhea (2.4˚ 0.8), visible blood in stool that synbiotic treatment is not an effective tool to (2.2˚ 0.8), nightly diarrhea (0.5˚ 0), urgency (1.9˚ 1.0) restore suppressed immunity, which might explain and consistency of stool (1.1˚ 0.8)[104]. Two patients the observation that synbiotic treatment, as well as reported significant bloating and wind but no other p robiotic treatment is more effective when adverse or side effects were reported. supplemented pre-trauma/operation and/or immediately or early after trauma/operation. TREATMENT-RESISTANT CONDITIONS T h e re is presently no solid explanation why Treatment with Synbiotic 2000 has failed in two seemingly synbiotic treatment is very effective in types of diseases: chronic liver disease, but is unable to reduce local inflammation and degree of disease in a chronic General Intensive Care patients: bowel disease such as Crohn«s disease. Two large studies have been performed in a general intensive care population; one with REFERENCES Synbiotic 2000 and one with Synbiotic 2000 FORTE. Synbiotic 2000 (40 billion LAB) was given to 162 1. Arias E, Smith BL. Deaths: preliminary data for 2001. Natl Vital Stat Rep 2003; 51:1-44. patients and only fiber to 168 patients. No 2. 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Review Article Depression in Patients with HIV/AIDS
Sammod Vardhana M, Bairy Laxminarayana K Department of Pharmacology, Kasturba Medical College, Madhava Nagar, Manipal, Karnataka, India
Kuwait Medical Journal 2007, 39 (3): 227-230 ABSTRACT Depression is common in patients with HIV/AIDS, and information on the epidemiology of depression in its identification and treatment are critically important in HIV/AIDS, review treatment options, and discuss disease management. Despite depression’s high prev a l e n c e possible interactions between antidepressants and other and major impact on patient’s quality of life, questions agents. This may be useful in the better management of remain re g a rding its epidemiology and pre f e r re d HIV/AIDS patients. treatment. The authors of this paper summarize available
KEYWORDS: depression, epidemiology, HIV/AIDS, treatment
INTRODUCTION regarding the influence of stage of HIV infection on Depression is one of the major disabling factors depression and anxiety. One study showed poor in any chronic illness. Diagnosis and optimal correlation with severity of apathy and cognitive treatment of depression in HIV/AIDS patients is performance with incidence of depre s s i o n[ 4 ]. complicated by interactions between the disease Another study conducted at a specialty HIV clinic conditions as well as among the pharmacological at a tertiary health care centre in South India agents used to treat them. Diagnostic challenge in reported 40% of seropositive individuals suffering many such chronic disorders is mainly due to fr om syndromal depression. Anxiety severe enough association of similar features as the symptoms of to fulfill the ICD-10 criteria for generalized anxiety the chronic disorder itself. HIV infection is one such disorder has been found in 90% of the HIV infected condition where the disease itself may cause many individuals with depressive symptoms. Suicidal symptoms resembling those of depression. On the tendency among HIV patients was highest during other hand, several psychiatric conditions including the first week after the revelation of the de p r ession may predispose individuals to acquiring seropositive status and all of those who attempted HIV infection as a consequence of their influence on suicide had past history of psychiatric illness[5,6]. be h a v i o u r [1 , 2 ] . Treatment of depression in HIV/AIDS Majority of studies done in India have reported patients is jeopardized not only by the inability to higher rates of depression among women compared diagnose the condition specifically but also by poor to men which is implicated to higher caregiver adherance to treatment, which has many social, burden, more social stigma and poor healthcare[7]. medical and non-medical factors. This re v i e w Greater severity of depression, on the other hand, summarizes the current knowledge on the has been found to be associated with gre a t e r epidemiology and different aspects in management f requency of injection risk behavior among of depression in HIV/AIDS. d e p ressed injection drug abusers making them more vulnerable to HIV infection[1,2]. EPIDEMIOLOGY Prevalence of depression among HIV infected DIAGNOSIS OF DEPRESSION IN HIV/AIDS population is shown to be varying from 0 - 47% in Several barriers exist in diagnosis of depression different studies. Despite this, a meta-analysis of in HIV/AIDS patients. Patients may be unwilling ten studies comparing HIV-positive and at risk HIV to discuss their moods and emotions with the - negative patients demonstrated a twofold increase health care provider for fear of being stigmatized in the prevalence of major depression in patients further[7]. For the health care provider diagnosis of infected with HIV[3]. This variation is wide enough depression in HIV/AIDS patients is not an easy to raise questions on the methods and criteria used task as the depressive symptoms such as fatigue, in the different studies. There are conflicting results insomnia, weight loss etc. may be taken as part of
Address correspondence to: Dr.K.L.Bairy, MD, PhD, Professor of Pharmaoclogy, Kasturba Medical College, Manipal 576104, India. E-mail: [email protected] 228 Depression in Patients with HIV/AIDS September 2007 disease itself, and serious thought to diagnose a TREATMENT OF DEPRESSION IN HIV/AIDS separate psychiatric disorder is not entertained. Further complicating the issue starting from The diagnosis may be further complicated by the diagnostic problems, treatment of depression in pr esence of comorbid neurological illness, substance HIV/AIDS patients faces many limitations from abuse and use of multiple drugs including both sides: patient and health care pro v i d e r. a n t i re t roviral drugs that are known to cause Patients already on multiple drugs for HIV and depressive symptom as a side effect. Importance of other infections may have tendency to have poor diagnosis of major depression in HIV/AIDS lies in compliance to antidepressants and health care the fact that response to therapy in HIV/AIDS provider may also be reluctant to add drugs to patients is as good as in uninfected population and patients who are already on multiple dru g s . when not recognized it has negative impact on Furthermore, it was seen in a trial with fluoxetine adherence with medical treatments, quality of life that the drug was found to be effective in and overall outcome[8]. To overcome the diagnostic comparison to placebo but the attrition rate was b a r r i e r, it is recommended that health care high. The trial also concluded that the severity of providers should encourage expression of emotions im m u n o s u p p r ession was not related to antidepres s a n t in clinics and non-specialists need training in the response, attrition or side effects and fluoxetine assessment of psychiatric syndromes in HIV treatment was not associated with change in CD4 patients[7]. Several types of clinical rating scales cell count[10]. have been developed for diagnosis and rating of Selective Serotonin Reuptake Inhibitors (SSRIs) depression. Study has shown that in otherwise now are the most widely used drugs for treatment asymptomatic HIV infected patients physical of depression in general population because of their symptoms of fatigue insomnia, weight loss are favorable safety profile and convenient once a day related to psychological disturbance possibly major dosing. SSRIs have been found to be effective in depression[9]. Difficulty in early diagnosis is an t reating depression in HIV/AIDS patients[ 1 0 , 11 ]. important issue because one study has shown that Choice of antidepressants in HIV infected patient is only about half of HIV infected patients in US still not guided by evidence as controlled trials receive antidepressants[10]. comparing SSRIs are lacking and it is suggested that most SSRIs can be used in HIV positive adults. D i fferential diagnosis of Major depression in When drug-drug interaction is a concern, sertraline, HIV/AIDS citalopram and escitalopram may be considered[11]. The differential diagnosis of depression includes A study examining ethnic differences in response to non-pathological states of grief and mourning antidepressant treatment showed that attrition rate which may be very severe in some cases and a was greater among Latinos than either blacks or variety of disorders related to both psychological whites. Black patients were more likely than whites and physiological disturbances. Complaints of to be nonresponders to fluoxetine. Latinos were d e p ressive syndrome can be re p resentative of more likely to respond to placebo compared with dementia, delirium, intoxication, CNS injury or blacks and whites. Ethnic groups did not differ in infection, and other acute medical conditions. AIDS the presence of treatment-emergent side effects[12]. dementia and other HIV related CNS conditions Dehydroepiandrosterone (DHEA) has been shown can produce a flat apathetic state that is often to be efficacious in treatment of non-major misdiagnosed as depression. Cocaine withdrawal persistent depression in patients with HIV/AIDS produces a depressive syndrome and delirium that being superior to placebo in reducing depressive can mimic many psychiatric conditions. CNS symptoms. The trial had showed not only low syphilis, otherwise a rare condition, may be attrition rate in the group of physically ill patients misdiagnosed as a psychiatric illness in HIV/AIDS but also there were requests for extended open patients[9]. label treatment showing high acceptance of the preparation[13]. But another controlled trial with Effect of depression on course of HIV infection testosterone did not show any benefit over placebo This is another area facing a lot of conflicts. in terms of reduction of depressive symptoms[14]. Some studies have shown lack of association between depression and course of HIV infection DRUG INTERACTIONS while others have shown poorer outcome in Since HIV/AIDS patients, when indicated, patients with depression. This may be due to poor receive multiple drug therapy for HIV infection adherence to treatment regimen and self-care as itself or for prophylaxis or treatment of well as stress induced immune dysfunction as opportunistic infections there is high chance of decreased number of natural killer cells and B d ru g - d rug interaction producing unfavorable lymphocytes have been shown at low viral load[7]. outcome. September 2007 KUWAIT MEDICAL JOURNAL 229
Because protease inhibitors (PIs) produce favorable Additional Issues long-term suppression of viremia, elevation of CD4 HIV/AIDS is not only responsible for individual lymphocyte count and retard disease progression morbidity and mortality but also is a familial and with improved survival when combined with other social burden by itself. Treatment of HIV infection antiretroviral agents, they form an integral part of is costly and complicated. High incidence of Triple therapy in HIV infection. Interaction of PIs is d e p ression and anxiety further aggravates the mainly due to inhibition of Cytochrome P450 complication. Besides pharmacotherapy, supportive enzymes CYP3A4 and CYP2D6. Potency of enzyme psychotherapy has an important part to play in the inhibition varies among diff e rent PIs, ritonavir treatment of those patients who interpret their being the most potent one. PIs other than ritonavir symptoms to be reaction to the diagnosis of HIV mainly inhibit CYP3A4 while ritonavir inhibits infection. Other forms of useful psychotherapy are CYP2D6 enzyme. PIs have been reported to increa s e interpersonal psychotherapy and cognitive- the concentration of bupropion, nefazodone and behavioral psychotherapy and they are more fluoxetine to toxic levels and to increase the effective when combined with pharmacotherapy concentration of desipramine by 100 to 150 for treatment of severe depression[8]. percent[15]. However, one pharmacokinetic study concluded that dose of ritonavir need not be CONCLUSION reduced in patients concomitantly re c e i v i n g Diagnosis and management of depression is an f l u o x e t i n e[ 1 6 ]. In patients receiving antire t ro v i r a l important factor for optimal outcome of HIV/AIDS therapy along with fluoxetine, sero t o n e rg i c patients. Safe and effective treatment of major syndrome has been reported and this should be depression, one of the most common comorbid suspected in patient on any sero t o n e rgic dru g conditions in individuals infected with HIV, taking cytochrome P450 enzyme inhibitors such as significantly lowers morbidity and mortality of PIs, non-nucleoside reverse transcriptase inhibitors HIV disease. While possibilities of underdiagnosis and grapefruit juice. Sero t o n e rgic syndrome is and over-diagnosis exist, optimum management characterized by mental status change, autonomic should be guided by correct diagnosis. dysfunction and neuromuscular abnormalities[15]. Important drug-drug interactions exist among PIs may also increase the plasma level of some the antiretrovirals, antidepressants and anti-anxiety benzodiazepines such as alprazolam, midazolam, agents which sometimes may lead to serious triazolam and non-benzodiazepine hypnotic consequences such as serotonin syndrome. To zolpidem[16]. Ritonavir, nelfinavir and amprenavir avoid these consequences therapy should be are also moderate inducers of some of the hepatic undertaken in a specialty clinic whenever possible enzymes including CYP3A4. This may complicate and alternatives to proper antidepressants such as the interaction on long term and therapeutic drug D H E A should be considered in moderate monitoring should be taken as guide for d e p ression particularly for debilitated patients antidepressant therapy and dosing when required. when the antidepressants are less likely to be F u r t h e r m o re, since generalized anxiety is very tolerated. common in depressives having HIV infections, along with antidepressants anti-anxiety agents may REFERENCES be re q u i red. Significant interactions between antidepressants and anxiolytics include-: tendency 1. Michael DS, David AS, Bbra SH, Bradley JA, Miller I. of fluvoxamine to increase the plasma concentration Depression severity and drug injection HIV risk behavior. Am J Psychiatry 2003; 160:1659-1662. of oxidatively metabolized benzodiazepines, and 2. Woody GE, Metzger D, Navaline H, McLellan T, O’Brien sertraline along with fluoxetine increasing the level C P. Psychiatric symptoms, risky behavior and HIV of benzodiazepines. Nefazodone potentiates infection. NIDARes Monogr 1997; 172:156-170. benzodiazepines other than lorazepam and 3. Ciesla JA, Roberts JE. Meta-analysis of relationship between oxazepam[16]. It has also been shown to increase HIV infection and risk for depressive disorders. Am J Psychiatry 2001; 158:725-730. [8] plasma level of indinavir and efavirenz . These 4. Castellon SA,Hinkin CH, Wood S, Yarema KT. Apathy, interactions may be important in HIV patients depression and cognitive performance in HIV-1 infection. J because the higher level of benzodiazepine may Neuropsychiatry Clin Neurosci 1998; 10:320-329. mask the improvement obtained by the use of 5. Mazruk PM, Tardiff K, Leon AC, et al. HIV seroprevalence antidepressants in terms of somatic as well as among suicide victims in New York City, 1991-93. Am J Psychiatry 1997; 154:1720-1725. psychological symptoms. Fluvoxamine and 6. Dannenberg AL, McNeil JG, Brundage JF, Brookmeyer R. fluoxetine increase the plasma level of most of PIs Suicide and HIV infection: mortality follow-up of 4147 HIV along with that of delaverdine and efavirenz. On s e ro-positive military service applicants. JAMA 1 9 9 6 ; the other hand, nevirapine decreases the plasma 276:1743-1746. level of both the antidepressants [8]. 7. Chandra PS, Desai G, Ranjan S. HIV and psychiatric disorders. Ind J Med Res 2005; 121:451-467. 230 Depression in Patients with HIV/AIDS September 2007
8. Treisman GJ, Angelino AF, Hutlon HE, Hsu J, Lyketsos GG. HIV-positive patients. Psychiatr Serv 1998; 49:239-240. Neuropsychiatric aspects of HIV infection and AIDS. In: 13. Rabkin JG, McElhiney MC, Rabkin R, McGrath PJ, Ferrando Kaplan and Sadock’s Comprehensive Textbook of SJ. Placebo-controlled trial of dehydro e p i a n d ro s t e ro n e P s y c h i a t r y. Sadock BJ, Sadock VA, editors. Lippincot (DHEA) for treatment of nonmajor depression in patients Williams and Wilkins; 2005, p 426-451. with HIV/AIDS. Am J Psychiatry 2006; 163:59-66. 9. PerkinsDO, Leserman J, Stern RA, et al. Somatic symptoms 14. Rabkin JG, Wagner GJ, McElhiney MC, Rabkin R, Lin and HIV infection: relationship to depressive symptoms S H . Te s t o s t e rone versus fluoxetine for depression and and indicators of HIV disease. Am J Psychiatry 1995; fatigue in HIV/AIDS: a placebo-controlled trial. J Clin 152:1776-1781. Psychopharmacol 2004; 24:379-385. 10. Rabkin JG, Wagner GJ, Rabkin R. Fluoxetine treatment for 15. DeSilva KE, Le Flore DB, Marston BJ, Rimland D. Serotonin depression in patients with HIV and AIDS: A randomised, sy n d r ome in HIV-infected individuals receiving antiret ro v i r a l placebo controlled trial. Am J Psychiatry 1999; 136:101-174. therapy and fluoxetine. AIDS 2001; 15:1281-1285. 11. Caballero J, Nahata MC. Use of selective serotonin-reuptake 16. Flexner C. A n i re t roviral agents and treatment of HIV inhibitors in the treatment of depression in adults with HIV. infection. In: Bruton LL, Lazo JS, Parker KL, editors. Ann Pharmacother 2005; 39:141-145. Goodman and Gilmans The Pharmacological basis of 12. Wagner GJ, Maguen S, Rabkin JG. Ethnic differences in Therapeutics. Mc Graw Hill; 2006, p 1273-1314. response to fluoxetine in a controlled trial with depressed September 2007 KUWAIT MEDICAL JOURNAL
Original Article Validity and Predictive Value of Exercise Induced Inverted T-wave Normalization for Diagnosis of Ischemic Heart Disease
Mousa AJ Akbar1, Mohamad Hussain Alkandary2, Bader A Abdelkader2, Aly Hegazy2, 1Department of Medicine, Al-Sabah Hospital, Kuwait 2Department of Medicine, Farwania Hospital, Kuwait
Kuwait Medical Journal 2007, 39 (3): 231-237 ABSTRACT
Objectives: To evaluate the usefulness and validity of the patients from both groups as regards the resting heart exercise-induced T wave normalization for prediction rate, the time of the exercise test, peak heart rate, heart and diagnosis of ischemic heart disease and to assess and rate recovery after exercise and QT dispersion after quantify its correlation to autonomic dysfunction. ex e r cise, (p = NS). Predictive indices revealed that exerci s e Design: A cohort study induced T wave normalization is sensitive but not a Se t t i n g : Department of Medicine, Farwania Hospital, Kuwait specific indicator for prediction of ischemic heart disease, Subjects: One hundred and twenty-one patients with as the sensitivity was 71%, specificity = 49.2%, accuracy = history of exertional chest pain with inverted T wave in 63.2%, positive predictive value = 74.4% and negative the resting ECG but without history of myocard i a l predictive value = 44.8%. A significant relation between infarction and 67 patients with T wave inversion during age, smoking status, diabetes mellitus status and exercise exercise test were included in the study. induced T wave normalization (p < 0.05) was observed. Intervention: All patients underwent treadmill exercise Conclusion: Exercise induced T wave normalization is a ECG test and stress thallium scintigraphy in the course of sensitive but not specific marker of exercise induced their management. myocardial ischemia and this may be due to autonomic Main Outcome Measures: Exercise induced T-wave dysfunction with impaired parasympathetic function Results: There was no significant difference between and unopposed sympathetic action.
KEY WORDS: exercise test, ischemic heart disease, repolarization phase
INTRODUCTION invasive diagnostic methods for detecting ischemic Treadmill exercise ECG test is one of the most heart disease and the establishment of diagnostic common non-invasive diagnostic methods used to techniques that reduce false positive and false detect ischemic heart disease[1]. Many modifications negative rates is clinically important[5]. However, have been proposed for improving its diagnostic the significance of exercise induced changes in a c c u r a c y[ 2 ]. However, false positive and false patients who have an abnormal ECG at rest has not negative results occur at an undesirably high rate been fully established[6]. The safety of the ECG despite all of these modifications[3]. One of the more stress test has been greatly enhanced by monitoring common ECG changes at rest among patients in and the publications show that an abnormal ECG whom ECG stress test is needed for diagnostic at rest does not contraindicate a monitored ECG purposes is the primary T wave abnormality. One stress test[7]. type of such abnormality persists frequently in The aim of this study was to prove or nullify our patients with healed transmural infarction or non- hypothesis that the treadmill exercise electrocardio- transmural infarction with normal QRS duration graphy (ECG) induced T wave normalization is and another type represents a common functional valid for diagnosis of ischemic heart disease in the repolarization abnormality in persons with chest p resence or absence of conventional exerc i s e pain of uncertain etiology [4]. induced significant ST-segment depression and Treadmill exercise ECG test still retains its that there is an association between impaire d clinical importance despite advances in non- autonomic nervous function and T wave normalization.
Address correspondence to: Dr. Mousa AJ Akbar, FRCPC, Consultant Cardiologist, Department of Medicine, Al-Sabah Hospital, Kuwait. E-mail: [email protected] 232 Validity and Predictive Value of Exercise Induced Inverted T-wave Normalization for ..... September 2007
PATIENTS AND METHODS measured 60 ms after the J point in all 12 leads. Study patients: Exercise induced significant ST-segment depression One hundred and twenty-one patients with was defined as horizontal or downsloping ST- history of exertional chest pain with inverted T segment depression ³ 1 mm in any lead. wave in the resting ECG but without history of Particular attention was given to the occurrence myocardial infarction and 67 patients with T wave of normalization of negative T waves during and inversion during exercise test between Febraury after exercise and to localize its site and height. 1998 and March 2004 were included in the study. All patients were referred by their physicians to Recovery after exercise: cardiologists in Farwania hospital for assessment of After achieving peak workload, the treadmill chest pain. All patients were evaluated clinically by was stopped and blood pressure, heart rate, rhythm looking at their medical history, physical and symptoms were recorded immediately with examination, 12-leads ECG and routine laboratory the patient in the standing position (no cool down investigations. period). The same data were also recorded at 1, 3, 5 and 6 minutes into recovery in the supine position. Exclusion criteria: Monitoring was terminated at six minutes into the Patients with history of acute myocard i a l recovery unless warranted by symptoms or in f a r ction, intraventricular conduction disturbances, electrocardiographic changes. Heart rate recovery strain patterns due to left ventricular hypertrophy, was calculated as reduction in heart rate from the atrial fibrillation, mitral valve prolapse, hypertrop h i c peak to one minute of the recovery time and a cut ca rd i o m y o p a t h y , pulmonary hypertension, pericardi a l off value of 12 beats/minute or less was considered rub, old or recent cerebrovascular stoke, treatment abnormal[8]. with antiarrhythmic drugs that affect the rep o l a r i z a t i o n interval and treatment with digoxin were excluded Measurement of the QT dispersion: from the study. Exclusion was based on medical The QT interval was measured manually by two h i s t o r y, physical examination and 12-lead observers using calipers from the onset of the QRS electrocardiogram to avoid confounding factors. to the end of the T wave defined as the return to the TP baseline. The QT dispersion (QTd) was defined Transthoracic echocardiography: as the diff e rence between the maximum and Two-dimensional and M-mode echocardi o g r a p h y minimum QT interval occurring in any of the 12 was performed for all patients in the study with the ECG leads[9]. use of Toshiba Power vision and a 3.5 MHZ phased array transducer. The leading edge to leading edge There were two groups: convention was used. Left ventricular dimensions Group I: included 121 patients with exercise were measured at or immediately below the tips of induced T-wave normalization. mitral leaflets and averaged over five heart cycles. Group II: included 67 patients without exercise LVM and LVM index were calculated. induced T-wave normalization.
Treadmill exercise ECG test protocol: Stress thallium 201 scintigraphy: All patients underwent the exercise ECG test All patients had underdone stress thallium using standard or modified Bruce models at the scanning in the course of their management in their baseline of the study. Resting blood pre s s u re countries (Egypt, India and Syria). The test was (m e a s u r ed manually by arm-cuff sphygmomanometer) considered positive if there was a reversible or was measured in supine and standing positions fixed defect and was considered negative if there be f o r e the test. Patients with orthostatic hypotension was no defect. (defined as a decrease of > 20 mmHg of systolic The patients from Group I were divided to two blood pre s s u re after standing) were excluded. subgroups: Resting ECG was done for all patients to exclude S u b g roup Ia: included 90 patients with those with significant ST- segment changes, left reversible thallium defects. bundle branch block or tachyarrhythmias. Subgroup Ib: included 31 patients with normal The stress ECG test was terminated, if there was stress thallium test. a decrease in blood pre s s u re (> 20 mmHg), significant arrhythmias (non-sustained or sustained Coronary angiography: ventricular tachycardia), typical chest pain (test Selective coronary cine angiography was limiting angina) or > 2 mm ST-segment depression performed in the course of their management in from baseline was noted. ST- segment level was their countries (Egypt, India, Kuwait and Syria). September 2007 KUWAIT MEDICAL JOURNAL 233
Fig. 1: Heart rate recovery after exercise ECG test in Group I
Co r onary stenoses w e re quantified visually and luminal n a r rowing of > 50% was considered a hemodynamically significant coronary artery lesion.
Twenty- four hour Holter monitor and heart rate variability: All subjects and patients of the study underwent Fig. 2: Number of patients had ST segment in both Groups continuous ambulatory 3-channel Holter monitoring for 24 hours. Time domain measures that were observers was verified by using the method of determined from normal to normal sinus beats Bland and A l t m a n[11 ] . Mean of the diff e re n c e included the mean R-R interval and its SD (SDNN), between two observers and SD were calculated to the percentage of successive R-R intervals that obtain limits of agreements. Upper limit of deviated by > 50% from the prior RR interval (p- agreement = mean of difference + 2SD. Lower limit NN50), the root mean square of successive RR of agreement = mean - 2SD. For good agreement at interval differences (r MMD) and the SD of the least 95% of values must lie within the limits of average of RR intervals in all 5-minute segments of agreement. the 24-hour recording (SDANN)[10]. The validity of exercise induced T wave normalization to detect ischemic heart disease was Statistical analysis: assessed by estimating the predictive indices and Continuous variables are summarized as a Kappa coefficient to determine the overall mean ± standard deviation (SD). Comparison agreement with the data obtained from the stress between two groups was performed with t-test for thallium scintigraphy. continuous variables and chi-square test for Kappa coefficient value (k) = (Observed categorical variables. A p-value < 0.05 was frequency of agreement - Expected frequency of c o n s i d e red statistically significant and a p-value agreement)/(Total observed - Expected frequency < 0.01 was considered statistically highly of agreement). significant. A stepwise multivariate re g re s s i o n model was used to identify possible independent Predictive indices: variables associated with exercise induced T wave True positive (TP), true negative (TN), false normalization. The strength of the association with positive (FP) and false negative (FN) were T wave normalization is presented as 95% calculated. Sensitivity = TP/(TP+FN), specificity= confidence intervals. Potential confounding of TN/(TN+FP), positive predictive value = TP/ clinical variables was entered as independent (TP+TN), negative predictive value =TN/(TN+TP) variables. The agreement between the two and accuracy =(TP+TN)/ (TP+TN+FP+FN). 234 Validity and Predictive Value of Exercise Induced Inverted T-wave Normalization for ..... September 2007
Table 1: Variables of the exercise ECG test in both study Table 2: Receiver operating characteristic (ROC) curve groups data of T wave normalization for prediction of ischemic heart disease in the patients with positive stress thallium Variables Group I Group II p-Value scintigraphy Exercise time (minutes) 8.13 ± 1.36 9.26 ± 1.22 NS Variables Sensitivity % False +ve % AUC POE % Peak heart rate (beat/min) 158 ± 8.58 149 ± 10.64 NS Heart rate recovery (beat/min) 18.4 ± 2.72 24.9 ± 4.07 NS T-wave 2-5 mm 75 39 0.696 34 QT dispersion (msec) 6.63 ± 0.76 7.59 ± 0.68 NS T-wave 5-9 mm 79 34 0.708 32 T-wave 10-15 mm 82 28 0.784 24 Simple linear regression (Least-square method) was used for correlation of the parameters of the AUC = area under curve, POE = probability of error with sensitivity study: Y (dependent variable) = b + aX 100%, mm = 0.1mv (independent variable), where, a = slope and b = intercept. 4.07 beats, p = NS, Table 1). There was an impairment of autonomic function in patients from RESULTS G roup I with exercise induced T wave Clinical characteristics: normalization and negative stress thallium test as As re g a rds age and gender, there was no there was a significant decreased decline in the significant difference between both groups of the heart rate recovery after exercise in those patients study (53.31 ± 8.24 versus 48.6 ± 3.43 years, than patients from Group I with positive stress respectively, p = NS, 100 (82.6%) versus 60 (89.6%) thallium test (7.9 ± 1.8 versus 19.3 ± 2.6 beats, p < males, p = NS and 21 (17.3%) versus 7 (10.4%) 0.05). females, p = NS) re s p e c t i v e l y. There was no There were 37 patients with a depression of ST significant diff e rence between both gro u p s segment at peak exercise heart rate with T wave regarding percentage of patients with history of normalization, only 18 patients had a downsloping smoking, hypercholesterolemia, hypertension and ST segment depression > 1 mm (12 patients had T diabetes mellitus [38 (31.4%) versus 24 (35.8%) wave normalization and six patients had persistent patients, p = NS, 32 (26.4%) versus 15 (22.2%) T wave inversion and 19 patients had upsloping ST patients, p = NS, 40 (33.4%) versus 28 (41.8%) segment depression (9 patients had T wave patients, p = NS, and 49 (40.5%) versus 30 (44.7%) normalization and 10 patients had persistent T patients, p = NS] re s p e c t i v e l y. There was no wave inversion). significant difference regarding the resting heart rate and blood pressure between both groups (89.25 Stress thallium scintigraphy: ± 5.93 versus 78.5 ± 8.72 beat/minute and 139.37 ± Out of 121 patients from Group I, 90 (74%) 18.26 versus 128.6 ± 11.51, p = NS). patients had a reversible defect after stress thallium test. Out of 69 (76.6%) patients with inverted T Resting ECG: wave normalization in V2-V5, 61 patients (88%) Out of 90 patients who had exercise induced T had defects in anterior, septal and apical segments wave normalization with reversible defects after and eight patients (12%) had defects in the inferior stress thallium test, 69 patients had a resting ECG T- segment. All patients with T wave inversion in lead wave inversion in the chest leads V1 - V5 and 21 III and aVF, had reversible defects in the inferior patients had a resting ECG T-wave inversion in the and posterior segments. standard inferior leads III and aVF. All patients had a normal axis deviation and normal QRS complex Coronary angiography: duration. No patients had prolonged PR or QT Out of 61 patients with inverted T- w a v e interval. normalization in V2-V5 and stress thallium defects in anterior, septal and apical segments of the left Exercise ECG test: ventricle, 44 patients (72%) had significant lesions There was no significant difference between in the left anterior descending coronary artery and both groups of the study as regards the duration of 17 patients (28%) had a significant lesion in the exercise ECG test, peak heart rate, blood pressure diagonal coronary artery. Out of eight patients who response during and after exercise and QT had inverted T wave normalization in V2-V5 and dispersion immediately after exercise, heart rate reversible thallium defects in the inferior segments, recovery after exercise and during recovery but five patients (62%) had a significant lesion in the there was non-significant decreased decline in the circumflex coronary artery and three patients (38%) heart rate recovery after exercise in those patients had a significant lesion in the right coronary artery. than patients of Group II (18.4 ± 2.72 versus 24.9 ± Out of 21 patients with inverted T wave September 2007 KUWAIT MEDICAL JOURNAL 235
Table 3: Stepwise logistic multivariate analysis of Table 4: Stepwise logistic multivariate analysis of patients versus those without T- wave normalization as patients versus those without T-wave normalization as regards age, gender, smoking, hypertension, diabetes regards antihypertensive drugs mellitus and ST depression >1mm at peak exercise heart rate Variables Coeffecient p-value 95% CI
Variables Coeffecient p-value 95% CI Beta blockers 0.1653 NS 0.524 - 1.091 ACE inhibitors 0.2341 NS 0.227 - 1.893 Age 0.4653 <0.05 1.125 - 4.091 AR blockers 0.3821 NS 0.761 - 1.590 Gender 0.2301 NS 0.621 - 3.505 Calcium channel blockers 0.1659 NS 0.228 - 1.236 Smoking status 0.5873 <0.05 1.723 - 2.723 ACE = angiotensin converting enzyme, AR = angiotensin receptors Hypertension status 0.1852 NS 0.617- 1.795 Diabetes mellitus status 0.4852 <0.05 1.420 - 2.438 ST depression >1mm 0.1914 NS 0.604 - 1.572 The validity: There was a good agreement between data of stress thallium scintigraphy and exercise induced T wave normalization with true positive = 90, true normalization in lead III, aVF and reversible defects negative = 30, false positive = 31, false negative = 37 after stress thallium test, nine patients (43%) had a and Kappa coefficient value = 0.678 (Table 5). significant lesion in the circumflex coronary artery and 12 patients (57%) had a significant lesion in the right coronary artery. Table 5: Agreement of the stress thallium 201 scintigraphy and the exercise induced T wave normalization as regards of Receiver operating characteristic (ROC) curve: prediction of ischemic heart disease ROC curve data of T wave normalization for Str. thallium Str. thallium Total prediction of ischemic heart disease in the patients +ve -ve with positive stress thallium scintigraphy revealed that there was sensitivity = 75%, false positive = T wave normalization 90 31 121 39%, area under curve = 0.696 with T wave T-wave inversion 37 30 67 Total 127 61 188 amplitude = 2-5 mm and the probability of error Kappa Coefficient value (k) = 0.689 was 34%. The sensitivity was 79%, false positive = 34%, area under curve = 0.708 with T wave Str. thallium = stress thallium test amplitude = 6-9 mm and probability of error = 32%, Correlation with autonomic function variables: but the sensitivity was increased to 82%, and there T h e re was a significant correlation between was a decrease in the false positive = 28% and the independent variables (Holter based and exercise area under curve = 0.784 with T wave amplitude = ECG test based variables of autonomic nervous 10-15 mm and there was decrease in probability of function) as X axis and dependent variable ( T wave error = 24% (Table 2). after normalization) as Y axis (Table 6). Forward stepwise logistic multivariate analysis: Table 6: Co r r elation of the T wave after normalization as dependent Multivariate analysis revealed a significant variable to the Holter based and exercise ECG based variables correlation between age of the patients, smoking, of autonomic function as an independent variable in patients and diabetes mellitus as independent variables and with normal stress thallium scanning, where, dependent exercise induced T wave normalization ( R = 0.4653, variable = Y + indepenent variable x Slope , (n=31) 0.573 and 0.4852, 95% CI = 1.125 - 4.091, 1.723 - 2.723 and 1.420 - 2.438, respectively, p < 0.05). Independent variables y Intercept Slope r p-value However there was no significant relation as re g a rds gender, hypertension, and presence of P-NN 50 (%) 1.376 6.792 0.625 <0.05 exercise induced ST-segment depression > 1mm r-MMD (msec) 2.082 2.831 0.690 <0.05 HR response during exercise test (b/m) 3.215 0.913 0.582 NS and antihypertensive drugs (p > 0.06, Table 3, 4). Decline in HR after exercise test (b/m) 2.241 7.082 0.785 <0.05 HR=heart rate The predictive indices: The predictive indices showed that exerc i s e Reproducibility: induced inverted T wave normalization is a useful T h e re was no significant diff e rence in marker for prediction of patients with ischemic in t e r observer variability and intraobserver variability heart disease as the sensitivity was 71%, specificity (p = NS). There was a good agreement between = 49.2%, accuracy = 63.8%, positive pre d i c t i v e both observers as > 95% of the measurements were value = 74.4% and negative predictive value = between the upper and lower limits of agreement 44.8%. (mean + 2SD and mean - 2SD). 236 Validity and Predictive Value of Exercise Induced Inverted T-wave Normalization for ..... September 2007
DISCUSSION Aravindakshan et al[1 7 ] postulated seven mechanisms Our inclusion criterion for patients in this study for exercise induced changes in T wave amplitude was the presence of an abnormal T wave at rest. and polarity, four of which were not dependent on This method of selection results in recruitment of the development of ischemia. In particular, they patients who differ from the cross-section of suggested that sympathetic stimulation may cause patients undergoing diagnostic ECG exerc i s e normalization of T waves. This mechanism may testing. In normal subjects, during exercise, the explain the T wave changes reported in normal positive T wave initially shows a mild decrease of subjects during exercise and isoproterenol infusion. amplitude and a significant increase at peak In patients with coronary artery disease, however, exercise. In patients exhibiting T wave inversion on different pathophysiologic mechanisms probably a resting electro c a rdiogram, the change of the apply. In this setting, T wave normalization occurs polarity during effort (normalization) has been predominantly secondary to previous myocardial variously interpre t e d[ 1 2 ]. Several studies have infarction or exercise induced ischemia [18]. Our data emphasized T wave normalization as a marker of supported the view that T wave normalization, my o c a r dial ischemia[1 3 ] . However, other investigators while not specific for the presence of underling have discussed the clinical significance and the coronary artery disease, is a consistent sign of specificity of this sign in an unselected population, exercise induced ischemia, as postulated by these particularly in identifying transient ischemia from p revious workers and there was a significant fixed defects. These conflicting results are probably correlation between impaired autonomic nervous justified by the heterogeneity of populations[14]. function and exercise induced T wave The primary goal of this study was to clarify the normalization in non-ischemic patients. clinical significance of T wave normalization in The previous studies revealed that the site of T patients undergoing exercise stress tests for wave normalization during the exercise test diagnostic evaluation of chest pain. The presence of localized the site of the thallium-201 imaging resting ECG abnormalities and the fact that abnormality in approximately 75% of card i a c thallium-201 scanning defects were present in segments analysed and similar results were also 74.4% of Group I patients strongly suggests that noted when patients taking digoxin were removed most patients in the study had coronary artery from analysis to exclude the effect of the drug on lesions and this was documented by coro n a r y the ST segment and T wave[19]. Exercise induced T angiography. In this population, our results show wave normalization in patients with coro n a r y that exercise T wave normalization represents an artery disease represents predominantly a primary abnormal response to exercise even in the absence change over the affected cardiac segment rather of exercise induced ST segment depression, as there than a reciprocal change due to abnormalities on was a significant ST segment depression in 12 the opposite ventricular surface. This applies to patients only out of the patients in Group I. both fixed and reversible thallium-201 imaging In an early study, Masters[15] considered exercise abnormalities and suggests that more than one T wave normalization suggestive of myocardial mechanism of T wave normalization is involved. ischemia if negative T waves became positive and Thus T wave normalization noted during reversible achieved an amplitude of at least 1.5 mm. This thallium 201 imaging defect may be due to an criterion was based on the observation that T wave i n c reased transmural left ventricular gradient changes of this amplitude were accompanied by (increased end-diastolic pressure)[20]. ischemic ST segment changes and it was therefore Our study revealed that there was a correlation the latter finding that constituted an abnormal between the site of the T wave changes and s t ress test. Urama et al[ 1 6 ] also concluded that thallium-201 imaging. It also suggests that T wave exercise T wave normalization was suggestive of normalization is due to abnormalities over the ischemia after observing it with exercise and affected cardiac sites in about 88% of instances and i s o p ro t e renol-induced angina in patients with may be reciprocal to abnormalities of the opposite angiographically proven coronary artery disease. wall in the remaining 12%. Ho w e v e r , the hypothesis that T wave normalization is diagnostic of exercise-induced ischemia had been Limitations of this study: challenged by other workers [12]. 1. Relatively small number of patients. The results of these studies suggest that exercise 2. Single center experience. T wave normalization occurs from a variety of 3. Unlike ST segment changes, T- w a v e e l e c t rophysiologic mechanisms not necessarily normalization does not occur with suff i c i e n t related to the presence of myocardial ischemia. This f requency to be useful for confirming the is not surprising, since the causes of T wave hypothesis of the study in the population, as out of normalization are complex and ill understood. the 1800 patients who performed exercise ECG test September 2007 KUWAIT MEDICAL JOURNAL 237 in our laboratory, only 121 patients without history 7. Ogawa T, Ishii M, Lida K, et al. Mechanisms of stress- of old MI had exercise induced inverted T wave induced ST elevation and negative T wave normalization normalization. studied by serial cardiomyogram in patients with a previous myocardial infarction. Am J Cardiol 1990; 65:962- 4. The study is not completely blind to 966. observers. 8. Hegazy AM, Abdulkader BA. Clinical significance of impaired heart rate recovery after treadmill exercise test in hypertensive CONCLUSION patients. Kuwait Medical Journal 2004; 36:19-25. 9. Koide Y, Yotsukura M, Yoshino H, Ishikawa K. Usefulness We conclude that exercise induced T wave of QT dispersion immediately after exercise as an indicator normalization is a sensitive but not specific marker of coronary stenosis independent of gender or exercise of exercise induced myocardial ischemia independent induced ST segment depression. Am J Cardiol 2000; of the presence or absence of exerc i s e - i n d u c e d 86:1312-1317. significant ST-segment depression. T wave 10. 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Pizzetti G, Montorfano M, Belotti G, Margonato A , induced normalization of the repolarization phase in B a l l a rotto C, Chierchia SL. Exercise-induced T- w a v e i n f a rcted patients: a positro n - e m i s s i o n - t o m o g r a p h y normalization predicts recovery of regional contractile assessment of regulation of myocardial blood flow and function after anterior myocardial infarction. Eur Heart J viability of myocardium. Coron Artery Dis 2001; 12:205-215. 1998; 19:420-428. 20. Mobilia G, Zanco P, Desideri A, et al. T wave normalization 6. Hasegawa K, Sawayama T, Inoue S, et al. Exercise induced in infarct-related electrocardiographic leads during exercise precordial T wave normalization associated with U wave testing for detection of residual viability: comparison with inversion in detection of left anterior descending artery positron emission tomography. J Am Coll Cardiol 1998; stenosis. Kokyu To Junkan 1991; 39:1015-1020. 32:75-82. KUWAIT MEDICAL JOURNAL September 2007
Original Article
Use of Controller Medications among Asthmatic Patients: A Family Medicine Centre based Study
Fotooh Ahmed Al-Jarky, Samia Salem Al-Musallam Primary Health Care, Khaldiya Clinic, Kuwait
Kuwait Medical Journal 2007, 39 (3): 238-242 ABSTRACT Objectives: To determine the prevalence of under use of and highest among parents whose children were of age 4- controller medication among asthmatic patients; and to 10 years. For adults, fear of steroids increased with age investigate associated factors. (60.7% for age > 40 versus 44.4% for age 20 to 30, p < Design: Cross-sectional sample study 0.001). Participants with higher than high school Setting: Khaldiya Primary Healthcare Centre, Kuwait education reported less fear of steroids than those with Su b j e c t s : On e - h u n d r ed and sixty-two patients were studied high school degree or less (57.6% versus 80%, p <.01). during September to December 2004, age range from 3.5 One hundred and five cases (64.8%) required initiation of to 83. Data were obtained through direct questionnaire. controller medication. Only 28 cases (17.3%) did not Main Outcome Measures: Socio-demographic data, use require alteration to their original management plan. of medication C o n c l u s i o n : Under use of controller medication in Results: Out of 162 patients, 140 (86.4%) reported not asthma patients is mainly due to concern about steroid using controller medication. One hundred and five dependence and/or side effects. Such concern increases participants (64.8%) had uncontrolled asthma, and only in older patients, younger children, and low level of 22 participants (13.6%) used controller medication prior to education of patient/parent. Concern was not limited to the study (prescribed by specialist). Fear of stero i d participants. Even doctors in the primary health care dependence and/or side effects was reported by 70.4%. showed reluctance to prescribe controller medication.
KEY WORDS: asthma, controller, fear, Kuwait, steroids, under use.
INTRODUCTION reported to suffer from asthma manifestations[3]. Asthma is now widely recognized as a chronic Kuwait ranked 13th among 56 countries in the inflammatory condition of the airways that prevalence of symptoms of asthma in children[4]. requires early pharmacological treatment and long- This is alarming because asthma is a serious and term management[ 1 ]. Anti-inflammatory agents, potentially life threatening disease. In this cross- particularly inhaled corticosteroids, are the most sectional study we aimed to determine the widely used and consistently effective controller prevalence of under use of controller medications medication for long-term maintenance therapy. and investigate the associated reasons for this C l i n i c a l l y, inhaled corticosteroids reduce the u n d e r-use of controller medications in asthma severity of asthma symptoms, improve peak flow patients at Khaldiya family medicine healthcare m e a s u rements and other measures of lung c e n t re and what might alter these tre a t m e n t function, prevent exacerbations and possibly patterns. prevent long-term lung remodeling. Despite significant advances in the understanding SUBJECTS AND METHODS of asthma and its pharmacological management, Khaldiya clinic is a family medicine clinic that the prevalence of asthma is on the incre a s e[ 1 ]. serves a population of 13,000. By using the ministry Although as previously mentioned, the most of health computer registry system, we identified effective long-term control medicines available are 1907 patients registered as asthmatics. Out of these, inhaled corticosteroids, a recent national survey in 1343 were Kuwaiti citizens and 564 were USA showed that four out five people with chronic expatriates. Only 364 were registered in the asthma asthma are not using these medicines[2]. Data in clinic registry. This number is explained by the fact Kuwait shows that 18% of the population is that many asthmatic patients seek help only during
Address correspondence to: Dr. Fotooh Al-Jarky, RCGP (UK), Primary Health Care, Khaldiya Clinic, Kuwait. Tel: (965) 4834065, Mobile: (965) 6682666, Fax: (965) 4817538 E-Mail: samq8tia @yahoo.com September 2007 KUWAIT MEDICAL JOURNAL 239 acute attack and are thus not registered in the Table 1: Sociodemographic characteristics of participants asthma clinic re g i s t r y. Also, the expatriate population has a high rate of turn over. In this Variables Frequency Percent cross-sectional sample, survey data were collected through a face to face interview using a structured Sex questionnaire. Male 97 59.9 Female 65 40.1 The sample comprised all adult patients and Age(In years) parents of children less than 18 years of age (n = < 4 2 1.2 162) attending the asthma clinic at Khaldiya 4- 41 25.3 healthcare centre for follow up during the period 10- 37 22.8 between September and December 2004. Patients 18- 9 5.6 30- 17 34.6 attending the clinic with acute asthma attacks were ³ 40 56 34.5 not included in the study. Level of education The age of participants ranged from 3.5 to 83 Below high school 15 9.3 years. The questionnaire included demographic data High school 81 50 such as age, sex, occupation, level of education for University and above 66 40.7 Occupation adults and parents of children less than 18 years of Student 80 49.4 ag e . Teacher 17 10.5 The height of patients was measured because it Employee 31 19.1 is a required parameter for the assessment of the House wife 20 12.3 expected peak flow rate (PFR). Actual PFR was Others 14 8.6 measured using a peak flow meter. Measurements years of age) and 82 adults (>18 years of age). One were done following the technique provided by the half of the sample was high school graduates. GINA guidelines[5]. Management plan and patient Students had the highest prevalence of asthma compliance to treatment were also noted. amongst all occupations (49.4%). Only 22 participants Participants were asked about the use of (13.6%) were followed up by a specialist. A majority controller mediation prior to interview and the (115 participants, 71%) reported that they were doctor who prescribed it and whether patient/ p a rent feared steroid dependence and/or side effects. Current symptoms were determined by asking about the number of days the patient experienced any asthma symptoms (including cough, wheeze, shortness of breath, or limited activity) during the past 14 days. All participants that were considered as uncontrolled were prescribed controller medication in the form of a separate or combined inhaler. For those already on c o n t roller medication, the dose was adjusted. Written instructions on how and for how long to use the medication and what were the major side effects were provided. Participants were seen two weeks later when their PFR was measured and Fig. 1: Use of controller medication enquiry about their symptoms was made. compliant to treatment. Statistical analysis Fig. 1 illustrates that 140 cases (86.4%) did not Data was analyzed using the statistical package use controller medication as compared to 22 cases for social science, SPSS, version 13 (Chicago, IL, (13.6%) that were on controller medication prov i d e d 2004). The value p £ 0.05 was used as the cut-off by a specialist prior to the study. The difference was level for statistical significance. The Chi-square test significant at p < 0.0001 for prior controller use and was used to assess the association between two p < 0.0001 for post controller use. However, 105 categorical variables. cases (64.8%) were in the category of uncontrolled asthma and were prescribed controller medication. RESULTS Out of 162 participants, 114 (70.4%) reported The demographic characteristics of our survey that they fear steroid dependence and their side sample of 162 patients are shown in Table 1. There effects as compared to 29.6 % who reported no fear was a male preponderance with male: female ratio of steroids (p < 0.0001, Fig. 2). 59.9:40.1. The sample included 80 children (< 18 Table 2 shows the association between demographic 240 Use of Controller Medication among Asthmatic Patients: A Family Medicine Centre based ... September 2007
Table 3: Difference between the original and the new management plan
Management Plan Frequency Percentage
Original Management Salbutamol inhaler as needed 23 14.2 Salbutamol nebulizer as needed 31 19.1 Salbutamol inhaler regular 58 35.8 Salbutamol nebulizer regular 20 12.3 Controller as needed 12 7.4 Controller regular 9 5.6 Others 9 5.6 New Management No change 28 17.3 Salbutamol regular 29 17.9 Combined therapy 40 24.7 Separate 59 36.4 Others 6 3.7
form of separate or combined therapy. Fig. 2: Fear of steroids DISCUSSION The data showed substantial under-use of Table 2: Association between demographic data and fear controller medication among patients attending the of steroids asthma clinic at Khaldiya family medicine healthcare center. Only 22 patients (13.6%) were on controller Variables Fear % p- value medication prior to our study despite the fact that Yes No 105 patients (64.8%) were in the category of Sex 0.1 uncontrolled asthma and were either prescribed Male 75.40 24.60 co n t r oller medication or the dose of their medication Female 67.00 33.00 was adjusted. This means that almost two thirds of Educational Level 0.01 participating patients were under treated with Below high school 80.00 20.00 High school 79.00 21.00 controller medication. University and above 57.60 42.40 In a previous study regarding under use of Age (In years) 0.001 controller medications, Finkelstien et al in 2002 < 4 50.00 50.00 found that 72.9% of children with persistent asthma 4- 90.20 9.80 we r e under users of anti-inflammatory medications[6 ] . 10 - 81.10 18.90 18- 44.40 55.60 Under use of controller medications in the 30- 47.10 52.90 presence of persistent symptoms was alarming. 40- 60.70 39.30 Goodman et al[7] found that only 29% of children in an HMO (Health Maintenance Organization) who factors and fear of steroids dependence and side were prescribed an anti-inflammatory agent had effects. Fear of steroids significantly varied with more than two canisters dispensed during a one age. It was noted that it was maximum at the age of year period. A study from the pediatric asthma care 4 - 10 years (90.2%) and this reflected parent’s fear PORT (patient outcome research team) reported of steroids. For adults the fear of stero i d s that 69% of those with three dispensings of a beta consistently increased with age (44.4% for ages agonist had a controller medication dispensed, and between 18-30 yrs, 47.1% for ages between 30 - 40 only 48% had repeated dispensing (³ 3)[ 8 ]. In yrs, and 60.7% ages ³ 40 yrs, p = 0.001). surveys of MCO (Medicaid Managed Care Participants with university and above level of Organization) members, Diette et al reported that 64 education reported less fear of steroids than those adult users of inhaled corticosteroids re p o r t e d with below high school level education (57.6% under dosing (use < 5 / wk)[9]. In another study versus 80%; p < 0.01) about under use of inhaled steroid therapy in Table 3 shows that of the 162 participants, only elderly patients with asthma, Sin et al found that 28 cases (17.3%) did not require alteration of their 40% of elderly patients did not receive inhaled management plan. The remaining 134 participants steroid therapy within 90 days of discharge from re q u i red changes in their original management their initial hospitalization from asthma. Patients > plan either by adjusting the dose of their 80 years of age were at greater risk of not receiving medication or adding controller medication in the inhaled steroid therapy compared to those 65 to 70 September 2007 KUWAIT MEDICAL JOURNAL 241 years of age[10]. under the care of specialist[10]. Hartert et al in their The present study showed that the main reason study about under-utilization of controller and for under use of anti-inflammatory medication is rescue medication concluded that despite widesprea d fear of steroid dependence and side effects. When promulgation of the National Asthma Education we examined the association between variables Program guidelines, providers caring for indigent with fear of steroids, we found that the level of fear older subjects with moderate to severe or was highest among young children (90.2%); this potentially fatal asthma were not following these reflects their parents’ fear of corticosteroids. Lim Sh g u i d e l i n e s[ 1 7 ]. In an article about strategies to et al found that 36% of parents either felt opposed to overcome steroid phobia by Margie Patlak, she inhaler therapy and / or preferred oral medication. quotes from Frank Leone, MD, a pulmonologist at The main reason for their reluctance to use inhalers the Thomas Jefferson University in Philadelphia was related to fear of dependence[11]. In a study ‘The nagging suspicion that the complications of about asthma knowledge and medication compliance inhaled corticosteroids are severe enough to among parents with asthma children Zhao et al[12] warrant worry has interfered with how clinicians found that only 43% of parents reported adherence use the medications’[18]. with prescribed anti-asthmatic medication for their Another reason for under-use of contro l l e r children. Reasons for non-compliance included fear medication could be attributed to the lack of of medication side effects and tolerance. Leickly et essential drugs in primary health centers in al[13] identified concerns about adverse effects and Kuwait. This was found in a study by Behbehani et doubts about the usefulness of medications. A al[4]. The study, which covered 36 primary care recent study about parental concern towards the centers, surveyed the availability of essential use of inhaled therapy in children with chronic asthma medications. None of the centers was found asthma Chan et al found that 66% of pare n t s to have high dose inhaled steroids. Low dose surveyed were concerned with inhaled therapy. beclomethasone inhalers were available regularly The most common concern with its use was in 11 out of the 36 centers (31%). A l t h o u g h medication side effects (91%) followed by inhaler beclomethasone is available in Khaldiya healthcare dependency (86%), cost of the inhaler (34%) and center it does not provide optimum control like the difficulty in using the inhaler (15%) [14]. new more expensive high dose steroid inhalers. As to reasons why patients refused treatment with inhaled steroids the following were found: In CONCLUSION a review by van Grunsven of the literature over the A significant proportion of adult patients and past 35 years, a general fear of adverse effects parents of asthmatic children attending Khaldiya played an important role for non acceptance. Lack asthma clinic showed under-use of contro l l e r of knowledge about efficacy and side effects of medications. This was mainly due to their concern t reatment is another important factor. Lack of about steroid dependence and/or side effects. Such symptoms is another factor for reluctance to use concern increases in older patients, younger children , drugs[15]. and in those patients/parents with low level of The finding that fear of steroids is highest education. These factors should be taken into among those with less than high school education account when planning an effective asthma is consistent with the findings of our study, education program. Not only were the participants Finkelstien et al[6] found that parents with more than concerned, but also the doctors in the primary high school education were less likely than those health care centers who showed reluctance to with a high school degree or less to have a child p rescribe controller medications. Based on this who under-uses controller medication. study, the need for programs designed to improve The finding that 134 participants re q u i re d asthma care in the primary healthcare centers in alteration to their current management plan and Kuwait is very much evident. the finding that 105 participants re q u i red the initiation of anti-inflammatory medication raises ACKNOWLEDGEMENT the issue of primary care physicians’ reluctance to The authors gratefully thank Dr. Siham Ali from use controller medication. This is consistent with Kuwait University for her assistance in the the conclusion of Leogorreta et al[16] that asthma statistical analysis of the data presented. specialists provided more thorough care than primary care physicians in treating patients with REFERENCES asthma. In the study by Sin et al, they also found that elderly patients who receive their care from 1. Tal A. Symbicort: controlling asthma in children. 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NJ 07033. towards their child’s use of inhaled medications for asthma 3. Ellul-Micallef, Al-Ali S. The spectrum of bronchial asthma therapy. J Paediatr Child Health 1996; 32: 306-309. in Kuwait. Clin Allergy 1984; 14: 509-517. 12. Zhao X, Furber S, Bauman A. Asthma knowledge and 4. Behbehani NA, Al-Yousifi K. Lack of essential asthma medication compliance among parents of asthmatic medications in primary care centers in Kuwait. Int J Tuberc children in Nanjing, China. J Asthma 2002; 39:743-747. Lung Dis 2003; 7:422-425. 13. Leicky FE, Wade SL, Crain E, Kruszon-Moran D, Wright 5. Global Initiative for Asthma (GINA). Global strategy for EC, Evans R lll. Self reported adherence, management asthma management and prevention report. Bethesda MD: b e h a v i o u r, and barriers to care after am emerg e n c y National Institute of Health, 2002. department visit by inner city children with asthma. 6. Finkelestien J, Lozano P, Farber H, Miroshnik I. Use of Pediatrics 1998; 101:e8. available at: http:// controller medication among Medicaid insured children www.pediatrics.org/cgi/content/full/101/5e8. with asthma. Arch Pediatr Adolesc Med 2002; 156:562-567. 14. Chan PW, DeBruyne JA. Parental concern towards the use 7. Goodman DC, Lozano P, Stukel TA, Chang C, Hecht J. Has of inhaled therapy in children with chronic asthma. Pediatr asthma medication use in children become more frequent, Int 2000; 42:547-551. more appropriate, or both? Pediatrics 1999; 104:187-194. 15. van Grunsven PM. The magnitude of fear of adverse effects 8. Adams RJ, Fuhlbrigge A, Finkelestien JA. Use of inhaled as a reason for nonparticipation in drug treatment: a short anti-inflammatory medication in children with asthma in review. J Asthma 2001; 38:113-119. managed care settings. Arch Pediatr Adolesc Med 2001; 16. Legorreta A, Christian- Herman, O’Connor R, Hassan M. 155:501-507. Compliance with national asthma management guidelines 9. Diette GB, WuAW, Skinner EA. Treatment patterns among specialty care. Arch Intern Med 1998; 158:457-464. adult patients with asthma. A rch Intern Med 1999; 17. Hartert TV, Togias A, Mellen BG, Mitchel EF. 159:2697-2704. U n d e rutilization of controller and rescue medications 10. Sin DD, Tu JV. Under use of inhaled steroid therapy in among older adults with asthma requiring hospital care. J elderly patients with asthma. Chest 2001; 119:720-725. Am Geriatr Soc 2000; 48:651-657. 11. Lim SH, Goh DY, Tan AY, Lee BW. Parents’ perception 18. Patlak M. Strategies to overcome ‘steroid phobia’. From the May ACPobserver, copyright 2004 by the American College of Physicians. September 2007 KUWAIT MEDICAL JOURNAL
Original Article Changing Patterns of Cardiovascular Risk Factors in Hospitalized Patients with Acute Myocardial Infarction in Babol, Iran
Karim O Hajian-Tilaki1, Farzad Jalali2 1Department of Social Medicine and Health, Babol Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran 2Department of Cardiology, Shahid Beheshti Hospital, Babol Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
Kuwait Medical Journal 2007, 39 (3): 243-247 ABSTRACT Objective: To investigate a 10-year trend of major year period. Overall, 62% patients were male and 32% c a rdiovascular risk factors in patients with acute had history of hypertension and their trends were not myocardial infarction (AMI) statistically significant. Roughly, 24% of patients had De s i g n : Aret r ospective study diabetes mellitus and 32% had a history of smoking; the Setting: Babol Shahid Beheshti Hospital, Babol, Iran trend of these two risk factors tended to decrease over 10 S u b j e c t s : A total of 1236 consecutive patients with years. There was a significant trend toward increasing diagnosis of AMI. diastolic blood pressure level at hospitalization (p < Main Outcome Measures: Major cardiovascular risk 0.0001). The mean (± SD) of cholesterol was 217 (64) factors including history of hypertension, diabetes mg/dl and the mean (± SD) of triglyceride was 147 (97) mellitus, mean of diastolic blood pres s u r e measurem e n t s , mg/dl. Their trend was not statistically significant. cholesterol and triglyceride level on the third day of Conclusion: A multidimensional intervention program is hospitalization, age and gender were extracted from necessary for prevention of cardiovascular risk factors. hospital records. There is a need to promote health-related educational Results: The mean age (± SD) of patients was 60.6 (± 11.2) programs and to control the nutritional behavior and years and its trend was not significant during the 10- hypertension in order to cope with changing life styles.
KEYWORDS: cardiovascular risk factors, myocardial Infarction, trend
INTRODUCTION pattern of cardiovascular risk factors in different Acute myocardial infarction (AMI) has a high societies[6,7]. An observational study in Australia, rate of morbidity and cost of hospitalization, long during 1985-1993 reported that the smoking rate, term disability and mortality. In the United States, diastolic hypertension and total cholesterol on an AMI causes a million deaths annually that account average decreased 3.3% for men and 4.1% for for over 50% of annual death[1,2]. Published data women annually in patients with coronary heart from United States showed that the mortality rate diseases but the prescription of card i o v a s c u l a r due of myocardial infarction (MI) decreased in the dr ugs increa s e d [6 ] . In contrast, a hospital based study decade of 1960’s. The decreasing rate was 54% in Tehran, Masinia (1996) rep o r t e d [8 ] that the smoking during 1963-90 and it reached 31% during 1982 to rate, the prevalence of diabetes mellitus, hypertension 1990. This decreasing rate was mainly due to and cholesterol in patients with AMI increased prevention of major risk factors by community during 1986-1996. In another report from Iran, it based intervention programs[2]. was concluded that the mean age of MI patients In epidemiologic studies, the major classical risk increased roughly 1.9 years in recent decade[9]. factors were documented very well and it was In developing countries, due to changing life clearly known that hypertension, hyperch o l e s t e ro l e m i a , styles and development of civilization, an increase diabetes mellitus, smoking and familial history in the incidence of MI was observed. Published increase the risk of MI[3-5]. Basic and clinical studies data from Ministry of Health, Iran showed that the have clearly shown the biological relation between percentage of death due to cardiovascular diseases, these risk factors and atherosclerosis. Published in particular MI, increased significantly in the studies showed diff e rent results on changing recent decade and roughly it accounted for 40% of
Address correspondence to: Dr Hajian-Tilaki KO, Department of Social Medicine and Health, Babol Faculty of Medicine, Babol, University of Medical Sciences, Babol, Iran. Fax N0: 0098-111-2229936, E-mail:[email protected] 244 Changing Patterns of Cardiovascular Risk Factors in Hospitalized Patients with Acute ... September 2007
Table 1: The changes in mean (± SD) of triglyceride, Table 2: The frequency and percentage of major cholesterol and diastolic blood pressure in patients with cardiovascular risk factors in male MI patients within AMI over calendar years two 5-year study periods and p-value
Calendar year Triglyceride level Cholesterol level Diastolic Blood Risk factors 1st 5-year 2nd 5-year Total p-value Mean ± SD Mean ± SD Pressure period period (mg/dl) (mg/dl) Mean ± SD (1992-1996) (1997-2001) (mm/Hg) n (%) n (%) n (%)
1992 145.8 ± 95.9 217.5 ± 58.9 76.1 ± 12.0 History of Hypertension 0.58 1993 164.1 ± 115.0 211.9 ± 47.8 78.9 ± 14.0 Yes 73 (22.6) 88 (20.9) 161 (21.6) 1994 158.7 ± 114.7 235.1 ± 60.7 78.4 ± 14.7 No 250 (77.4) 333 (79.1) 583 (78.4) 1995 139.7 ± 74.1 202.4 ± 42.4 72.9 ± 11.7 Total 323 (100) 421 (100) 744 (100) 1995 140.1 ± 93.8 210.8 ± 53.7 76.5 ± 15.2 Hypertension at Hospitalization 1997 128.3 ± 80.4 208.3 ± 58.0 76.5 ± 15.2 Yes 28 (8.6) 68 (15.9) 96 (12.7) 0.002 1998 135.8 ± 87.9 225.4 ± 89.4 81.5 ± 13.8 No 299 (91.4) 359(84.1) 658 (87.3) 1999 153.2 ± 100.7 219.4 ± 60.9 81.9 ± 16.2 Total 327 (100) 427 (100) 754 (100) 2000 145.6 ± 92.9 235.7 ± 73.0 80.6 ± 12.8 Diabetes Mellitus 0.74 2001 147.5 ± 94.1 200.5 ± 58.5 82.1 ± 14.1 Yes 53 (16.4) 65 (15.5) 118 (15.9) No 271 (83.6) 355 (84.5) 355 (84.1) Overall mean 147.0 ± 97.1 217 ± 63.9 79.5 ± 14.2 Total 324 (100) 420 (100) 744 (100) Hypercholesterolemia 0.37 all deaths[10]. In this regard, the question is how the Yes 108 (34.2) 149 (37.4) 257 (36.0) pattern of cardiovascular risk factors varies in MI No 208 (65.8) 249 (62.6) 457 (64.0) Total 316 (100) 398 (100) 714 (100) patients. This study was conducted to assess the Hypertriglyceridemia 0.64 changing profile of cardiovascular risk factors in Yes 27 (8.5) 30 (7.6) 57 (8.0) hospitalized patients with AMI over a decade in No 288 (91.4) 364 (92.4) 652 (92.0) Babol, north of Iran. Total 315 (100) 394 (100) 709 (100) Smoking 0.007 Yes 168 (51.9) 173 (41.9) 341 (46.3) SUBJECTS AND METHODS No 156 (48.1) 240 (58.1) 396 (53.7) Aretrospective study was conducted over a 10- Total 324 (100) 413 (100) 737 (100) year period from 1992 to 2001, based on existing Age 0.03 data on medical records of patients with AMI (both Under 50 Years 58 (17.5) 84 (19.6) 142 (18.7) ST and non-ST elevation) who were admitted to the 50-64 Years 153 (46.2) 158 (36.8) 311 (40.9) ³ 65 Years 120 (36.3) 187 (43.6) 307 (404) Shahid Beheshti hospital in Babol, Iran. Overall, Total 331 (100) 429 (100) 760 (100) 1236 patients with AMI were examined during the study period. The diagnosis criteria of AMI were RESULTS the presence of at least two from three WHO cr i t e r i a Out of 1236 cases under study, 61.8% were male (p r esence of typical chest pain, ECG changes and and 38.2% were female. The overall mean age (± serum cardiac enzyme (CKMB) rising). The data of SD) of MI patients was 60.6 ± 11.2 years; the age age, sex, history of hypertension, the mean of mean for men and women was 60.1 ± 11.8 and 61.5 several measurement of diastolic blood pressure ± 11.0 years respectively and the diff e re n c e (DBP) at hospitalization, cholesterol (Chol) and appeared to be significant statistically (p = 0.03). triglyceride level (TRG) at third day of hospitalization, Table 1 shows that the overall mean DBP was 79.5 ± history of diabetes mellitus (DM-type II) and 14.2 mmHg and the F-test in ANOVA model shows smoking status and calendar year were extracted a significant linear trend toward increasing DBP from hospital charts. A DBP > 90 mmHg was over the 10-year study period (p < 0.0001). The defined as hypertension; total Chol > 220 mg/dl mean cholesterol level was 217 ± 63.5 mg/dl and its and TRG > 250 mg/dl were considered as abnormal trend was not statistically significant (p = 0.38). and were labeled as hyperc h o l e s t e rolemia and Also, the mean (± SD) of TRG was 147.0 ± 97 mg/dl hypertriglyceridemia respectively. Also, a fasting and changes in its trend were not significant (p = blood sugar > 140 mg/dl at pre-hospitalization was 0.39). defined as diabetes mellitus. Statistical analysis was On the whole, considering both genders done using SPSS software. The F-test for linear together, (pooling data of Tables 1 and 2), the trend with ANOVA model was used to assess the proportions of major risk factors such as history of changes on mean of risk factors on continuous hypertension, diabetes mellitus, hypercholestero- scales over a 10-year period and Chi-square test lemia, triglyceridemia, smoking and age less than was used to assess the changes on the prevalence of 50 years were 32.2%, 24%, 43.6%, 11%, 30.7% and major risk factors over two 5-year periods; a p-value 15.7% respectively. In comparison to two 5-year < 0.05 was considered significant. study periods, proportion of hypertension at September 2007 KUWAIT MEDICAL JOURNAL 245
hypertension at hospitalization for 5-year period Table 3: The frequency and proportion (percentage) of was greater in men than women (7.3% Vs 4.2%). major cardiovascular risk factors in female MI patients Although the value of decreasing rate of smoking within two 5-year study periods and p-value for women was 1% and for men 10% and the Risk factors 1st 5-year 2nd 5-year Total p-value percentage of MI under 50 years in comparison for period period the two 5-year study period, the value of increasing 1992-1996 1997-2001 rate was greater in women as compared to men n (%) n (%) n (%) (6.8% Vs 2.1%).
History of Hypertension 0.53 Yes 91 (47.4) 138 (50.4) 229 (49.1) DISCUSSION No 101 (52.6) 136 (39.6) 237 (50.9) The findings of this study showed a significant Total 192 (100) 274 (100) 466 (100) increasing trend of the mean DBP at hospitalization Hypertension At Hospitalization 0.22 in patients with MI during a 10-year study period Yes 24 (12.6) 46 (16.8) 70 (15.1) but the smoking rate decreased over the same time. No 166 (87.4) 228(83.2) 394 (84.9) Total 190 (100) 190(100) 464 (100) The mean of total cholesterol level and triglyceride Diabetes Mellitus 0.69 however, did not change significantly over the Yes 73 (38.0) 100 (36.2) 173 (37.0) times. No 119 (62.0) 176 (63.8) 295 (63.0) Based on the finding of this study, the rate of Total 192 (100) 276 (100) 468 (100) female patients with MI increased over a decade. Hypercholesterolemia 0.60 Yes 103 (53.8) 136 (53.8) 239 (54.8) Overall, 38.2% of patients were female and 61.8 No 85 (43.7) 117 (46.2) 197 (44.2) were male. But the percentage of female patients Subtotal 183 (100) 253 (100) 436 (100) increased from 36.8 at the first 5-year period (1992- Hypertriglyceridemia 1996) to 39.3 in the second five years study period Yes 25 (13.7) 44 (17.5) 69 (15.9) 0.28 (1997-2002). In particular, the proportion of female No 158 (86.3) 208 (82.5) 366 (84.1) Total 183 (100) 252 (100) 435 (100) MI patients under the age of 50 years increased Smoking 0.62 from 6.8% to 13.6% between the two 5-year periods. Yes 12 (6.3) 14 (5.2) 26 (5.7) This increasing rate might be due to the higher No 179 (93.7) 255 (94.8) 434 (94.3) p revalence of three major risk factors, namely, Total 191 (100) 269 (100) 460 (100) h y p e rc h o l e s t e rolemia, hypertension and hyper- Age 0.004 Under 50 Years 13 (6.8) 38 (13.6) 51 (10.8) triglyceridemia among women seen in our study. 50-64 Years 108 (56.3) 118 (42.3) 226 (48.0) In general, the proportion of female MI patients D65 Years 71 (37.0) 123 (44.1) 194 (41.2) was 38.9%. Other studies like al-Adsani et al (2000) Total 192( 100) 471 (100) 471 (100) in Kuwait[11], Zubaid et al (2004) in Kuwait[12] and Sawaya et al (1999) in Lebanon[13] reported that hospitalization significantly increased in the second 15.1%, 13% and 22.9% of MI patients respectively 5-year study period (16.3 Vs 10.0%, p = 0.001) while were females. The increasing proportion of female the proportion of smoking was seen to decrease MI patients in our study may be explained by the significantly in comparison with the first 5-year differences of ecologic, genetic and life style factors. study period (27.4 Vs 35.1, p = 0.0004). With regard It might also be due to the tendency of women to be to occurrence of MI under the age of 50 years, the more conscious about their health and to visit a rate increased in the second study period (7.2% Vs physician earlier. Overall, as regards the age-sex 13.7%). distribution of MI patients, the age mean of our Tables 2 and 3 compare the proportion of risk patients was similar to that reported from other factors between two 5-year study periods, 1992- Middle Eastern countries[14] while the proportion of 1996 and 1997-2001 in men and women MI patients aged ³ 65 years was tending to be respectively. greater in women than men. On an average, the age When comparing men and women, the three of occurrence of MI was roughly one year higher in major risk factors including hypertension at women compared with men. These findings are hospitalization (12.7% for men Vs 15.1% for also consistent with those reported in published women), hypercholesterolemia (36% for men Vs data[11,13,15]. In addition, we found that the proportion 54.8% for women) and diabetes mellitus (15.9% for of female patients was increasing over time. men Vs 37% for women) were significantly more Regarding history of hypertension and presence common among women than men (p < 0.0001). of hypertension at hospitalization, we found a However, smoking rate was significantly greater significantly increasing rate of about 10% between among men than women (46.3% Vs 5.7%). A s the two 5-year study periods. Although, the regards the temporal changing on cardiovascular prevalence of hypertension in our study was lower risk factors, the amount of increasing rate of c o m p a red with published data from a Chilean 246 Changing Patterns of Cardiovascular Risk Factors in Hospitalized Patients with Acute ... September 2007 h o s p i t a l[ 1 6 ] (49%) and a Kuwait study a m o n g Because of unbalanced diet, improper nutritional hospitalized Arab (28.5%) and south Asian (20.6%) behavior and lack of physical activity, the women MI patients living in Kuwait [17], we must still worry population might have a higher rate of these two of its significant increasing trend over these 10 risk factors. This may explain the incre a s i n g years. In comparison with the Tehran study in proportion of female patients in our study period. hospitalized patients with MI[7], the proportion of A similar result was also found in another study[20]. hypertension increased by 11.5% over a 5-year In fact, some reports have shown that the period and this is greater than our findings. prevalence of obesity in adult women is greater In terms of smoking behavior of MI patients, we than men[21, 22]. observed a significant decreasing rate in the In our study, the most common risk factors in MI p roportion of smokers within the two 5- year patients were hyperch o l e s t e r olemia, hypertension, periods. The proportion of smokers decreased from history of smoking and diabetes respectively while 51.9% to 40.9% (the decreasing rate was roughly Thomas et al (2000) reported that the order of most 10%) for men while among women the prevalence common risk factors was diabetes mellitus, of smokers was low (5%) and the changes in the hypertension, hyperch o l e s t e r olemia and smoking[1 8 ] . decreasing rate was not clearly obvious (roughly The differences in the order of these four major risk 1%). In comparison to other published study in factors might be due to differences in nutritional Tehran[7], the proportion of smokers in our MI behavior and life style in the general population. patients was much lower (30.6% Vs 52.3%). This A major limitation of this study is that the study might be due to temporal effect of decre a s i n g did not include those subjects who died before smoking rate in our general population during the getting to the hospital, since roughly 15% of MI two diff e rent periods. Other published studies, patients die during their first heart attack before Prieto et al (1999)[16], Thomas et al (2000)[18] and arriving at the hospital[2]. This may eliminate real Zubaid et al (2004)[19] reported that the proportion of severe cases with major classic risk factors from our smokers was 40, 30 and 51.7% respectively. Because study sample. In addition, the setting of our study of cultural issues, in the general population of our was limited to a single educational and th e r a p e u t i c study area, the prevalence of smokers was low hospital. Thus, conducting a multicenter prospective among women. Thus, the overall proportion of study with a larger sample size will help us judge smoker was lower in our study. On the other hand, the temporal changes in cardiovascular risk factors a decreasing rate in the 10 years under study might better. be due to the increased awareness of our general population on the risks of smoking and promotion CONCLUSION of health education for cessation of smoking during As our study found an increasing trend of the last decade. hypertension, increasing proportion of MI In this study, the overall proportion of diabetes o c c u r rence under the age of 50 years and an mellitus was 24%; this proportion increased to 37% especially, high prevalence of hypercholesterolemia in women. We did not find any changes in its in women and high rate of smoking in men, there is proportion over the study period. In Tehran study, a need to promote health educational programs for Masinia (1997) reported the prevalence of diabetes increasing awareness of the general population on mellitus as 20.4% during 1989-1996 that is roughly c a rdiovascular risk factors. We recommend a close to our findings[7]. However, in some published systematic health education program using multi studies, it was also reported that up to 53% of MI media and the health system to increase knowledge patients were diabetic[ 1 8 , 1 9 ]. The prevalence of and to change the attitude and behavior of subjects diabetes in our study was about 25% and re g a rding major risk factors in population. In corresponded with that reported by the classic particular, a multidimensional community based reference[3]. intervention program is needed to cope with Our findings also revealed that the prevalence changing lifestyle and nutritional behavior. of diabetes mellitus and history of hypertension among women is more than two times higher than REFERENCES men (37% Vs 15.9% for diabetes and 49.1% Vs 1. Braunwald E, Faucy AS, Kaper DL, et al. Harrison’s 21.6% for hypertension). These results also principle of internal medicine. 15th edition, Mc Graw Hill, Medical Publication Division, 2001; 1383. correspond with findings from other studies that 2. Antman EM, Braunwald E. Acute myocardial infarction. In: these two risk factors are more prevalent among Braunwald E, Zioes DP, Libby P, editors. Heart Disease: a women patients with MI[11,13]. These differences may textbook of cardiovascular medicine, 6th ed. 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New York: Health Profession Division; 1998. p 1175, 1180. myocardial infarction:clinical characteristics, measurement 4. Rao SV, Donahua M, Pi-Sunyer FX, et al. Obesity as a risk and outcome in a university medical centre in developing factor in coronary artery disease. Am Heart J 2001; 142:1102- Middle Eastern country. Can J Cardiol 2004; 20:789-793. 1107. 15. Gottlieb S, Harpaz D, Shoton A, et al. Sex differences in 5. Belmin J. Prevention of cardiovascular disease in elderly. management and outcome after acute myocardial infarction Press Med 2000; 24:1234-1239. in the 1990s: a prospective observational community based 6. Dobson AJ, McElduff P, Heller R, Alexander H, Colley P. study. Israeli Thrombolytic Survey Group. Circulation2000; D’Este K. Changing patterns of coronary heart disease in 102:2458-2459. the hunter region of New south Wales, Australia. J Clin 16. Preito JC, Corbalan R, Chavez E. Lanas F, Cumsille F, Epidemiol 1999; 52:761-771. Nazzal C. Acute myocardial infarction in Chilean hospitals. 7. Masinia F. Changing risk factors of myocardial infarction in Final results of the GENI study. Rev Med Chil 1999; 127:795- relation to passed time. Pajouhandeh Journal, Sahid 762. Beheshti Medical Science University, Iran, 1997; 7:77-82. 17. Suresh CG, Zubaid M, Thalib L, Rashed W, David T. 8. Brown N, Young T, Gray D, Skene AM, Hamton JR. In: Racial Variation in risk factors and occurrence of acute Patient deaths from acute myocardial infarction, 1982-92: m y o c a rdial infarction: complication between Arab and analysis of data in the Nothingham heart attack register. South Asian men in Kuwait. Indian Heart J 2002; 54:266- BMJ 1997; 315:159-164. 270. 9. Shamkani K, Hosiani-Akbar M, Samadi E, Habibi G. A 18. Thomas CN, Titus G, Williams D, Simeon D, Pitt-Miller P. comparing of mean age of AMI occurrence in 1989 and Two year mortality and its determinants following acute 1999. Journal of Gilan University of Medical Sciences, Iran myocardial infarction in Trinidad and Tobago. West Indian 2001; 10:36-41. Med J 2000; 49:112-114. 10. Ministry of Health and Medical Education of Iran. Areport 19. Zubaid M, Suresh CG, Thalib L, Rashed W. Differential of survey of Iranian health, Tehran; 1997. p 234. distribution of risk factors and outcome of acute coronary 11. al- Adsani A, Memon A, Peneva A, Baidas G. Clinical syndrome in Kuwait: three years’ experience. Med Prin epidemiology of acute myocardial infarction in Kuwait. Pract 2004; 13:63-68. Acta Cardiol 2000; 55:17-23. 20. Widdershoven JW, Gorgels AP, Vermeer F, et al . Changing 12. Zubaid M, Rashed WA, Husain M, et al. A registry of characteristics and in-hospital outcome in patients a c u t e m y o c a rdial infarction in Kuwait: Patient admitted with acute myocardial infarction. Observations characteristics and practice patterns. Can J Cardiol 2004; from 1982 to 1994. Edu Heart J 1997; 18:1073-1080. 20:783-787. 21. Azadbakht L, Mirmiran P, Azizi F. Prevalence and 13. Sawaya JI, Jazra C, Eid EV, Sabra RF. Gender differences in associates of obesity in Tehran adults: Tehran Lipid and the diagnosis and treatment of acute myocardial infarction Glucose Study. Int J Endcorinol Metab 2004; 5- Abstract. in Lebanon. J Med Liban 1999; 47:2-6. 22. James PT, Leach R, Kalamrs E, Shayeghi M. The worldwide 14. Dakik HA, Koubeissi Z, Kleiman NS, et al. A c u t e obesity epidemic. Obes Res 2001; 9:228S-233S. KUWAIT MEDICAL JOURNAL September 2007
Original Article Non-cystic Fibrosis Bronchiectasis: the Experience in Saudi Arabia
Hanaa Hasan Banjar Department of Pediatrics, King Faisal Specialist Hospital and Research Centre (KFSH&RC), Saudi Arabia
Kuwait Medical Journal 2007, 39 (3): 248-252
ABSTRACT O b j e c t i v e : To review the etiological factors and tachypnea, wheezing, sputum production and failure to associated diseases of Non-cystic fibrosis bronchiectasis thrive. 91 (60%) had associated diseases: pulmonary (NCFB) diseases in 48 (32%), immunodefficiency in 27 (18%), Design: A retrospective cohort study of all patients with CNS in 10 (7%), cardiac in 10 (7%), and asthma in 103 confirmed NCFB by chest X-ray and/or CT chest in a (68%) of the patients. Left lower lobes was commonly pulmonary clinic for the period 1993-2005. involved in 114 (76%). 68 (67%) were found to have Setting: A tertiary care center in Riyadh, Saudi Arabia. sinusitis. Fourtynine (32%) developed gastroesophgeal Subjects: Children less than 14 years of age with NCFB reflux (GER). Hemophilus influenza was cultured in 56 Main Outcome Measures: Association with other (37%), Strept pneumoniae in 25 (17%), and Pseudomonas diseases, radiological pattern, bacteriological pattern and aeruginosa in 24 (16%) of the patients. 80% of the patients pulmonary function test abnormalities (PFT). who had PFT had abnormal changes. Results: A total of 151 cases were diagnosed with NCFB. C o n c l u s i o n : NCFB is a common problem in Saudi 75 (49.7%) were male, 76(50.3%) were female. 148(98%) Arabia. Early diagnosis and identification of associated are alive. More than 2/3 of the patients had cough, diseases is needed to prevent progression of the disease.
KEY WORDS: bronchiectasis, chest infection, developing countries
INTRODUCTION of lower respiratory tract infections made possible Bronchiectasis was called an orphan disease for by the increased availability of broad-spectrum the last two decades as its incidence decreased antibiotics during that period[6]. Other contributing markedly and it became an uncommon clinical factors include the prevention of measles and entity among adults and children in developed pertussis through immunization and the marked co u n t r i e s [1 ] . It is defined as a permanent dilatation of decrease in primary pulmonary tuberculosis in the the bronchi that typically involves the second to pediatric population brought about by better public sixth order of segmental bronchi[2]. It was first health measures and improved treatment regimens described by Laennec in 1819 based on examination for this disease[ 3 ]. The incidence of childhood of postmortem specimens[ 3 ]. Bierrring (1956) bronchiectasis has been documented to have an studied 151 patients in Copenhagen following ongoing decline in the literature[ 2 ]. Clark pneumonia and found only one child (0.7 %) to summarized many series from 1900 - 1950s and in h a v e bronchiectasis[4]. Ruberman and colleagues his own report of 116 children in 1963[7] noted that (1957) evaluated 69 patients with persistent half of the children developed bro n c h i e c t a s i s abnormalities on chest radiographs by following severe pneumonia. He estimated the bronchoscopy[5]. Out of 1711 young adults (18 to 25 annual incidence of bronchiectasis to be 1.06/ years of age) treated for pneumonia at a U.S. army 10,000 children. Most series indicate a male/ female hospital, 29 (1.7%) were found to have bron c h i e c t a t i c ratio about 1:1.4[1-6]. c h a n g e s[ 5 ]. Fileld noted a dramatic decrease in In this report, we present the experience of a admission rates for bronchiectasis at five British tertiary care center in Saudi Arabia on childhood hospitals from an average of 48 per 10,000 in 1952 to bronchiectasis and review the etiological factors 10 per 10,000 pediatric admissions in 1960[6]. She and associated diseases of Non-cystic fibro s i s speculated that this was due to improved treatment bronchiectasis (NCFB).
Address correspondence to: Dr. Hanaa Banjar, MD, FRCPC, Consultant Pediatric Pulmonologist, Department of Pediatrics, King Faisal Specialist Hospital and Research Ce n t r e (KFSH&RC), P.O.Box. 3354, MBC-58, Riyadh 112 1 1, Saudi Arabia. Tel: + 9661- 442-7761, Fax: +966-1-442-7784, E-mail: hanaa@kfshrc. e d u . s a September 2007 KUWAIT MEDICAL JOURNAL 249
SUBJECTS AND METHODS Mild lung changes: defined as forced expiratory We undertook a retrospective review of the volume in one second (FEV1) = 65 - 75% of pred i c t e d medical records for all patients referred to the values pulmonary clinic for evaluation of recurrent chest Moderate lung changes: FEV1 = 55 - 65% pred i c t e d infection from January 1993 to August 2005 at the Severe lung changes: FEV1 < 55% predicted King Faisal specialist hospital and research center (KFSH & RC) in Riyadh region. This center is RESULTS considered a tertiary care center for referral of Out of a total of 900 cases re f e r red with complicated cases in Saudi Arabia. Demographic, recurrent chest infection to the pulmonary clinic radiological patterns, associated diseases, and from January 1993 to August 2005, 200 patients pulmonary function test (PFT) data were collected. were diagnosed to have cystic fibrosis (CF). Of the remaining 700, 151 cases were diagnosed as NCF Patient management: All confirmed cases of bronchiectasis (based on high resolution CT of the bronchiectasis were screened for cystic fibrosis by chest in 145 cases, 96% and chest X-ray in six cases, sweat chloride test, PPD skin test, re s p i r a t o r y 4%) due to severe bilateral cystic dilatation of cultures for virology, acid-fast bacilli and other bronchi. Seventy-five (49.7%) were male and 76 pathogenic bacteria. They were followed-up every (50.3%) were female. One hundred and forty eight 1-3 month according to the severity of their disease. (98%) are alive and three (2%) have died. One They were taught how to do regular chest hundred and forty-four (95%) were Saudi nationals physiotherapy to mobilize secretion and how to and seven (5%) non - Saudi. One-hundred and forty self-administer salbutamol and inhaled stero i d (93%) were full term. Twenty-two (14.6%) were according to their need. Antibiotic treatment orally from the eastern region, 26 (17.2%) from the central or intravenously was advised during exacerbation region, 39 (25.8%) from the western region, 33 of their symptoms (increasing cough, sputum (21.9%) from the southern region and four (2.6%) production, change in the color of their sputum to f rom neighboring countries. Ninety-eight (65%) yellowish or greenish or respiratory distress). patients had consanguineous parents. Eighteen Patients who showed clinical deterioration in patients (12%) had one or two siblings with the form of recurrent fever, increase in sputum or bronchiectasis and five patients had three to four cough, and radiological deterioration in the form of siblings with similar disease. The age at which involvement of another lobe with bronchiectatic symptoms started was 2.3 ± 2.2 years. The age for changes or PFT deterioration in all parameters, referral to our center was 6.3 ± 4 years. The age at were admitted to the hospital for intensive chest which bronchiectasis was diagnosed was 7.3 ± 4.1 intravenous physiotherapy, airway clearance and years. There was usually a period of 5 ± 3.2 years antibiotics (according to bacterial organism from between the start of symptoms to the diagnosis of the respiratory cultures) for approximately 7-10 bronchiectasis. The period of follow up was 5.5 ± days, in addition to inhaled albuterol and steroid. 3.9 years. Lobectomy was done to prevent deterioration when medical treatment failed to stabilize PFT and Clinical presentations: More than two thirds of radiological pictures. It was usually done in the patients presented with cough, tachypnea, wheezing, most severely affected lobe radiologically. sputum production and failure to thrive. Clubbing was found in 50 (33%) patients. Cyanosis and oxygen Statistical analysis: SPSS program for Windows requirement was reported in 35 (23%) patients. (release 11.0.0) was used for data analysis. Chi- Hemoptysis was only reported in seven (5%) cases. S q u a re (X2) was used to compare categorical variables. The level for statistical significance was Underlying etiology: Ninety-one (60%) had a p-value £ 0.05. associated diseases (Table 1). Pulmonary diseases were found in 48 (32%), immunodeficiency in 27 DEFINITIONS (18%) (Fig. 1), central nervous system (CNS) Progression of disease: is a qualitative measurem e n t , involvement in 10 (7%), cardiac involvement in 10 defined as a radiological deterioration with more (7%), skeletal anomalies in 10 (7%) and asthma in lobes involved in addition to clinical deterioration 103 (68%) patients (Table 1). More than two-third with increased sputum production, cough and / or patients had two or more associated diseases. fever. Radiological findings: The following were rep o r t e d : PFT severity is a quantitative measurement of consolidation of one or two lobes in 137 (91%), airflow in PFT: compensatory hyperinflation in 103 (68%), interstitial 250 Non-cystic Fibrosis Bronchiectasis: the Experience in Saudi Arabia September 2007
Fig. 1: A patient with common variable hypogammaglobulinemia, and Table 1: Bronchiectasis and disease association (n = 91, LLLbronchiectasis 60%)
Disease association n (%) Disease association n (%)
Pulmonary: Immunodefficiency: Kartagener 4 (4) Hypogammaglobulinemia 3 (3) FBA 6 (7) SCIDS 3 (3) Immotile cilia syndrome 17 (19) HIV 1 (1) Lipid pneumonia 7 (8) Hyper IgE 1 (1) Interstitial pneumonia 2 (2) IgG subclass defficiency 6 (7) ABPA 2 (2) Hyper IgM 2 (2) T.B. 2 (2) Whiscott Aldrich syndrome 1 (1) RMLsyndrome 1 (1) Poor antibodies response 4 (4) TEF repair 4 (4) Common variable- Bronchogenic cyst 2 (2) hypogammaglobulinemia 3 (3) Cystic lung disease 5 (5) T-cell deficiency 3 (3) Lung collapse 3 (3) Barre lymphocyte syndrome 1 (1) Prematurity 3 (3) 1A: CT chest showing mild dilatation in the posterior aspect of the LLL Cardiac Diseases: Central nervous system disease: with failure of normal tapering when the bronchi are approaching the periphery of the lung. The bronchi also show some crowding. Dextrocardia 4 (4) Cerebral palsy/seizure disorder 4 (4) Congestive heart failure 1 (1) Apnea 1 (1) three patients by barium swallow alone, 10 patients Ventricular septal defect 2 (2) Craniosynostosis 1 (1) Atrial septal defect 1 (1) Cutis laxa/developmental delay 1 (1) by milk scan alone and six patients by both Pulmonary hypertension 1 (1) Down syndrome/ Seizure 2 (2) radiological pro c e d u res. Twenty-two of the 49 Mitrale valve prolapse 1 (1) Fatty acid oxidation defect 1 (1) patients with GER (45%) re q u i red Nissen Skeletal: Other disease associations: fundoplication. Pectus excavatum 2 (2) Neuroblastoma 1 (1) Scoliosis 4 (4) Antithrombin III deficiency 2 (2) Absent ribs 3 (2) Corrosive ingestion 2 (2) Types of organisms: Respiratory cultures were Marfan’s syndrome 1 (1) Liver cirrhosis 1 (1) done in 105 (70%) patients by sputum cultures (if Ethmoid mucocele 1 (1) patients were able to produce sputum) or by Bulllous skin lesion/septicemia 1 (1) nasopharyngeal aspirates (for patients less than FBA= Foreign body aspiration four years). The following were grown: My c o b a c t e r i u m ABPA= Allergic bronchopulmonary aspergillosis TB = Tuberculosis tuberculosis in one patient, Hemophilus influenza (H- RML= Right middle lobe flue) was cultured in 56 (37%), S t re p t o c o c c u s TEF = Tracheoesophageal fistula SCIDS = Severe combined immunodeficiency pneumoniae in 25 (17%), Pseudomonas aeruginosa in 24 (16%), Branhamella cattarrh a l e s in 13 (9%), pattern in 49 (33%), atelectasis in 117 (78%), Staphylococcus aure u s (Staph.) in 11 (7%) and peribronchial wall thickening in 115 (76%) and Methicillin resistant Staphylococcus aureus (MRSA) lymph node enlargement of the paratracheal region in three (2%) patients. Candida albicans was grown in 33 (22%) patients. Left lower lobes (LLL) was in two (1%) patients. About 50% patients had more involved in 114 (76%), right middle lobe (RML) in than one organism simultaneously. Viral cultures 82 (54%), and right lower lobe (RLL) in 76 (50%), w e re done in 33 (22%) patients: re s p i r a t o r y lingula in 73 (48%), right upper lobe (RUL) in 39 syncytial virus in was found in three (9%), and (26%), and left upper lobe (LUL) in 27 (18%) enterovirus in one (3%) patient. patients. More than two-third patients had more than two lobes affected with bro n c h i e c t a s i s . PFT: Seventy-seven (49%) patients were able to do Bilateral lobar involvement was seen in 112 (71%) pulmonary function test (PFT). Sixty-eight (88%) of patients. them had abnormal PFT results. Seventeen (22%) had obstructive lung changes, 14 (18%) had Bronchoscopy was done in 20 out of 117 patients restrictive lung changes and 37 (48%) had who had persistent atelectasis of the affected lobes combined obstructive and restrictive lung changes. and showed no evidence of foreign body Mean values ± SD (standard deviation) were as aspiration. The remaining 97 patients had partial follows: FVC (forced vital capacity) = 67 ± 19, FEV1 improvement of the atelectatic lobes. A total of 102 (forced expiratory volume in one second) = 65 ± 2, patients had sinus X-ray and 18 (12%) had CT scan FEV1 / FVC ratio = 98 ± 16, MMEF = 25 - 75% of the sinuses. Sixty-eight (67%) out of 102 patients (maximum mid expiratory flow) = 53 ± 27, peak “who had sinus radiological investigations” were expiratory flow = 67 ± 20, FRC (functional residual found to have sinusitis. Gastroesophgeal reflux capacity) = 106 ± 21, RV (residual volume) = 152 ± (GER) was diagnosed in 49 (32%) patients: thirty - 40, RV / TLC ratio = 46 ± 1 and RV / TLC% = 180 ± September 2007 KUWAIT MEDICAL JOURNAL 251
1B: V/Q lungs scan: There is large defect in the LLL, which is matched in ventilation and perfusion. The ventilation defect is slightly worse than the perfusion defect.
45. Sixteen (21%) had mild air flow limitation, 30 so u r ce of pulmonary disease. However, the children (39%) moderate air flow limitation and 22 (28.5%) reported lived in conditions of relative poverty: had severe air flow limitation. small crowded houses heated by wood-burning stoves, with limited access to running water, and Prognosis: Disease progression developed in 72 70% of households had one or more family (48%) patients and it was related to the development members who smoked tobacco which promotes of symptoms before five years of age, persistent chronic airway mucous secretion and recurrent atelectasis of the affected lobes and involvement of respiratory infections[10,11]. R L L with bronchiectasis (p < 0.05). Unilateral Published reports from some developing countries lobectomy was done in 21 (14%) patients whereas suggest that childhood bronchiectasis may not be bilateral lobectomies were performed in three (2%) disappearing, and that it re p resents a more patients. Follow up of patients who had lobectomy common problem than in developed countries[12]. showed that in 16 out of 21 patients, clinical, Karakoc from Turkey described 23 children with radiological and PFT status had improved, while in bronchiectasis and found that factors other than five patients it had deteriorated due to other infections have contributed to the development of associated diseases. Recurrent otitis media was b ronchiectasis, such as i m m u n o d e f i c i e n c y, reported in 12 (8%) patients. All three patients who primary ciliary dyskinesia and asthma[2]. A report died developed acute lung infection in a local by Dawson from United Arab Emirates from Abu hospital that required ventilation and progressed to Dhabi region described 32 children with respiratory failure and death. One of them who bronchiectasis from a population of 300,000[9]. He died at 16 years of age had repair of esophageal found that congenital anomalies of the respiratory a t resia and tracheo - esophageal fistula with system, prematurity, immunodeficiency were some esophageal - colonic anastomosis and recurrent of the factors that contributed to the cause of the aspiration that required right pneumonectomy. The disease in addition to viral or bacteria infections[9]. second patient had hype IgM syndrome with In our report, the incidence of bronchiectasis lympho - proliferative disorder and CMV infection. was found to be one in four cases that presented The third patient had lipid pneumonia that was with recurrent chest infection in our center, which complicated with bilateral necrotizing pneumonia, makes it a common problem in this part of the bilateral pneumothoraces, chronic ventilation that world. Bacterial infection with the common req u i r ed tracheostomy, acute hepatitis, staphylococcal respiratory organisms such as Staph aureus, H-flue, septicemia, and recurrent pleural effusion and died Pneumococcus, and Pseudomonas was positive in at four years of age. 51% of the patients. The Southwestern re g i o n accounted for 50% of the reported cases. DISCUSSION E n v i ronmental factors such as humidity and Arecent review of bronchiectasis among Alaska crowdedness during pilgrimage time may have native children residing in the Yukon-Kuskowkim contributed to such increase in its incidence[ 1 2 ]. delta region reported a persistently high incidence R e c u r rent aspiration pneumonia due to CNS of 110 / 10,000 in 1940s and 140/ 10,000 persons anomalies or seizure is described for the first time born in the 1980s[8]. Alaska is considered part of a in the literature and might be related to recurrent developed nation, with adequate immunization aspiration of secretions due to swallowing inco- programs, and tuberculosis is no longer a major o rdination and / or GER. Our report is in 252 Non-cystic Fibrosis Bronchiectasis: the Experience in Saudi Arabia September 2007 agreement with another report of early start of REFERENCES symptoms before five years of age in 83% of our p o p u l a t i o n[ 2 ] with a delay of diagnosis of 1. Callahan CW, Redding G. Bronchiectasis in childre n : [12] Orphan disease or persistent problem? Pediatr Pulmonol bronchiectasis by an average of 5 - 10 years . Most 2002; 33:492-496. of the patients had bilateral lobar involvement and 2. Karakoc GB, Yilmaz M, Altintas DU, Kendiri SG. se v e r e PFT changes at pres e n t a t i o n . Fifty percent of Bronchiectasis: Still a problem. Pediatr Pulmonol 2001; our patients had radiological and clinical 32:175-178. p ro g ression inspite of medical treatment with 3. Brown MA, Leman RJ. Bronchiectasis. In: Chernick V, Boat T, editors. Kendig’s disorder of the respiratory tract in antibiotic prophylaxis, which may suggest the children. 6th edition. Philadelphia: WB Saunders; 1998. p adoption of surgical intervention in patients with 538-560. progressive disease. Lobectomy was done in only 4. Biering A. Childhood pneumonia, including pertussis, 16% of our population compared to 60-70% in other pneumonia and bronchiectasis: a follow-up study of 151 reports[2,9-15]. Asthma was a common association in patients. Acta Pediatr 1956; 45:348-351. 5. Ruberman W, Shaufer I, Bioondo T. Bronchiectasis and 68% of the patients, which is in accordance with acute pneumonia. Am Rev Tuber 1957; 76:761-765. [16-18] other reports and treatment with inhaled steroid 6. Field CE. Bronchiectasis: Third report on a follow-up study and b2 agonist may need to be considered in some of medical and surgical cases from childhood. Arch Dis patients. Immunodeficiency is common in our Child 1969; 44:551-555. country due to consanguinity and was found to be 7. Clark NS. Bronchiectasis in childhood. Br Med J 1963; 1:80- 87. the second most common disease association after 8. Singleton R, Morris A, Redding G, et al. Bronchiectasis in pulmonary disease (Table 1). Sinusitis was also a Alaska Native children: causes and clinical courses. Pediatr common presentation in 68% cases and such Pulmonol 2000; 29:182-187. patients may need to be treated for a longer period 9. Dawson KP, Bakalinova D. Child bronchiectasis in a desert of time (4 - 6 weeks) as suggested by other reports[3]. location. Middle East Pediatrics 1996; 1:6-8. 10. Karron RA, Singleton RJ, Bulkow L, et al. Severe respiratory Persistent atelectasis of the affected lobe has been Syncytial virus disease in Alaska native children. RSV contributing to the development of bronchiectasis Alaska study group. J Infect Dis 1999; 180:41-49. in our population, which may warrant encouragement 11. Ezzati M, Kammen DM. Quantifying the effects of exposure of chest physiotherapy, and postural drainage in to indoor air pollution from biomass combustion on acute patients with such a problem. Atelectasis is respiratory infections in developing countries. Enviro n Health Perspect 2001;109:481-488. commonly found in many patients with pneumonia, 12. Alan F, Barker J, Bardana JR. State of the Art, Bronchiectasis: aspiration or asthma and repeat chest X-ray should Update of an Orphan disease. Am Rev Respir Dis 1988; be done after clinical improvement to ensure the re- 137:969-978. expansion of the atelectatic part of the lung. Gastro- 13. Dogan R, Alp M, Kaya S, et al. Surgical treatment of esophageal reflux and re c u r rent aspiration was bronchiectasis: a collective review of 487 cases. Thorac Cardiovasc Surg 1988; 37:183-186. found in 32% of our patients and may have 14. Wilson JF, Decker AM. The surgical management of contributed to the development of bronchiectasis or childhood bronchiectasis. Ann Surg 1982; 195:354-363. complicated its pro g re s s i o n[ 1 9 ]. Lobectomy was 15. Fujimoto T, Hillejan L, Stamatis G. Current strategy for done in only 16% of our patients compared to 60- surgical management of bronchiectasis. Ann Thorac Surg 70% in other reports. This is considered a small 2001; 72:1711-1715. 16. Ip MS, So SY, Lam WK, Yam L, Liong E. High prevalence of proportion in view of the excellent improvement of asthma in patients with bronchiectasis in Hong Kong. Eur clinical picture seen in three-fourths of our patients Respir J 1992; 5:418-423. who had lobectomy (16 out of 21), and may need to 17. Bahous J, Cartier A, Pineau L, et al. Pulmonary function test be considered early if medical treatment failed to and airway responsiveness to methacholine in chro n i c improve clinical or radiological pictures[14,15]. A case bronchiectasis of the adults. Bull Eur Physiopath Respir 1984; 20:375-380. control study needs to be done to identify the actual 18. Varpela E, Laitinen LA, Leakinen H, Konhala D. Asthma, risk factors of developing such disease in our allergy and bronchial hperreactivity in bronchiectasis: a country. Efforts should be made to diagnose it early, controlled study. Thorax 1989; 44:948-951. be aware of contributing factors, provide early 19. El-Serag HB, Gilger M, Kuebeler M, Rabeneck L. t reatment and referral before development of Extraesophageal association of gastroesophageal re f l u x disease in children without neurologic defect. progression. Gastroenterology 2001; 121:1294-1299. September 2007 KUWAIT MEDICAL JOURNAL
Original Article
Predictive Value of Tests in Screening Urine Samples for Bacterial Culture
Prem Anand Nagaraja, El Sayed M M El Aasar Department of Microbiology, Farwaniya Hospital, Kuwait
Kuwait Medical Journal 2007, 39 (3): 253-258 ABSTRACT
Objective: To evaluate the predictive values of screening predictive value of 100% and a specificity of 100% related parameters which would be useful in identifying urine to the outcome of bacterial culture. However, the samples that would yield positive results on culture. analytical parameters taken singly or in combination Design: Prospective study showed good predictive values in some age groups only. Setting: Out patients’ clinic, Farwaniya Hospital, Kuwait Substantial savings were realized when unnecessary Subjects: A total of 7951 urine samples received in the urine cultures were avoided. department of microbiology over a period of thre e Co n c l u s i o n s : Sc r eening tests are not only useful in prov i d i n g months were chosen for the study. a rapid indication of presence of urinary pathogens, but Main Outcome Measures: The predictive values of the also help cut costs of unnecessary cultures and proc e s s i n g s c reening parameters which would be useful in of urine samples. A high negative predictive value with a identifying urine samples that would yield significant high sensitivity of a combination of leucocytes and nitrite growth in culture were analyzed. with either protein or pH assay is useful in identifying Results: Mid-stream urine samples from all age groups cases that are not UTIs. The predictive values of scree n i n g analyzed with a combination of leucocyte esterase and parameters also help in identifying those patients who nitrite test with either pH or protein assay had a negative may be placed on empiric antibiotic therapy.
KEY WORDS: negative predictive value, positive predictive value, sensitivity, significant bacteriuria, specificity, urinary tract infection
INTRODUCTION 105 CFU/ml and so are not used to screen out urine Semi-quantitative urine cultures are done to samples obtained by catheterization, suprapubic conclusively diagnose urinary tract infections aspiration or by cystoscopy[1]. The objectives of this (UTIs), to isolate, identify bacterial pathogens and study were to evaluate the screening criteria perform antimicrobial susceptibility testing. The applied to urine samples sent to the laboratory for time and the cost involved in such processing is routine examination and/or bacterial culture and substantial and it is imperative that tru l y assess the predictive values of combination of these re p resentative mid-stream urine samples are criteria in various age groups like adults, pediatrics collected from clinically identifiable cases in order and neonates. A d d i t i o n a l l y, the utility of the to lower the financial burden of diagnostic p redictive values of these screening criteria in laboratories. UTIs are among the most common suggesting empiric therapy for clinical cases of bacterial infections encountered in clinical urinary tract infections (UTI) is dealt upon. practice[1]. Urine analyses are by far the commonest and the most frequently requested tests by SUBJECTS AND METHODS clinicians, as an aid to diagnosis of UTI[1]. As many Patients attending the out-patient clinics and as 60 to 80% of all urine samples received for admitted patients undergoing investigation for culture in medical center laboratories contain no urinary tract infections in Farwaniya Hospital are etiological agents of infection or contain only usually asked to submit mid-stream urine samples c o n t a m i n a n t s[ 1 ]. Microbiology laboratories apply for urine analysis and culture. A total of 3821 urine screening assays to identify urine samples that are samples were submitted to the micro b i o l o g y suitable for culture. These screening methods are department for routine examination while 3159 insensitive when the bacterial counts are less than m i d - s t ream urine samples were submitted for
Address correspondence to: Dr. Prem Anand Nagaraja, Microbiologist, Farwaniya Hospital, Post Box 18373, Safat, State of Kuwait. Tel: +965 - 4888000, Ext. 3344, [email protected] 254 Predictive Value of Tests in Screening Urine Samples for Bacterial Culture September 2007
Table 1: Screening criteria for urine samples designated Table 2: Standard growth and processing criteria for interpretation of suitable for culture[1] culture plates[1] a. All mid-stream urine samples from pregnant women, Result Specimen Type or Workup irrespective of screen results Clinical Condition b. All samples from children less than three years of age c. Urine samples obtained by catheterization, suprapubic ³ 10 4 CFU/ml of a single CCMS Urine/pyelonephritis, CW aspiration or cystoscopy potential pathogen or acute cystitis, asymptomatic d. Clinical cases of urinary tract obstruction for each of two potential bacteriuria or catheterized e. Follow-up after removal of an indwelling catheter pathogens urines f. Follow-up after a previous therapy for proven UTI ³ 103 CFU/ml of a single CCMS urine/symptomatic CW g. Presence of one or more of these five parameters: Alkaline potential pathogen males or catheterized urine pH, leucocytes ³ 100/ml (2+), positive nitrite test, protein ³ 2+ or acute urethral syndrome or erythrocytes ³ 500/ml (3+) ³ Three organism types CCMS or catheterized urine Possible specimen with no predominating contamination Repeat analysis and bacterial culture, both over a period of organism specimen requested t h ree months from August to October 2005. Two or three organism CCMS Urine CW for the Requests for bacterial culture had been made to types with predominant predominant organism rule out cystitis or lower urinary tract infection growth of one type and and description of the 4 (UTI), pyelonephritis, as a routine in pregnant women < 10 CFU/ml of the others. other type(s) and from catheterized patients. Urine samples from ³ 102 CFU/ml of any Suprapubic aspirates or CW pregnant women were sent for analysis during number of organism surgically obtained urine their ante-natal visits or if the patient had types (Culture setup specimens (like ileal symptoms of UTI. All urine samples of pregnant with a 0.001 or 0.01 ml conduits and cystoscopy) women were processed for detection of significant calibrated loop) bacteriuria irrespective of the screening results. CFU = Colony Forming Units, CCMS = Clean-Catch Mid Stream, CW = Complete Workup Urine samples were processed immediately on including bacterial identification and antibiotic sensitivity, Predominant growth = 104 - ³ 105 arrival by performing a semi-quantitative urinalysis CFU/ml using COMBUR10 TE S T ® (Roche Diagnostics GmbH, reported as “No growths” while samples showing Germany), a 10-parameter assay on a MIDITRON® mi x t u r e of organisms were reported as “contaminated” M (Roche Diagnostics GmbH, Germany), followed (Table 2). Significant growth in culture plates as by microscopy of uncentrifuged urine for determined by standard criteria[1] were processed evaluation of leucocytes. Quality control of the on VITEK-2 (bio-Me_rieux SA, France) for both instrument and strips was performed daily as part identification and antimicrobial susceptibility. of the standard laboratory practices. Out of the 3821 Data was collected for all the samples urine samples received for routine examination prospectively for three months and analyzed using only, samples which were found to conform to the Microsoft FoxPro® for MS-DOS® (Version 2.6). screening criteria (Table 1) were processed further by culture; provided the urine sample was RESULTS submitted in a sterile container. Urine samples A total of 7951 samples were submitted for submitted for culture conforming to any of the routine examination and / or bacterial culture over screening criteria (Table 1) were also processed for a period of three months. Out of the 3821 samples bacterial culture using standard methodology[1] and submitted for routine examination, 400 urine identification along with antimicrobial susceptibility samples (10.5%) received in sterile containers and was done once the standard growth criteria (Table conforming to the screening criteria were processed 2) were fulfilled. All mid-stream urine samples that for identification of significant bacteriuria by were screened and excluded from being processed c u l t u re. 2759 of the 4130 mid-stream samples for bacterial culture were reported as “Culture Not (66.8%) submitted for bacterial culture were Recommended” (CNR). Clinicians were aware of decided suitable for processing, while a total of this method of reporting CNR and this was applied 1371 samples (33.2%) were reported as CNR. Out of to urine samples submitted for bacterial culture the total 3159 samples that were cultured, 905 excepting those that fulfilled the screening criteria samples (28.7%) were found positive for significant (Table 1). However, urine samples submitted for bacteriuria, while 1960 samples (62%) were routine exam alone were processed as such without reported as “no growths” and 294 samples (9.3%) a CNR comment. Mid-stream urine samples from were reported as “contaminated”. Among the 400 pregnant women were cultured irrespective of the samples cultured from the routine group, 312 (78%) screening results. Processed samples showing no showed no growth, 54 (13.5%) were positive for growth after 24 hours incubation at 37° C were significant bacteriuria and 34 samples (8.5%) September 2007 KUWAIT MEDICAL JOURNAL 255
Table 3: Results of the urine cultures - group-wise breakup (%) Table 4: Positive and negative predictive values of the screening parameters in relation to bacterial culture results (%) Culture No growths Mixed Total Patients Category PPV NPV Sensitivity Specificity positives growths n (%) n (%) n (%) n (%) Samples from adult patients PPV NPV Sensitivity Specificity pH 11.9 87 11.4 87.5 Adult males 73 (17.3) 339 (80.5) 9 (2.1) 421 (13.3) Leucocytes 31.4 62 65 62 *Adult females 334 (28.1) 686 (57.8) 167 (14.1) 1187 (37.6) Nitrite 74.1 87 24.4 98.3 Pregnant women 155 (27.3) 361 (63.7) 51 (9) 567 (17.9) pH + Nitrite 100 87 1.6 100 Pediatrics (males) 58 (29) 134 (67) 8 (4) 200 (6.3) pH + Leucocytes + Nitrite + Protein Pediatrics (females) 242 (39.9) 324 (53.4) 40 (6.6) 606 (19.2) + Erythrocytes 87 99.5 Neonates (males) 24 (28.2) 56 (65.9) 5 (5.9) 85 (2.7) Leucocytes + Erythrocytes + Nitrite 90.6 87 31.9 99.3 Neonates (females) 19 (20.4) 60 (64.5) 14 (15) 93 (2.9) Samples from pediatric patients Total 905 (28.7) 1960 (62) 294 (9.3) 3159 Nitrite 83.3 74.5 13.5 98.9 Leucocytes 57.1 96 42.9 96 *The category “Adult Females” include only non-pregnant women Protein 50 74.5 1.03 99.6 pH + Nitrite 100 74.5 2.04 100 showed mixed growth. A total of 567 samples of Leucocytes + Erythrocytes + Nitrite 92.3 74.5 11.1 99.6 urine (17.9% of all cultures) were from pregnant Leucocytes + Erythrocytes + pH + women attending the antenatal clinic or admitted Protein 100 74.5 1.03 100 in the hospital. Among these, 155 samples (27.3%) Erythrocytes + Leucocytes + Protein 80 74.5 7.7 99.3 showed significant bacteriuria while 350 samples Samples from neonates Leucocytes 55.6 28 15.2 28 (61.7%) had one or more of the scre e n i n g Nitrite 75.4 100 parameters positive. Leucocytes + Nitrite 100 24.6 3.5 32.6 The group-wise breakup of the results of culture Leucocytes + Nitrite + Erythrocytes is depicted in Table 3. Results of samples from + pH 100 75.4 3.5 100 adults have been categorized to pregnant women pH + Nitrite 100 75.4 3.5 100 Leucocytes + Nitrite + Erythrocytes and a group comprising of adult males and non-preg n a n t + Protein 100 75.4 3.5 100 women (henceforth referred to comprehensively as Samples from pregnant women “adults”). A total of five parameters and 25 pH 11.8 82.7 5.6 91.6 combinations of these were evaluated against a Leucocytes 32.2 34 59 34 positive culture separately in samples obtained Nitrite 85.7 82.7 26 98.8 pH + Nitrite 82.7 100 f rom adults, pregnant women, pediatric and Leucocytes + Nitrite 76.9 17.3 22.7 20.5 neonatal cases. The positive pred i c t i v e value (PPV), pH + Leucocytes + Nitrite + negative predictive value (NPV), sensitivity and Erythrocytes + Protein 82.7 100 specificity of the various parameters and their Note: combinations with respect to positive culture a. The category “adult patients” includes all adult males and non-pregnant results are depicted in Table 4. Taking only the five adult women. b. Results of other parameters and their combinations are not depicted for parameters into consideration, the PPV ranged lack of space. from zero for protein in neonates to 83.3% for nitrite c. PPV = Positive Predictive Value, NPV = Negative Predictive Value in pediatric cases, while the NPV ranged from 28% lactamase (ESBL) producing E. coli were isolated. for leucocytes in neonates to 96% for leucocytes in ESBL production was confirmed by testing the pediatric cases. The various combinations analyzed isolates with Etest TZ/TZLand CT/CTLstrips (AB showed a diverse range of values and consensus BIODISK, Solna, Sweden) according to standardi z e d among the combinations or parameters taken alone procedures. The details are depicted in Table 5. was difficult to show between the four grou p s . Ho w e v e r , the combination of pH and nitrite showed DISCUSSION a PPV of 100% in all groups except pregnant women S c reening assays in urinalysis play a very and specificity of 100% for all the four groups. important role in preliminary identification of cases Considering only the results of urine samples in of lower urinary tract infection or of pyelonephritis p regnant women, the PPV of the scre e n i n g in both adults and children so that empiric parameters was 45% with a specificity of 96%. antimicrobial therapy is started early in the course Out of the 905 positive cultures, members of the of disease thereby limiting morbidity. Even a brief family Enterobacteriaeceae accounted for 76.35% of delay in instituting therapy in children below two all isolates with 550 isolates of Escherichia coli and years is known to cause permanent renal scarring 105 isolates of Klebsiella pneumoniae. A total of 36 and thus a reliable indicator of urinary tract samples showed growth of a second organism. A infection is needed[ 2 ]. However, the concept of total of 23 strains (4.2%) of extended spectrum b- screening using rapid assays is controversial in 256 Predictive Value of Tests in Screening Urine Samples for Bacterial Culture September 2007
dipstick nitrite test indicates that these organisms Table 5: Isolates in bacterial culture (%) are present in significant numbers (i.e. more than Adults Pregnant Pediatric Neonates Total 10,000 per ml)[3]. This test is specific but not highly women cases sensitive[3]. The nitrite dipstick reagent is sensitive n n n n n (%) to air exposure, so containers should be closed Escherichia coli 229 71 232 18 550 (60.8) immediately after removing a strip. After one week Klebsiella pneumoniae 58 22 10 15 105 (11.6) of exposure, one third of these strips give false- Enterobacter spp. 7 3 8 0 18 (2.0) Pseudomonas aeruginosa 17 1 8 2 28 (3.1) positive results, and after two weeks, three fourths Enterococcus fecalis 11 3 13 3 30 (3.3) give false-positive results[4]. Non-nitrate-reducing Acinetobacter baumanii 9 2 0 0 11 (1.2) organisms also may cause false-negative results, Staphylococcus aureus 8 3 1 2 14 (1.5) and patients who consume a low-nitrate diet may Streptococcus agalactiae 29 37 6 0 72 (8.0) have false-negative results[4]. Both these reactions Others 39 13 22 3 77 (8.5) Total - (%) 407 (45) 155 (17.1) 300 (33.1) 43 (4.8) 905 require concentrated urine and an early morning urine specimen is well-suited to these tests. pregnant women. The American Family Physicians, Studies have investigated the efficacy of the [5-7] Canadian Task Force on Preventive Health Care dipstick LE test in detecting pyuria in adults . The and the National Health Services (NHS), UK do not sensitivity of the test ranges from 78.0 to 99.3% [8] recommend use of screening tests. On the other whereas the specificity ranges from 69.0 to 99.3% . hand, the American Academy of Pediatrics (AAP) Studies involving children have suggested that and the American College of Obstetrics and dipstick tests (the LE test with or without the nitrite Gynecologists (ACOG) strongly recommend use of test) are as accurate as microscopic examination in [9-11] screening assays for urinalysis in pregnant women. predicting bacteriuria . The accuracy of using the Detection of cases of pyuria helps to avoid dipstick LE test to detect pyuria in childre n , [11] extensive invasive diagnostic proc e d u r es. Micros c o p i c however, remains uncertain . examination of urine is the standard method used A negative dipstick test alone and a negative to detect pyuria. The dipstick test used widely as a microscopy alone have NPV of 95.8 and 96.8%, rapid measure of urinary leukocyte esterase (LE) re s p e c t i v e l y. This may be adequate in the activity is quick, inexpensive, and does not require asymptomatic older child, but in ill febrile children, technical expertise. This test is commonly used to the combined negative dipstick and microscopy, identify pyuria in accident and emerg e n c y which has a NPV of 98.1%, virtually excludes [ 1 2 ] departments and in out-patient clinics in which a urinary tract infection . A combination of a urine microscopy service is not available. Clinics negative dipstick test for nitrite and LE has shown which can avail the assistance of a well-equipped a NPV for UTI of 96.9% and a specificity of 98.7%. laboratory can utilize the service of complete In children less than a year old these values were [13] urinalysis than just depend on a two-parameter 96.7 and 99.2% respectively . Studies in adults dipstick. These laboratories would have facilities to have shown the sensitivity of the leucocyte esterase perform screening tests, bacterial culture and method with or without nitrite detection to be 75 to identification of microbes on mid-stream urine 90%, while nitrite alone had a sensitivity of 35 to [14] samples. It is important to note that the quality of 85% . We observed the sensitivity of leucocytes to urine specimens would determine the outcome of be 65% in adults which dropped down to 49.2% in such testing. It is hence ideal to have an early combination with nitrite, whereas nitrite alone has morning mid-stream urine specimen submitted in a shown a low sensitivity (Table 4). Nitrite detection, sterile container. Single use sterile urine bags are in our study has shown a reasonably good PPV, employed for collecting urine samples for neonates NPV and a good specificity. However, 70.5% of o and infants. Urine samples are stored at 4 C in case adult samples and 85% of pediatric samples they are not tested at the earliest, to avoid false showed false negativity to nitrite alone. The false positive test results. positives in the same groups were 25.9 and 17% The LE test detects esterases released fro m re s p e c t i v e l y. False-positive and false-negative [15] degraded white blood cells (WBCs). It is therefore, results are not unusual in dipstick urinalysis . [14] an indirect measure of WBCs whose presence is Patel et al found that a NPV of 98% and a induced by urinary bacteria. The nitrite test detects sensitivity of 98.3% with a specificity of 19.2% were nitrites produced by urinary bacteria - usually observed with leucocytes, protein, erythrocytes and limited to Gram-negative organisms. Nitrites nitrite taken together. We report a NPV of 87% in normally are not found in urine but result when adults, 82.7% in pregnant women, 74.5% in bacteria reduce urinary nitrates to nitrites. Many pediatric cases and 75.4% in neonates for the same Gram-negative and some Gram-positive organisms combination. The sensitivity was observed to be a re capable of this conversion, and a positive 15.1% in adults and 17% in pregnant women, but September 2007 KUWAIT MEDICAL JOURNAL 257 very low in the other two categories. However, the findings reported by the Belgian study[18]. It is a specificity was high in all the four groups (Table 4) wasteful exercise to culture all urine samples and this is an indication that this combination could without screening for presence of infection. be used for exclusion of UTI. The pH and nitrite combination showed a PPV Use of the screening parameters in children has of 100% with a specificity of 100% in all the study been shown to have a PPV of 69.4%, an NPV of groups except among pregnant women. Prompt 98.6%, and a sensitivity of 97.1% and specificity of institution of empirical therapy in patients with a 82.5%[16]. The same study had also evaluated a positive urine screen result for both pH and nitrite commercial catalase test as a screening procedure would therefore mean earlier remission rates and a and reported it to have a high rate of false-positive reduction in the incidence of complications. Follow results. The NPV of all the five parameters together up of culture results in these cases can help in our study was 87% in adults, 82.7% in pregnant document a cure or change the therapeutic regimen women, 74.5% in pediatrics and 75.4% in neonates. if indicated. However, the PPV has been seen to be undeter- Screening of pregnant women for asymptomatic minable since no culture positive sample has had bacteriuria by an enzymatic urine-screening test all the five parameters in the positive range. It is has been reported to have 100% sensitivity and a suggested to use the combination of all the five NPV of 100%[19]. However, the authors conclude more for exclusion of UTI than for inclusion. We that the UriscreenTM used in the study could not report a NPV of 87% with a specificity of 99.5% and replace the urine culture, but say that a policy a false negativity of 65% among adult samples change of performing cultures in samples with a when the combination of leucocyte esterase, nitrite positive test could save 80% of unnecessary and protein is considered. The NPV of the same cultures[20]. In our study, the NPV of the screening combination in pediatric cases was 75.5% with a parameters except for leucocytes, taken singly or in specificity of 100%. A study reported from France combination in samples from pregnant women was showed the predictive value of negative test (NPV) 82.7% with a high specificity (Table 4). Even for the above combination to be 99.4% with no [17] though, as a policy, we culture all the urine samples difference between boys and girls . We have not from pregnant women, the overall positivity rate in seen any difference of NPV or specificity between our study was 27.3% with Streptococcus agalactiae both the sexes in pediatric cases. being the second commonest isolate (23.8% of Dipstick testing has been found to be no better positives). This probably reflects genital colonization. than urine microscopy and both techniques have Abalos[21] in a review of screening tests for pregnant only modest sensitivities and specificities (around women concludes that although combined tests 80%) when compared to quantitative culture[2]. One seem to be quite promising in detection of consistent result reported in most studies is the bacteriuria in asymptomatic patients there is high negative predictive value (> 95%). This may insufficient evidence to reassure clinicians that a reflect the low prevalence of UTIs (4 -14.8%) in negative result is a truly negative one. Our results these studies (which included some symptomatic individuals). In the asymptomatic population it is in samples from pregnant women also suggest the likely that the negative predictive value would same conclusions. A total of 28 samples (4.9%) exceed 99% for both sexes [ 2 ]. A high negative which had a negative screen showed significant predictive value is extremely useful as it helps to bacteriuria while 197 samples (34.7%) had a decide which urine samples to culture and which to positive screen but showed no growth. The practice discard. We have also encountered high NPVs for of mandatory cultures of urine samples fro m most of the parameters and their various pregnant women may be justified in the light of combinations in all the age groups analyzed. inconclusiveness of the screening parameters. [ 2 2 ] H o w e v e r, dipstick analysis also has been A study done in the UK reports that an reported to be disappointing for scre e n i n g additional 1.7% samples that were negative by hospitalized patients, in a study reported from screening were positive for bacteriuria in culture. In Belgium. This study reported a false negative rate our study, 54 (13.5%) of the 400 urine samples of 77% and a false positive rate of 6% when both LE requested for routine examination were positive by and nitrite were combined[18]. We have also noted a c u l t u re after having been processed following high rate of false negatives when both leucocytes inclusion criteria fulfillment. Using the screening and nitrite were considered together, in adults criteria set by our laboratory (Table 1), a total of (76.6%), among pediatric cases (75%) or in neonates 1371 samples were not processed for culture over (97%). The false positive rate was 20% in adults, the period of three months, saving approximately 6.2% in pediatrics and 0% in neonates for the same an amount of US $ 20,565, averaging about US $ combination. This appears to be consistent with 6800 per month. 258 Predictive Value of Tests in Screening Urine Samples for Bacterial Culture September 2007
However, the 400 samples that were processed Am J Emer Med 1990; 8:121-123. for culture following urinalysis in the period of 5. Gillenwater JY. Detection of urinary leukocytes by chemstrip-1. J Urol 1981; 25:383-384. study yielded 54 extra culture positives and 6. Kusumi RK, Grover PJ, Kunin CM. Rapid detection of contributed to detection of UTIs. Among these, pyuria by leukocyte esterase activity. JAMA1981; 245:1653- 13.1% were adult cases, 17.07% pediatric and 12.5% 1655. neonate urine samples that showed inclusion 7. Herlihy RE, Wilkerson R, Roy JB. New and rapid method criteria by urinalysis. The overall 13.5% extra for detection of pyuria by leukocyte esterase reaction. Urology 1984; 23:148-149. positives detected by culture, which would 8. Kiel DP, Moskowitz MA. The urinalysis: A c r i t i c a l otherwise have been missed have helped make an appraisal. Med Clin North Am 1987; 71:607-624. additional impact on patient care, more so in 9. Goldsmith BM, Campos JM. Comparison of urine dipstick, pediatrics. This can be considered good justification microscopy, and culture for the detection of bacteriuria in for screening urine samples prior to bacterial children. Clin Pediatr 1990; 29:214-218. 10. Shaw KN, Hexter D, McGowan KL, Schwatz JS. Clinical culture, in terms of the clinical impact that can be evaluation of a rapid screening test for urinary tract achieved. infection in children. J Pediatr 1991; 118:733-736. 11. Weinberg AG, Gan VN. Urine screen for bacteriuria in CONCLUSION symptomatic pediatric outpatients. Pediatr Infect Dis J Screening urine samples is a necessary step in 1991; 10:651-654. 12. Anad FY. A simple method for selecting urine samples that the laboratory diagnosis of UTI. A combination of need culturing. Ann Saudi Med 2001; 21:104-105. leucocyte esterase and nitrite test along with either 13. Sharief N, Hameed M, Petts D. Use of rapid dipstick tests protein positivity or an alkaline pH has been found to exclude urinary tract infection in children. Br J Biomed to have both high specificity and high NPV and Sci 1988; 55:242-246. could hence be a valuable indicator for exclusion 14. Fihn SD, McGee SR. Outpatient medicine. Philadelphia, Pa, Saunders, 1992. diagnosis of UTI in all age groups excluding 15. Simerville JA, Maxted WC and Pahira NJ. Urinalysis: A pregnant women. A urine screen positive for both Comprehensive Review. Am Fam Physician 2005; 71:1153- alkaline pH and nitrite could be a good guideline 1162. for instituting empirical therapy in all age groups 16. Waisman Y, Zerem E, Amir Land Mimouni M. The Validity except pregnant women. The inconclusiveness of of the Uriscreen Test for Early Detection of Urinary Tract Infection in Children. Pediatrics 1999; 104:41. urine screening justifies mandatory cultures for 17. Lejeune B, Baron R, Guillois B, and Mayeux D. Evaluation samples from pregnant women. Urine samples that of a screening test for detecting urinary tract infection in do not fit into inclusion criteria after analysis can be newborns and infants. J Clin Pathol 1991; 44:1029-1030. excluded from being cultured to save valuable 18. Zaman Z, Borremans A, Verhaegen J, Verbist L, Blankaert resources, time and money. N. Disappointing dipstick screening for urinary tract infection in hospital inpatients. J Clin Pathol 1998; 51:471- 472. REFERENCES 19. Gartlehner G, Kahwati L, Lux L, West S. Screening for asymptomatic bacteriuria: A brief evidence update for the 1. Forbes BA, Sahm DF, Weissfeld AS. Bailey & Scott’s US Preventive Services Task Force. AHRQ 2004; Publication Diagnostic Microbiology. St. Louis, Mosby, 1998; 354-361. No. 05-0551-B. 2. Smith MBH. Screening for urinary infection in 20. Hagay Z, Levy R, Miskin A, Milman D, Sharabi H, Insler V, asymptomatic infants and children. In: Canadian Ta s k Uriscreen, a rapid enzyme screening test: Useful predictor Force on the Periodic Health Examination. Canadian Guide of significant bacteriuria in pregnancy. Obstet Gynecol to Clinical Preventive Health Care. Ottawa: Health Canada, 1996; 87:410-413. 1994. p 220-230. 21. Abalos EJ. Review of two rapid screening tests for 3. Pels RJ, Bor DH, Woolhandler S, Himmelstein DU, asymptomatic bacteriuria during pregnancy. 2003. Geneva La w r ence RS. Dipstick urinalysis screening of asymptomatic Foundation for Medical Education and Researc h . adults for urinary tract disorders. II. Bacteriuria. JAMA www.gfmer.ch 1989; 262:1221-1224. 22. Patel HD, Livsey SA, Swann RA, Bukhari SS. Can urine 4. Gallagher EJ, Schwartz E, Weinstein RS. Performance dipstick testing for urinary tract infection at point of care characteristics of urine dipsticks stored in open containers. reduce laboratory workload? J Clin Path 2005; 58:951-954. September 2007 KUWAIT MEDICAL JOURNAL
Original Article Comparison of Human T- cell Leukemia Virus Type-1 (HTLV-1) Seroprevalence in High Risk Patients (Thalassemia and Hemodialysis) and Healthy Individuals from Charmahal - Bakhtiari Province, Iran
Ali Karimi, Mohamed-Reza Nafici, Reza Imani Cellular and Molecular Research Center, Shahre-Kord University of Medical Sciences, Shahre-Kord, Iran
Kuwait Medical Journal 2007, 39 (3): 259-261 ABSTRACT Objective: To comapare the seroprevalence of Human T- Results: The ELISA results showed that 27 out of 357 lymphotropic virus type 1 (HTLV-1) in high risk group (7.6%) samples from the the case and five out of 800 patients (such as those with thalassemia or those who are (0.62%) from the control group tested positive for HTLV- on hemodialysis) with normal healthy individuals. 1 specific antibody. The Western blotting results showed Design: Prospective study that 24 of 27 (89%) ELISA-positive samples from the case Setting: Charmahal - Baktiari province, Iran. and five out of 800 (0.62%) from the test group were Subjects: A total of 357 serum samples from the patients HTLV-1. The mean age of the patients in the two groups (case) and 800 from the healthy individuals (control) was almost the same. were tested for HTLV specific antibody. Conclusion(s): The seroprevalence of HTLV-1 among I n t e r v e n t i o n s : Enzyme linked immunosorbent assay both the high risk patients and the healthy individuals (ELISA). All ELISA positive samples were assayed by from this province was significantly high and was almost Western blotting analysis. The individuals in the two similar to that in another endemic region in the country. groups were both age and sex matched (p > 0.05). Therefore, this province may be considered an endemic Main Outcome Measures: Seroprevalence of HTLV-1 area for this virus in Iran.
KEYWORDS: ELISA, HTLV-1, thalassemia, Western blotting
INTRODUCTION concentrates appear not to cause infection[ 8 , 9 ]. Human T-lymphotropic virus type 1 (HTLV-1) is Although this virus is distributed worldwide it is a retrovirus which was first identified in humans in endemic in certain parts of the world such as 1980[1] and then in 1982[2]. It causes two distinct southwestern Japan, the Caribbean basin, Africa, human diseases, adult T-cell leukemia or lymphoma[3 ] part of South America, southern Italy, Taiwan, and and a chronic, progressive demyelinating disorder the United States[10]. In Iran, the first case of adult-T- known as HTLV-1-associated myelopathy/tropical cell leukemia (ALT) was reported in 1986[11] and spastic parapares i s [4 ] . Like human immunodeficiency subsequently Mashhad has been recognized as an virus (HIV), infection with HTLV 1 and 2 are endemic area for HTLV-1 infection[12-14]. persistent retroviral infections and are life-long. Patients with thalassaemia and those on Less than 5% of those infected progress to one of th e hemodialysis are at high risk for HTLV-1 infection HT L V-r elated diseases, but these are debilitating due to their need for repeated blood transfusion[15- with few treatment options and a poor prognosis 1 9 ]. It was reported that 1.25% and 1.6% of and they are often fatal [5]. thalassemic patients in Shiraz[20] and Zahedan[21], The virus is transmitted through breastfeeding, respectively were seropositive for HTLV- 1 sexual contact, blood transfusion and contaminated infection. Another study in Shiraz indicated the needles among drug abusers. Tr a n s p l a c e n t a l high prevalence of this virus (25.6%) among transmission is also suspected[6,7]. Cellular blood thalassemic patients[22]. p roducts are the main source of transfusion- This might suggest that this virus could be associated HTLV transmission, whereas fresh froz e n present in other areas of Iran and Mashhad may not plasma, cryoprecipitate, or coagulation factor be the only city in this country where HTLV
Address correspondence to: Dr. Ali Karimi, Ph. D, Department of Microbiology and Immunology, Faculty of Medicine, Shahre-Kord University of Medical Sciences, Shahre- Kord, Iran. Tel: (#98-381) 333 4691, Fax. (#98-381) 333 4911, E-mail: [email protected] 260 Comparison of Human T- cell Leukemia Virus Type-1 (HTLV-1) Seroprevalence in High Risk...September 2007 infection is endemic. Therefore, this study was antibody. Subsequently, the Western blotting results conducted to determine seroprevalence of HTLV-1 showed that of 27 ELISA positive samples, 24 in both thalassemic and hemodialysis patients and (6.8%) were HTLV-1 and three (0.9%) were not compare it with that in healthy individuals from a confirmed. central province of Iran (Charmahal-Baktiari). Seroprevalences of HTLV-1 in healthy individuals SUBJECTS AND METHODS A total of 800 serum samples from the healthy Subjects: Three hundred and fifty-seven serum individuals (control) were tested for HTLV- 1 samples from both thalassemics and hemodialysis specific antibody. In the primary screening, five of patients (case) and 800 healthy blood donors the 800 (0.62%) samples tested positive by ELISA. (control) were tested for HTLV specific antibody Almost all of the five positive samples were f rom 2005 to 2006. The patients comprised of confirmed using Western blotting (only one of them almost all the hemodialysis and thalasemics was suspect). exsisting in this province. The individuals in both groups were well matched as regards age and DISCUSSION gender. As the HTLV-1 infection is a chronic and u n t reatable disease, the adequate standards of Serological assays: Serum samples were screened diagnosis, prevention, care and support as well as for HTLV-1 specific antibodies using enzyme- surveillance should be provided[12]. This infection is linked immunosorbent assay (ELISA; Vironostika endemic in certain parts of the world [5] as well as in HTLV I/II, Organon Teknica). All of the ELISA the northern city of Mashhad in Iran[ 6 - 8 ]. Both positive samples were confirmed by We s t e r n thalassemic and hemodialysis patients, who are blotting analysis (WB; HTLV blot 204 kit; Gene Lab blood transfusion dependent are at high risk of Diagnostic, Ltd). acquiring this infection[15,16]. In Iran, there is some evidence suggesting a relatively high prevalence of Demographic data: A q u e s t i o n n a i re including this virus in these patients[20,21]. This case-control questions about socio-demographic status, history study was conducted to provide some of disease and the number of transfusion received epidemiological data regarding the prevalence of was filled in by the patients. The data about sex and this virus. age of the individuals in the control group was Using ELISA, the overall sero p revalence of obtained using a similar questionnaire. H T LV in both thalassemic and haemodialysis patients (test) in our study was 7.6%. Based on the Statistical analysis: The data was analysed using T Western blotting confirmation, the vast majority of test and SPSS software (Chicago. Lt. Version 12 ). these samples (6.7%) tested positive for HTLV-1. This rate was greater than that shown in Tehran RESULTS (unpublished result), Shiraz[20], and Zahedan[21]. Our Demographic analysis of individuals in both the results also showed that 6.2% of healthy test and the control groups: individuals from the control group were HTLV-1 A total of 1157 serum samples from both the case positive. This prevalence was almost similar to that (thalassemics and hemodialysis patients) and reported from another endemic region in this co n t r ol (healthy individuals) were tested for HTLV-1 country, Mashhad[22]. Therefore, this region may be specific antibody. The percentage of females in the case and in the control group was 58% and 54%, an endemic area for this virus and perhaps this is respectively (p > 0.05). The age-range and their the best explanation for higher seroprevalence of percentage in the case and control groups were well HTLV-1 among the high risk patients in this region. matched (p > 0.05) and included people from 0-10 Surprisingly, in another study in Shiraz, 25.6% to 81-90 years old. of thalassemic patients were seropositive for anti- HTLV-1 antibody [23]. Although this finding is much Seroprevalence of HTLV-1 in both thalasemic and higher than that found in our study, it does confirm hemodialysis patients our results. Also, these two findings are consistent A total of 357 serum samples from both with the suggestion that following transfusion, the thalassemics and hemodialysis patients (case) were anti-HTLV-1 antibody titer might increase in both [17,18,23] tested for HTLV-1 specific antibody during March thalassemic and hemodialysis patients . to October 2005. In the primary screening, 27 of 357 Western blotting is also used to distinguish (7.6%) samples tested positive by ELISA. Eighteen HTLV-1 from HTLV-2[22]. Based on the Mashhad out of 250 (7.2%) thalassemic and nine out of 107 report, we used the same methods and 4.82% of (8.4%) hemodialysis patients were positive for the H T LV detected by ELISA w e re HTLV-2. Our September 2007 KUWAIT MEDICAL JOURNAL 261
Western blotting results did not show any HTLV-2. molecular survey for HTLV-1 infection in a high-risk Based on our results, the prevalence of this virus Middle Eastern group. Lancet 1990; 336:1533-1535. [15-19] 11. Tabei SZ, Rajabian R, Shirdel H, et al. Adult T- c e l l is higher than that in some other countries . leukemia/lymphoma in the northern province of Iran. Iran However, our findings are in agreement with the J Med Sci 1986; 13:85-86. overall prevalance of this virus (10%) in endemic 12. Dougan S, Payne LJ, Tosswill JH, Davison K, Evans BG. areas[15,16,22]. The results of a seroprevalence study on HTLV infection in England and Wales in-results from an serum samples from 20 different largest cities of enhanced national surveillance system. Commun Dis Public Health 2004; 7:207-211. Iran indicated that some areas of this country and 13. Farid R, Poryamoth N, Godarzi A, et al. A f a m i l i a l [22,24] particularly, Mashhad is an endemic region . s e roepidemiological survey of HTLV-1 in Mashhad, In conclusion, all evidence suggests that in Northeastern Iran suggested an important mother to child addition to Mashhad, this virus might be endemic transmision. J AIDS Hum Retrovirol 1995; 10:209-212. in other parts of Iran. Also, the results of our study 14. Farid R, Etemadi MM, Baradaran H, et al. Screening sera f rom adult populations of Mashhad and Gonbad for support the hypothesis that this province is another antibodies to HTLV-1. Med J Islamic Rep Iran 1992; 6: 85-86. endemic region for the virus infection. 15. Hathirat P, Iamslip W, Chiewsilp P. HTLV-I antibody screening in donated blood and thalassemic patients. J Med REFERENCES Assoc Thai 1993; 2:103-105. 16. Boturao NE, Covas DT, Zago MA. The frequency of blood- 1. Poiesz BJ, Ruscetti FW, Gazdar AF, et al. Detection and born viral infections in a population of multi-transfused isolation of type c retrovirus particles from fresh and Brazilian patients. Rev Inst Med Trop Sao Paulo 1993; cultured lymphocytes of a patient with cutaneous T-cell 35:271-273. lymphoma. Proc Natl Acad Sci 1980; 77:7415-7419. 17. de Montalembert M, Costagliola DG, Lefre re JJ, et al. 2. Kalyanaraman VS, Sarngadharan MG, Poiesz B, et al. Prevalence of markers for human immunodeficiency virus Immunological properties of a type C retrovirus isolated types 1 and 2, human T- l y m p h o t ropic virus type I, from cultured human T-lymphoma cells and comparison to cytomegalovirus, and hepatitis B and C virus in multiple other mammalian retroviruses. J Virol 1981; 38:906-915. transfused thalassemia patients. The French Study Group 3. Blattner WA, Takatsuki K, Gallo RC. Human T- c e l l On Thalassaemia. Transfusion 1992; 32:509-512. leukemia-lymphoma virus and adult T-cell leukemia. 18. Agliano AM, Vania A, Gandini O, et al. Post-transfusional JAMA1983; 250:1074-1080. human retrovirus infection in 41 Italian beta-thalassemic 4. Gessain A, Barin F, Vernant JC, et al. Antibodies to human patients. Haematologica 1992; 77:54-59. T- l y m p h o t ropic virus type-1 in patients with tro p i c a l 19. Prati D, Capelli C, Rebulla P, et al. The current risk of spastic paraparesis. Lancet 1985; 2:407-410. retroviral infections transmitted by transfusion in patients 5. Payne LJ, Tosswill JH, Taylor GP, Zuckerman M, Simms I. In who have undergone multiple transfusions. Cooleycare the shadow of HIV-HTLV infection in England and Wales, Cooperative Group. Arch Intern Med 1998; 27:1566-1569. 1987-2001. Commun Dis Public Health 2004; 7:200-206. 20. Sotuodeh M, Tabei SZ. Detection of Human T-cell leukemia 6. Monplaisir N, Neisson-vernant C, Bouillot M et al. HTLV-1 virus carriers in thalassemia patients in Shiraz. Irn J Med Sci maternal transmission in Martinique using serology and 1994; 29:4-12. polymerase chain reaction. AIDS Res Hum Retrovir 1993; 21. Moradi A. Seroepidemiology of HTLV-1 in thalassemia 9:869-874. patients from both Zahedan and Zabol in 1380. The Scient J 7. Murphy EL, Figueroa JP, Gibbs WN, et al. Sexual Zanjan Uni Med Sci 2004; 43:43-47. transmission of human T-lymphotropic virus type I (HTLV- 22. Abbaszadegan MR, Gholamin M, Tabatabaee A, et al. 1). Ann Intern Med 1989; 111:555-560. Prevalence of human T-lymphotropic virus type 1 among 8. Hjelle BR, Mills G, Mertz G, Swenson S. Transmission of blood donors from Mashhad, Iran. J Clin Microbiol 2003; HTLV-1 via blood transfusion. Vox Sang 1990; 59:119-122. 41:2593-595. 9. Okochi KH, Hinuma Y. Aret r ospective study on transmission 23. Ghaderi AA, Habib-Agahi M. High prevalence of anti-HCV of adult T-cell leukemia virus by blood transfusion: and HTLV-1 antibodies in Thalassemia major patients of seroconversion in recipients. Vox Sang 1984; 46:245-253. southern Iran. Irn J Med Sci 1996; 21:62-64. 10. Meytes D, Schochat B. Lee H, et al. Serological and 24. Rezvan H, Ahmad J, Farhadi M. A cluster of HTLV-1 infection in northeastern of Iran. Transfusion Today 1996; 27:8-9. KUWAIT MEDICAL JOURNAL September 2007
Original Article Hematological Changes in Malaria: Relation to Plasmodium Species
Khaled Taha1,2, Soheir Zein El-Dein1,2, Majid Idrees2, Gamal Makboul1, Ghassan Baidas3 1Faculty of Medicine, Alexandria University, Egypt 2Infectious Diseases Hospital, Kuwait 3Department of Internal Medicine, Sabah Hospital, Kuwait
Kuwait Medical Journal 2007, 39 (3): 262-267 ABSTRACT Objective: To evaluate different hematological changes blood picture (red and white blood cells, platelets, and in patients with malaria and to establish a possible role of reticulocytes) was studied in all patients. Plasmodium species in the pathogenesis of these changes. Results: Anemia and thrombocytopenia were the two Design: Hematological changes were prospectively studied most important hematological abnormalities seen in in randomly selected patients, immediately on admission cases of acute malaria infection. The degree of anemia and on a daily basis after starting anti-malarial trea t m e n t . was related more to P. falciparum infection, while, Setting: Infectious Diseases Hospital, Kuwait, during the thrombocytopenia was associated with P. vivax infection year 2004. and mixed infections. Hematological changes were mild Subjects: The study enrolled 103 patients with malaria, in the first 24 hours, but continued to deteriorate for few (37 infected with Plasmodium falciparum, 34 infected with days after anti-malarial therapy. One P. falciparu m Plasmodium vivax, and 32 infected with both species i.e., infection was associated with severe hematologic mixed infections). abnormalities, disseminated intravascular coagulopathy Intervention: Antimalarial drugs (DIC), and acute respiratory distress syndrome (ARDS). Main Outcome Measures: Beside history taking, clinical Conclusion: We recommend that subsequent checkup of examination, and routine laboratory work, thick and thin blood cells and platelets are of utmost importance blood films were pre p a red and examined from all particularly in cases infected with P. falciparum or mixed patients for defining the species involved. In addition, infections.
KEY WORDS: fibrinogen degradation products, hemoglobin, malaria parasite, platelets, red blood cells, white blood cells
INTRODUCTION drugs and occurrence of systemic complications[3]. Malaria continues to be a great health problem Most of the systemic complications from malaria in some of the most populated areas of the world. results from hyperparasitemia. Mortality is very The infection rate for the world population is 250 high (10-30%) in complicated P. falciparum in f e c t i o n . million per year and the mortality rate is 1-2 Hematologic changes are the most common million per year[1]. Kuwait is considered as a non- complications encountered in malaria and play a endemic area for malaria. Imported malaria in major role in the fatality[ 3 ]. Prediction of the Kuwait originated from several endemic countries, hematological changes enables the clinician to from where large number of workers migrated to establish an effective and early therapeutic Kuwait. These workers came to Kuwait seeking intervention in order to prevent the occurrence of jobs following the great development of the local major complications. The aim of our study was to economy which requires a large number of skilled investigate the diffe r ent hematological changes in workers in diff e rent fields. However, it was patients with malaria and to define the possible reported by the Ministry of Health in Kuwait that role of Plasmodium species in the pathogenesis of the number of imported malaria cases is decreasing these changes. because the immigrant workers are now screened for the disease in their home countries before SUBJECTS AND METHODS coming to Kuwait [2]. One hundred and three patients infected with To d a y, the most important problem in the malaria and admitted to the Infectious Diseases management of malaria is drug resistance of Hospital (IDH), Kuwait, during the year 2004 were Plasmodium falciparum to the various antimalarial randomly selected and prospectively studied. It
Address correspondence to: Dr. Khaled Taha, Consultant Physician, Infectious Disease Hospital, Kuwait. Tel: 9519936, Fax: 4871816, E-mail: [email protected] September 2007 KUWAIT MEDICAL JOURNAL 263 included 37 patients infected with P. falciparum, 34 and standard deviation (S). The arithmetic mean patients with P. vivax and 32 patients infected with (X) was used as a measure of central tendency, both species, i.e., mixed infections. Infection with while the standard deviation (S) was used as a Plasmodium species was diagnosed after repeated measure of dispersion. examinations of blood films in the parasitology The following statistical tests were used: laboratory of IDH. Patients who were not l Independent samples t-test was used as a diagnosed in the IDH laboratory, and those who parametric test of significance for comparison w e re not followed up according to the study between two sample means, after performing the protocol were excluded from the study. Levene’s test for equality of variances. l The Fisher’s exact test was used as a non- All patients were subjected to: parametric test of significance for comparison l T h o rough history taking with a special between the distribution of two qualitative attention to history of previous malaria infection variables whenever the c2 -test was not and travel to an endemic area. appropriate. This gives a p-value directly. l Complete physical examination. A 5% level was chosen as the level of l Examination of blood film for Plasmodium significance in all statistical tests. species: venous blood, collected in EDTA tube, was sent to the parasitology laboratory of IDH, Kuwait. RESULTS This laboratory provides 24 hours service for the This study included 103 patients infected with diagnosis of malaria. The species of Plasmodium malaria. Seventy-seven were male (74.8%) and 26 was diagnosed by microscopy of 10% Giemsa- were female (25.2%). Their ages ranged from 18 to stained thick and thin blood films[4]. Slides were 55 years with a mean of 33.2 ± 8.3 (Table 1). examined at least twice to record the species of the plasmodium parasite. Table 1: Some demographic data l Hematologic investigations: complete blood picture (white and red blood cell count, hematocrit, Falciparum Vivax Mixed Total p-value hemoglobin and red blood cell indices) and malaria malaria malaria n = 37 n = 34 n = 32 n = 103 coagulation profile were done immediately on admission. Blood cells, hematocrit, hemoglobin, Age (years) 30.9 ±7.6 33.97±7.9 34.9 ±9.1 33.2 ±8.3 0.099 platelet count and blood film were checked on a Mean ± SD daily basis after anti-malarial therapy until no Sex: n (%) evidence of active infection was found as indicated Male 30 (81) 20 (58.8) 27 (84.4) 77 (74.8) 0.019* Female 7 (19) 14 (41.2) 5 (15.6) 26 (25.2) by the absence of schizont or ring stages from the +ve travel 16 (43.2) 21 (61.8) 14 (43.7) 51 (49.5) 0.169 blood films. Cases with active infection by fifth day Previous were followed at day seven and 14. infection 7 (18.9) 3 (8.8) 4 (12.5) 14 (13.6) 0.413
l Complete biochemical check up including ren a l *: significant at level of p < 0.05 and hepatic functions tests and serum electrolytes. Nationality-wise, there were 71 (68.9%) Indians, 20 Statistical analysis: (19.4%) Pakistanis, six Africans (5.8%), thre e Data were collected and coded then entered into Kuwaitis (2.9%), two Afghanistan and one patient an IBM compatible computer using the SPSS from Bangladesh (Fig. 1). Past history of travel to version 12 for Windows. Qualitative variables were endemic areas was encountered in 51 patients e x p ressed as number and percentage while (49.5%, Table 1). Fourteen patients (13.6%) had past quantitative variables were expressed as mean (X) history of malaria infection (Table 1). Most patients
Fig 1: Nationality of patients 264 Hematological Changes in Malaria: Relation to Plasmodium Species September 2007
Table 2: Some clinical data Table 3: Blood cells on admission and after 3-5 days treatment Falciparum Vivax Mixed Total p-value malaria malaria malaria On admission After treatment p-value n = 37 n = 34 n = 32 n = 103 Mean ± SD Mean ± SD n (%) n (%) n (%) n (%) RBCs x 1012/l 4.22 ± 0.84 3.98 ± 1.02 0.316 Symptoms: Hb (g/l) 120.57 ± 22.09 112.04 ± 20.17 0.425 Classic 27 (73) 33 (97.1) 27 (84.4) 87 (84.5) 0.016* Hematocrit 0.36 ± 0.07 0.31 ± 0.05 0.05* Other 10 (27)* 1 (2.9) 5 (15.6)* 16 (15.5) TWBC x 109/l 6.41 ± 2.67 7.21 ± 2.14 0.816 Splenomegaly 23 (62.2) 22 (64.7) 16 (50) 61 (59.2) 0.313 Platelet x 109/l 123.23 ± 91.29 129.54 ± 82.41 0.523 Hepatomegaly 11 (29.7) 9 (26.5) 11 (34.4) 31 (30.1) 0.806 Complications 1 (2.7) 0.00 0.00 1 (0.97) — * : significant at level of p < 0.05
*: significant at level of p < 0.05 significant difference between the studied groups of plasmodia. Blood indices including mean presented with classic malarial symptoms in the corpuscular volume (MCV), mean corpuscular form of fever, rigors and sweating (84.5%), while hemoglobin (MCH), and mean corpuscular 15.5% patients presented with other symptoms hemoglobin concentration (MCHC), showed such as jaundice, diarrhea, vomiting, and even normocytic normochromic RBCs. Reticulocyte shock (Table 2). percentage was within normal range with a mean Statistical analysis showed that the classic of 1.94 ± 1.01% (normal = 0.2 - 2.02%), and there malarial symptoms of fever, rigor and sweating was no significant difference between the groups. were significantly found in all groups of malaria. However, on repeating the blood picture 3-5 Meanwhile, the other symptoms were significantly days after starting the anti-malarial treatment, mild detected in patients with P. falciparum and mixed drop in the mean hematocrit values, RBC counts Plasmodium infection (Table 2, p = 0.016*). Clinical and hemoglobin levels was detected. Yet, these examination of the study cases showed that splenic changes were not statistically significant except for e n l a rgement was encountered in 61 (59.2%) the hematocrit value which showed a significant patients and hepatomegaly was seen in 31 (30.1%) difference (p = 0.05*, Table 3). patients. There was no significant difference in the oc c u r r ence of hepatomegaly or splenomegaly between Changes in the white blood cells (WBCs): patients with different malaria species (Table 2). At the time of diagnosis, total WBCs had a mean Moreover, one patient infected with P. falciparum count of 6.41 ± 2.67 x 109/l with no significant had developed acute respiratory distress syndrome difference between the different malaria species (ARDS) and shock and was immediately transferred (T able 4). The neutrophil percentage was significantly to the Intensive Care Unit (ICU) (Table 2). higher in patients infected with P. falciparum and Results of blood film examination for malaria mixed Plasmodium species (p = 0.01*). The mean species are shown in Table 1. Thirty seven patients lymphocyte percentage was within normal (25.6% (36%) had P. falciparum, 34 (33%) had P.vivax and 32 ± 13.33) with a significant lower value in mixed (31%) had mixed infection with P. vivax and P. infection. However, a significant relative monocytosis falciparum. No cases with P. ovale or P. malariae were was detected in patients infected with P. vivax as detected. All patients had active malaria as co m p a r ed to the other groups (p = 0.001*). Similarly, evidenced by presence of schizont and ring stages. the mean eosinophil percentage was normal in all Cases started to be inactive by the third day and groups. However, statistical comparison between most of them (96 patients, 93%) were rendered the groups demonstrated significantly low inactive by the fifth day after starting anti-malarial eosinophil percentages in patients infected with therapy. Other patients became inactive by day falciparum and mixed malaria (p = 0.037*, Table 4). seven after treatment. On repeating the blood picture 3-5 days after starting the anti-malarial treatment, there was a Changes in the red blood cells (RBCs): non-significant rise of the mean total WBC count, (p On admission, the total RBC count ranged = 0.816, Table 3). between 1.9 - 5.6 x 1012/l (normal = 4 - 5.4) with a mean of 4.22 ± 0.84 x 1012/l. Hemoglobin level had Changes in the blood platelets: a mean value of 120.57 ± 22.09 g/l (normal = 120 - The mean platelet count in patients with 160) with no significant difference between the falciparum malaria was normal (168.8 ± 100.4 x groups of different malarial parasites. Packed cell 1 09/l), while the mean count in patients with volume (hematocrit value) was within normal malaria v i v a x showed mild thro m b o c y t o p e n i a range with a mean of 0.36 ± 0.07and there was no (107.06 ± 92.12 x 109/l), and it was lowest in cases September 2007 KUWAIT MEDICAL JOURNAL 265
Table 4: Changes in the white blood cells Table 6: Changes in blood coagulation
Falciparum Vivax Mixed Total p-value Falciparum Vivax Mixed Total p-value malaria malaria malaria malaria malaria malaria n = 37 n = 34 n = 32 n = 103 n = 37 n = 34 n = 32 n = 103 Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD
TWBCs x 109/l 6.51 ± 3.26 6.08 ± 2.26 6.64 ± 2.32 6.41 ± 2.67 0.664 PT (Sec) 12.83 ± 1.03 13.19 ± 0.87 13.65 ± 1.12 13.2 ± 1.06 0.005* Neutrophil % 60.00 ± 15.4 56.1 ± 14.8 67.6.1 ± 15.4 61.07 ± 15.8 0.010* INR 1.27 ± 0.10 1.31 ± 0.09 1.35 ± 0.13 1.31 ± 0.11 0.007* Lymphocyte % 28.2 ± 12.5 26.4 ± 13.8 21.6 ± 13.2 25.6 ± 13.3 0.001* APTT (Sec) 35.44 ± 1.41 35.53 ± 1.44 36.47 ± 2.29 35.79 ± 1.78 0.032* Monocyte% 8.3 ± 4.84 13.9 ± 5.39 9.75 ± 4.4 10.6 ± 5.41 0.001* FDPs : n (%) Eosinophil % 0.65 ± 0.62 3.24 ± 7.8 0.75 ± 1.12 1.615 ± 4.85 0.037* <500 (IU/L) 21 (58.3) 19 (55.9) 13 (39.4) 53 (51.5) NS Basophil % 0.28 ± 0.27 0.39 ± 0.23 0.23 ± 0.25 0.30 ± 0.26 0.023* 500-1000 (IU/L) 11 (30.6) 10 (29.4) 13 (39.4) 34 (33.0) NS >1000 (IU/L) 4 (11.1) 5 (14.7) 7 (21.2) 16 (15.5) NS *:significant at level of p < 0.05 TWBCs: total white blood cells * : significant at level of p < 0.05 NS : not significant.
Table 5: Changes in blood platelets (APTT) was significantly prolonged in patients with mixed malaria infections than those with Falciparum Vivax Mixed Total p-value single species infection (p = 0.032*). malaria malaria malaria n = 37 n = 34 n = 32 n = 103 M o re o v e r, fibrinogen degradation pro d u c t s (FDPs) were estimated to predict the development Platelet x 109/l 168.8 ±100.4 107.1 ± 92.1 87.7 ± 51.1 123.2 ± 91.3 0.001* of disseminated intravascular coagulopathy (DIC, Mean ± SD Table 6). Fifty three patients out of 103 had normal Platelet volume 8.04 ± 1.23 8.2 ± 1.04 8.81 ± 1.12 8.33 ± 1.17 0.016* FDPs levels (less than 500 IU/l), 34 patients had Mean ± SD (fL) FDPs between 500 - 1000 and 16 patients exceeded * : significant at level of p < 0.05 FDPs level of 1000 IU/l. There was no significant difference between the three groups of patients. with mixed infections (87.72 ± 51.14 x 109/l) (Table 5). Statistical analysis demonstrated a significant DISCUSSION lower mean platelet count in cases infected with The development of Kuwait economy, due to oil malaria vivax and mixed infections (p = 0.001*). revenues, has attracted a large labor force from The mean platelet volume was normal in all many malaria endemic countries such as India, groups. However, patients with mixed infections Pakistan, Srilanka, Bangladesh, A f g h a n i s t a n , showed a significantly bigger platelet volume (p = Philippines, and some African countries like Sudan, 0.016*, Table 5). Nigeria, and Borkina Faso [2]. Despite the presence of mild to moderate Malaria continues to be a great health problem d e g rees of thrombocytopenia, no cases had in some of the most populated areas of the world. hemorrhagic manifestations. On repeating platelet The global resurgence of malaria has also impacted examination 3-5 days after anti-malarial treatment, on Kuwait, a non-endemic country. Imported the mean platelet count started to rise and malaria continues to be a problem since most of the continued to increase slowly thereafter (Table 3). 60% of the resident population come from endemic Patients showed continuous improvement in all areas of Asia and Africa[5]. In contrast to previous blood elements with no evidence of active infection reports from Kuwait [ 6 , 7 ], mixed malaria was in their blood films when investigated on day 7 and relatively high among the studied malaria patients 14 post-treatment. admitted to IDH. Such finding might be explained by the fact that not all malaria cases in Kuwait are Changes in blood coagulation: re f e r red to the IDH. Asymptomatic cases are The mean prothrombin time of all the studied usually treated as outpatients and many single- g roups was within normal range but it was species malaria cases are treated in their local area significantly less in patients with P. falciparum hospitals. Moreover, many asymptomatic cases of infection when compared to the other groups (p = malaria were re f e r red from ports and bord e r s 0.005*) (Table 6). Similarly, international normalized health section and were treated as outpatients ratio (INR) ranged between 1.07 - 1.65 with a total without hospital admission. mean of 1.31 ± 0.11. Statistical analysis revealed a significant reduction of INR in patients with Red blood cells, hemoglobin, and packed cell falciparum malaria than those with mixed malaria (p volume: = 0.007*). The activated partial thromboplastin time On admission, our patients had mild reduction 266 Hematological Changes in Malaria: Relation to Plasmodium Species September 2007 in the red blood cells (RBCs), hemoglobin (Hb) seems to be due mainly to a reduced platelet life level and packed cell volume (PCV) with span and splenic pooling. The reduced platelet life normochromic normocytic features of the RBCs. span may be caused by binding of malaria antigen The reduction was more evident in f a l c i p a r u m onto platelets followed by antibody mediated infection. Moreover, these parameters fell after start phagocytosis[17] or to platelet activation in vivo[18]. of anti-malarial treatment and continued to fall Macrophage activation and hyperplasia especially slowly for some days. This drop was statistically in the spleen may also play a role[18]. The release of significant for PCV (Table 3). Our results coincides platelet contents can activate the coagulation with the previous report which stated that in cascade and contributes to DIC and consequently uncomplicated acute malaria the hemoglobin and further thrombocytopenia[19]. hematocrit (PCV) are usually normal during the The incidence of DIC is reported to be 4 - 13% first 24 hours after the onset of fever. The PCV and usually occurs in patients with P. falciparum continues to falls for some days after antimalarial infection and hyperparasitemia[1,3]. DIC was found therapy[8]. A community-based study of malaria in one of our patients with falciparum malaria which p revention in Ta n z a n i a[ 9 ] has confirmed that was complicated by ARDS, thro m b o c y t o p e n i a , f a l c i p a r u m malaria was an important cause of increased FDPs and prolonged prothrombin time. It childhood anemia with PCV falls comparable to our results. was reported that P. falciparum infection is associated with increased levels of plasminogen White blood cells: activator inhibitor, factor VIII, reduced levels of During the first day of admission, the mean p rotein C, protein S and anti-thrombin III. WBC and neutrophil counts were within normal Moreover, in severe complicated malaria there is range. However, neutrophil percentage was activation of coagulation cascade by release of significantly higher in mixed malaria infection various procoagulants due to lysis of platelets and while falciparum malaria showed a significantly RBCs, release of tissue factor from monocytes and higher lymphocyte percentage. There was no damaged endothelial cells, cytokines and [19] significant diff e rence in WBC and neutro p h i l microcirculatory stasis . counts before and after anti-malarial treatment. In conclusion, the pathophysiological processes P revious studies demonstrated an increase of causing the hematological changes in malaria are neutrophil count during the first two days of fever complex, multiple and incompletely understood. due to f a l c i p a r u m malaria and subsequent Anemia and thrombocytopenia were the two most decrease[10]. Similarly, mean lymphocyte percentage important hematological abnormalities seen in our was normal in our cases. However, other reports cases of acute malaria infection. The degree of showed lymphopenia in some cases of acute anemia was related more to P. falciparum infection, m a l a r i a[ 11 ] which is probably caused by a while, thrombocytopenia was associated with P. redistribution of lymphocytes with sequestration in vivax infection and mixed infection due to vivax and the spleen [ 1 2 ]. There was significantly lower falciparum species. Some P. falciparum infection may eosinophil percentage in our patients with be associated with severe hematologic abnormalities, falciparum and mixed malaria infections and this is DIC, and even ARDS. in agreement with previous studies which reported As the hematological changes in our patients eosinopenia in patients with acute P. falciparum were usually mild during the first 24 hours and infection[10,13]. continued to deteriorate for a few days after anti- During malaria infection, leukocyte activation is malarial therapy, we recommend that subsequent associated with release of cytokines like TNF, IL-1, blood count check should be performed especially IL-2, IL-6 and IFN which are involved in the in cases infected with P. falciparum or mixed pathogenesis of hematological abnormalities such infections. We also recommend that these as cyto-adherence, thrombocytopenia, DIC, hematological changes should be further studied in hypoglycemia and lactic acidosis[14,15]. relation to the level of parasitemia. More o v e r, similar multi-center studies should be carried out Platelet changes: all over Kuwait to define the prevalence pattern of A mild to moderate thrombocytopenia was all types of malaria infections. demonstrated in our patients who had P. vivax and mixed malaria infection. This is in agreement with ACKNOWLEDGEMENT previous studies which reported frequent incidence We thankfully acknowledge the technical of thrombocytopenia in acute malaria and usually support given by the hematology, biochemistry, unassociated with DIC[12,16]. This thrombocytopenia and parasitology laboratories of the IDH, Kuwait. September 2007 KUWAIT MEDICAL JOURNAL 267
REFERENCES 10. Abdalla SH. Peripheral blood and bone marrow leucocytes in Gambian children with malaria: numerical changes and 1. World Health Organization: Malaria situation in the world. evaluation of phagocytosis. Ann Trop Ped 1988; 8:250-258. World Health Organ Wkly Epidemiol Rec 1997; 36:269-276. 11. Lisse IM, Aaby P, Whittle H, Krudsen K. A community 2. Public Health A u t h o r i t y, Ministry of Health, Kuwait. study of T lymphocytes subsets and malaria parasitaemia. Kuwait Report 2000. Trans Roy Soc Trop Med Hyg 1994; 88:709-710. 3. Wickramasinghe SN, Abdalla SH. Blood and bone marrow 12. Kueh YK, Yeo KL. Hematological alterations in acute changes in malaria. Bailliere’s Clin Hematol. Harcourt Pub malaria. Scand J Haematol 1982; 29:147-152. Ltd; 2000; 13:277-299. 13. Davis TM, Ho M, Supanaranond W, Looareesuwan S, 4. Hira PR, Behbehani K. Acetone-fixed, Giemsa-stained thick Pukrittaya Kamee S, White NJ. Changes in the peripheral blood films for the diagnosis of malaria. Ann Trop Med blood eosinophil count in falciparum malaria. Acta Trop Parasitol 1984; 78:77-79. 1991; 48:243-246. 5. Iqbal J, Sher A, Hira PR. Malaria in non-endemic Kuwait: 14. Rockett K, Awburn M, Rockett E, Clark IA. TNF and IL-1 detection of very low level Plasmodiumfalciparum infections synergy in the context of malaria pathology. Am J Trop Med using polymerase chain reaction. Med Princ Pract 1998; Hyg 1994; 50:735-742. 7:277-282. 15. Beal PJ, Cormak JD, Oldery TBN. Thrombocytopenia in 6. Iqbal J, Sher A, Hira PR, Al-Anezi AA. Risk of introduction malaria with immunoglobulin (IgM) changes. Brit Med J of dru g - resistant malaria in a non-endemic country, 1972; 1:345-349. Kuwait: a real threat?. Med Principles Pract 2000; 9:125-130. 16. Kelton JG, Keystone J, Moore J, et al. Immune-mediated 7. Shweiki HM, Al-Harbi M, Sethi SK, West PWJ, Hira PR. thrombocytopenia of malaria. J Clin Invest 1983; 71:832-836. Status of imported malaria in Kuwait: experience from Al- 17. Essien EM, Ebhota MI. Platelet hypersensitivity in acute Jahra Hospital. Kuwait Medical Journal 2002; 34:201-204. malaria (Plasmodium falciparum) infection in man. 8. Pillips RE, Looareesuwan S, Wa r rell DA, et al. The Thrombosis and Haemostasis 1981; 46:547-549. importance of anemia in cerebral and uncomplicated 18. Horstmann RD, Dietrich M. Malaria-induced throm b o c y t o p e n i a . falciparum malaria: role of complications, dyserythropoiesis Annals of Hematol 1981; 42:157-164. and iron sequestration. Quarterly J Med 1986; 58:305-323. 19. Mohanty D, Ghosh K, Nandwani SK, et al. Fibrinolysis, 9. Shiff C, Checkley W, Winch P, Prenji Z, Minjas J, Lubeqa P. inhibitors of blood coagulation, and monocyte derived Changes in weight gain and anemia attributable to malaria coagulant activity in acute malaria. Am J Hematol 1997; in Tanzanian children living under holoendemic conditions. 54:23-29. Trans Roy Soc Trop Med Hyg 1996; 90:262-265. KUWAIT MEDICAL JOURNAL September 2007
Case Report A Complex Atheromatous Plaque of the Thoracic Aorta: The Role of Transesophageal Echocardiography
Muath Alanbaei1, Suzanne Morin2, Thao Huynh 1 1Division of Cardiology, McGill University, Montreal, Quebec, Canada 2Division of Internal Medicine, McGill University, Montreal, Quebec, Canada
Kuwait Medical Journal 2007, 39 (3): 268-270 ABSTRACT
L a rge mobile pro t ruding aortic arch atheromas are is reported. This finding led to a surgical resection of the s t rongly associated with strokes and other vascular diseased part of the aorta and graft replacement without events. Transesophageal echocardiography is the imaging complications. The case illustrates the utility of modality of choice for diagnosis and risk stratification. transesophageal echocardiography in defining the The optimal therapy is unclear. complexity of the atheromas. Surgery in selected patients A case of a large mobile aortic atheromatous plaque with is a reasonable option. recurrent systemic embolization in a 47-year-old female
KEYWORDS: aorta, atherosclerosis, echocardiography, embolism, plaque
INTRODUCTION computerized tomography (CT) scan of the Atherosclerosis of the aorta is a common disease abdomen revealed multiple hypodense lesions that may present in unusual ways. We report a case involving the spleen and both kidneys, particularly of a large protruding mobile atheromatous plaque the left one, consistent with multiple infarcts. A of the descending thoracic aorta with recurrent work up for vasculitis was negative. systemic embolization, and discuss the appropriate Two-dimensional transthoracic echocardiogram management. (TTE) was normal. CT angiogram of the chest and abdomen showed focal bulge at the pro x i m a l Case report portion of the descending aorta, suspicious of focal A 4 7 - y e a r-old female presented to our dissection with intimal flap. Magnetic resonance institution in 1998 with nausea, vomiting, diarrhea angiography (MRA) was done which showed and abdominal pain, for a few days prior to irregularity in the thoracic aorta, suggesting focal admission. She had diabetes mellitus and hypertension dissection or mobile atherosclerotic plaque. since five years. She was a heavy smoker (60 pack A transesophageal echocardiogram (TEE) was years). She also had a transient ischemic attack in performed. This showed a large mobile pedunculated 1997 with normal transthoracic echocard i o g r a m mass measuring 1.5 x 3 cm at the descending and carotid doppler. A month prior to admission, thoracic aorta, just after the arch distal to the she developed painful bluish discoloration of the subclavian artery, consistent with atherosclerotic right big toe, with spontaneous resolution. Her plaque (Fig. 1). symptoms on presentation were vague abdominal The patient was urgently operated upon with pain, nausea, vomiting, and watery diarrh e a , resection of the diseased part through a left without fever, chills or rigors. Physical examination p o s t e ro-lateral thoracotomy approach, with was normal apart from severe left costo-vertebral clamping of proximal descending thoracic aorta angle tenderness. between the left subclavian and left carotid artery. The laboratory data showed a leucocytosis at D i s t a l l y, the thoracic aorta was occluded few 22.5 x 10 9/l, thrombocytosis at 1240 x 109/l, normal centimeters above the diaphragm. A segment of 5 renal function, and a septic work up was negative. to 7 cm of atheromatous aorta containing a An abdominal ultrasound was normal. A pedunculated atheroma with a white thrombus
Address correspondence to: Dr. Muath Alanbaei, MD FRCP(C), Cardiology Division, McGill University Health Centre (MUHC), Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. Tel: (514) 934-1934, ext. (36151); Other Tel: (965) 2548418, Fax: (514) 843 2813, E-mail 1: [email protected]; E-mail 2: [email protected]; E-mail 3: [email protected] September 2007 KUWAIT MEDICAL JOURNAL 269
Fig. 1: Transesophageal echocardiography of the descending thoracic aorta showing the large pedunculated atheroma Fig. 2: Macroscopic picture of the large atheromatous plaque after resection. A: Significant thrombotic material on the atheromatous plaque
and Grade V is mobile atheroma[2]. Grade IV and V carry a risk of peripheral embolization that is almost fourfold the risk of Grade I lesions. F u r t h e r m o re, in patients undergoing coro n a r y artery bypass surgery; these lesions have been associated with increased stroke and mortality[3]. Atherosclerotic plaques ³ 4 mm thick in the aortic arch are significant predictors of recurrent brain infarction and other vascular events[4]. Complex atheromas carry higher risk of strokes than non- complex atheromas. The risk of ischemic stroke in elderly patients with arch atheromas is more
B: Resected part of the aorta with fatty streaks and ulcers strongly related to the complexity of the lesion than to its size [5]. was resected. The aorta was reconstructed with a Atherosclerotic lesions of the thoracic aorta may tubular Dacron graft 20 mm in diameter. The aortic ulcerate and penetrate the internal elastic lamina of occlusion time was 22 minutes. We inserted two the aortic wall. This can result in the formation of chest tubes in the left pleura and the chest wall was intramural hematoma, aneurysms, aortic dissection closed in the usual way. The macroscopic and or rupture. Penetrating atherosclerotic ulcers occur m i c roscopic examinations were consistent with most commonly in the descending thoracic aorta. atheromatous plaque of the aorta with significant Among patients with penetrating atherosclerotic thrombotic material (Fig. 2). ulcers who are not treated surgically, the majority The patient had an uneventful postoperative have prog r essive aortic enlargement, with formation course and was subsequently discharged fro m of saccular or fusiform pseudoaneurysms and hospital. Four years later, the patient is doing well intraluminal thrombus[6]. apart from intermittent claudication tre a t e d Different imaging modalities have been used to medically. assess athero s c l e rosis of the thoracic aorta. Transesophageal echocardiography is one of the DISCUSSION better available imaging tools to clearly define the Atherosclerosis of the aorta can be extensive plaques. It is superior to transthoracic echocardio- and form large complex plaques. These gram in visualizing the plaque’s size, site, and atherosclerotic plaques may embolize and be life complexity i.e., ulceration or mobile components[7]. t h reatening in rare cases. Moderate or severe It is also useful to assess the flow dynamics, and the atherosclerosis of the thoracic aorta can be detected aortic intima. The combination of aortic spontaneous by transesophageal echocardiography (TEE) in e c h o c a rdiographic contrast and any complex approximately 15-20% of patients ³ 50 years and in a t h e ro s c l e rosis has the highest risk of 33% of patients ³ 80 years[1]. Atheromas are graded embolization[8]. MRA has been used to examine I to V. Grade I is minimal intimal thickening, Grade atherosclerotic disease in the thoracic aorta. MRA II is extensive intimal thickening, Grade III is had been compared to TEE in the evaluation of the sessile atheroma, Grade IV is protruding atheroma thoracic aorta atherosclerosis. Both techniques are 270 A Complex Atheromatous Plaque of the Thoracic Aorta: The Role of Transesophageal... September 2007 complementary but TEE can identify more high- embolization. The role of anticoagulation and other risk plaques[9]. strategies to regress atheromatous plaque such as The optimal management of patients with aggressive lipid lowering and anti-platelet therapy protruding mobile Grade IV-V aortic atheroma is is unknown and needs to be evaluated still unclear. Anticoagulation appears to be a prospectively. reasonable treatment for patients whose atheromas have a mobile component, because these REFERENCES components have been shown to be thrombotic material[10] and have been reported to resolve with 1. Wareing TH, Davila-Roman VG, Daily BB, et al. Strategy for [11] [12] the reduction of stroke incidence in cardiac surg i c a l anticoagulation . In a study by Dressler et al , patients. Ann Thorac Surg 1993; 55:1400-1408. warfarin was found to be effective in preventing 2. Borner N, Erbel R, Braun B, et al. Diagnosis of aortic strokes in patients presenting with systemic emboli dissection by transesophageal echocard i o g r a p h y. Am J and mobile aortic atheroma on TEE. They Cardiol 1984; 54:1157-1158. suggested that anticoagulation is beneficial in the 3. Katz ES, Tunick PA, Rusinek H, Ribacove G, Spencer FC, Kronzon I. Protruding aortic atheromas predict stroke in presence of a mobile component of the atheroma elderly patients undergoing cardiopulmonary bypass: irrespective of its dimension. On the other hand, experience with intraoperative transesophageal systemic anticoagulation is not free of risk. In echocardiography. J Am Coll Cardiol 1992; 20:70-77. addition to the potential hemorrhagic complication 4. Amarenco P, Cohen A, Tzourio C. et al. Atherosclerotic of anticoagulation, bleeding into athero s c l e ro t i c disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474-1479. plaques with plaque ru p t u re and cholestero l 5. Di Tullio MR, Sacco RL, Savoia MT, Sciacca RR, Homma S. [ 1 3 ] embolization has been re p o r t e d . Successful Aortic atheroma morphology and the risk of ischemic thrombolysis has also been reported[14], but it is s t roke in a multiethnic population. Am Heart J 2000; theoretically possible that thrombolytic agents may 139:329-336. selectively lyse the stalk of pedunculated lesions 6. Harris JA, Bis KG, Glover JL, Bendick PJ, Shetty A, Brown OW. Penetrating atherosclerotic ulcers of the aorta. J Vasc and embolize the lesion in the systemic circulation. Surg 1994; 19:90-99. Aortic endarterectomy had been successfully 7. Kronzon I, Tunick PA. Atheromatous Disease of the thoracic performed in selected patients. Surgical removal of aorta: pathologic and clinical implications. Ann Intern Med the aortic arch atheromas may be considered in 1997; 126:629-637. patients with re c u r rent systemic embolization. 8. Finkelhor RS, Youssefi ME, Lamont WE, Bahler RC. Embolic risk based on aortic atherosclerotic morphologic Gandjbakhch et al suggested surgery under three f e a t u res and aortic spontaneous echocard i o g r a p h i c conditions. First, when the atheroma is larg e , contrast. Am Heart J 1999; 137:1088-1093. exuberant and stenotic; second, when the atheroma 9. Kutz SM, Lee VS, Tunick PA, Krinsky GA, Kronzon I. has been complicated by systemic embolism and A t h e romas of the thoracic aorta: A comparison of f i n a l l y, when there is a potential embolic risk, transesophageal echocardiography and bre a t h - h o l d gadolinium-enhanced 3-dimensional magnetic resonance especially neurological, during open-heart angiography. J Am Soc Echocardiogr 1999; 12:853-858. [15] surgery . 10. Tunick PA, Culliford AT, Lamparello PJ, Kronzon I. Atheromatosis of the aortic arch as an occult source of CONCLUSION multiple systemic emboli. Ann Intern Med 1991; 114:391- Thoracic aortic athero s c l e rosis is a common 392. 11. Bansal RC, Pauls GL, Shankel SW. Blue digit syndrome: cause of cerebral and peripheral embolization. transesophageal echocardiographic identification of P ro t ruding atheroma, intimal ulceration, and thoracic aortic plaque-related thrombi and successful superimposed mobile components are the most outcome with warfarin. J Am Soc Echocardiogr 1993; 6:319- important predictors of embolization of an 323. atheromatous plaque. 12. Dressler FA, Craig WR, Castello R. Labovitz AJ. Mobile aortic atheroma and systemic emboli: efficacy of Transesophageal echocardiography appears to anticoagulation and influence of plaque morphology on be the imaging modality of choice for the diagnosis. recurrent stroke. J Am Coll Cardiol 1998; 31:134-138. Early diagnosis and treatment of athero m a t o u s 13. Hollier LH, Kazmier FJ, Ochsner J, Bowen JC, Procter CD. plaques may prevent life-threatening embolic “Shaggy” aorta syndrome with atheromatous embolization complications. The optimal therapy remains to be to visceral vessels. Ann Vasc Surg 1991; 5:439-444. 14. Hausmann D, Gulba D, Bargheer K, Niedermeyer J, determined. However, surgery is a re a s o n a b l e Comess KA, Daniel WG. Successful thrombolysis of an alternative, but because of the increased risks, it a o r t i c - a rch thrombus in a patient after mesenteric should be reserved for patients with larg e , embolism. N Engl J Med 1992; 327:500-501. exuberant, obstructive plaques with high risk of 15. Gandjbakhch I, Jault F, Rama A. Should aortic atheromatous plaques be excised?. Arch Mal Coeur Vaiss 1997; 90:25-28. September 2007 KUWAIT MEDICAL JOURNAL
Case Report Adult Intussusception: A Radiological Approach
Margaret Linny Austin1, Venkatanarayana Ravi Hoisala1, Majid Ali Jamal 2 Departments of 1Radiology and 2Surgery, Jahra Hospital, Kuwait
Kuwait Medical Journal 2007, 39 (3): 271-274 ABSTRACT
Intussusception is defined as the telescoping of p resent the imaging findings and diagnosis by consecutive segments of bowel. While being relatively sonography and computed tomography (CT) of common in the pediatric population, intussusception is intussusception in a young adult male with ulcerative an unusual cause of small bowel obstruction in the adult colitis. The clinical findings were masked by the steroid group and is often due to an underlying lead point. We cover given for ulcerative colitis.
KEYWORDS: adult, imaging, intussusception
INTRODUCTION supply eventually causing ischemia. Hence early Bowel intussusception is described as the diagnosis is essential to prevent onset of infarction progressive invagination of one segment of bowel - and perforation[3]. the intussusceptum into an adjacent segment-the Small bowel intussusceptions are generally intussuscipiens. Intussusception is the commonest related to benign neoplasms including lipomas, cause after appendicitis, of acute abdomen in the leiomyomas, neurofibromas, hemangiomas; other pediatric age group between three months and benign causes include adhesions, Meckel’s three years[1]. It may present with the classic triad of diverticulum, lymphoid hyperplasia, and adenitis, severe colicky, abdominal pain, “red currant” jelly trauma, celiac disease, intestinal duplication, stools and a palpable mass, accompanied by villous adenoma of the appendix and Henoch- vomiting and diarrhea[2]. The incidence is higher in Schonlein purpura. Malignant etiology is rare and spring and autumn suggesting a viral etiology. In usually due to metastases especially fro m 90% the cause is idiopathic. Less than 10% of melanomas. Large bowel intussusceptions have a c h i l d ren have a lead point usually a Meckel’s more sinister cause including adenocarcinoma and diverticulum, hemangioma or a polyp[3]. lymphoma[5]. In adults, intussusception is uncommon, accounting A significant incidence of intussusception has for only 5% of mechanical small bowel obstruction. been linked with acquired immunodeficiency 20% of cases are idiopathic. A demonstrable cause syndrome (AIDS). This is due to association of is found in 80%, the majority being caused by AIDS with a variety of infectious and neoplastic primary colonic carcinomas. Other causes include conditions of the bowel, including Crohn’s disease, lipomas, polyps, edema or post-operative fibrosis. lymphoid hyperplasia, Kaposi’s sarcoma, and non- Symptoms include non-specific chronic abdominal Hodgkin’s disease[5]. pain related to re c u r rent sub-acute obstru c t i o n , All authors agree that, in adult intussusception, bleeding per rectum or an abdominal mass. Ileo- l a p a rotomy is mandatory in view of the high colic intussusceptions are common in children, while possibility of an underlying pathology[6]. colo-colic intussusceptions are common in adults[3]. Intussusception is also more common in the post- CASE REPORT operative period due to edema or adhesions[4]. A 26-year-old man (non-alcoholic, non-smoker), Intussusception is a continuous telescoping was admitted with a one month history of recurrent p rocess due to abnormal peristalsis pro d u c i n g attacks of abdominal pain and straining at stool, unequal longitudinal forces in the intestinal wall. with evacuation of blood stained motions. The bowel wall invaginates into the lumen and is He had been diagnosed two weeks earlier as propelled onwards. Pressure builds up in the wall, having ulcerative colitis by sigmoidoscopic biopsy impeding first the venous followed by the arterial and was on steroid therapy. Clinical examination
Address Correspondence to: Dr. Margaret Linny Austin, Department of Radiology, Al-Jahra Hospital, Kuwait. P.O. Box 21396, Safat 13074, Kuwait. Tel: 4577198, E-mail: [email protected] 272 Adult Intussusception: A Radiological Approach September 2007
Fig. 2: Longitudinal sonography showing the “sandwich” sign
Fig. 3: Transverse sonography showing the “doughnut” sign of concentric Fig. 1: Plain radiograph abdomen showing soft tissue density on the right rings of intussusception revealed a vague tender mass in the right side of was seen to invaginate the ascending colon with the abdomen thought to be an inflammatory or intervening layers of fat attenuation representing appendicular mass and was re f e r red for the mesentery (Fig. 5). A “target” appearance of ultrasound. Laboratory tests were normal. concentric rings of the bowel was seen in the lower Plain X-ray of the abdomen revealed a soft cuts at the initial level of the intussusception. No tissue opacity in the right side of the abdomen definite lead point could be identified. At the time shifting all bowel loops to the left (Fig. 1). Sonography of imaging, there was no evidence of bowel in the longitudinal plane revealed a long tubular infarction. mass in the right side of the abdomen, related to the The patient was rushed to surgery. The terminal ascending colon. The mass was made up of ileum was seen to invaginate the ascending colon multiple parallel stripes of varying echogenicity till the hepatic flexure. The last 60 cm of the giving a “sandwich” like or “pseudo kidney” intussuscepting ileum was found to be gangrenous. appearance (Fig. 2). A limited right hemi-colectomy was performed. Transverse scanning revealed several concentric The pathological specimen revealed an ileo- rings known as the “doughnut” sign or “target” cecal intussuception due to a single lipomatous sign, classically described for intussusception (Fig. polyp measuring 5.5 x 2 cm. The terminal segment 3). Since the patient was an adult, it was decided to of the ileum was found to be gangrenous. proceed to CT abdomen to further evaluate this The post-surgical course was uneventful. The mass and rule out other possibilities for thickened patient is on regular follow-up for his ulcerative bowel including an inflammatory mass or colitis. lymphoma as well as to search for an underlying cause or a lead point. DISCUSSION For computed tomography, oral, rectal and IV Plain radiography contrast was administered prior to imaging. A long Initial radiographs may be normal. Subsequent tubular, sausage shaped mass was seen in the right radiographs may show right sided paucity of gas side of the abdomen (Fig. 4). The terminal ileum especially absence of cecal gas, being replaced by September 2007 KUWAIT MEDICAL JOURNAL 273
safer and cheaper. In adults, contrast enemas are rarely employed for non-operative therapy, since an underlying lead point is usually demonstrated[3].
Ultrasound This technique has proved to be most efficacious in the diagnosis of intussusception especially in children[7]. The radiologist initially searches for a 3 - 5 cm diameter soft tissue mass. Transverse scanning shows the classical “target lesion” or “doughnut” sign representing concentric layers of bowel. The hypoechoic halo is produced by the mesentery and the edematous wall of the intussuscipiens; the inner Fig. 4: Axial CT scanning showing the “target” sign of intussuception hyperechoic center is produced by the mucosal, submucosal and serosal surfaces of the intussusceptum. On longitudinal imaging, the hyperechoic center assumes a tubular shape in continuity with the intestinal lumen and is covered on each side by the hypoechoic intussuscipiens - called the sandwich sign[ 7 ]. Intraperitoneal fluid is an occasional finding. Color Doppler sonography can detect early ischemia, precluding a non- operative reduction. The major limitation to sonography is the presence of air-filled bowel, leading to poor transmission of the beam[6]. With increasing experience, more radiologists are relying on sonography for diagnosis or exclusion of intussuception[2]. False positives are obtained with
Fig. 5: CT showing “reniform” appearance of invaginating ileum and impacted stool, Crohn’s disease of terminal ileum, mesentery, with ileo-cecal valve volvulus and needs clinical correlation. soft tissue density. There may be evidence of Computed tomography (CT) proximal small bowel dilatation and obstruction. This modality is availed of primarily in adults to The apex of the intussusception may show the confirm the diagnosis and evaluate for an pathognomonic radiolucent “crescent” sign. This underlying cause or lead point. Intussusception has sign is due to intestinal gas being trapped between a virtually pathognomonic appearance on CT[5]. It the apposing intestinal surfaces. This lucent appears as a complex soft tissue mass consisting of c rescent is wider than normal bowel and an outer intussuscipiens and central intussusceptum. superimposed on the round soft tissue density of There is an eccentric, crescent-like low attenuation the intussusception. Due to the high occurrence of fatty mass, representing entrapped mesenteric fat[8]. false negatives on plain radiography, ultrasound is The intussusception will appear as a “target” when recommended as the primary imaging technique[1,2]. the beam is perpendicular to the long axis of the mass and a sausage-shaped or reniform mass when Barium studies the CT beam is parallel to it[5]. These patterns of CT The classic appearance of intussusception on appearance can also reflect the severity and barium studies is the coil spring appearance of duration of the disease process, the targ e t barium trapped between the intussusceptum and appearance being the earliest stage, progressing to intussuscipiens[1]. Previously, a contrast enema was a sausage-shaped mass. Finally a reniform or considered to be the diagnostic and therapeutic “pseudokidney” mass develops due to edema, method of choice in children, provided the child mural thickening, and vascular compromise[1,3]. The was clinically stable and a pediatric surgeon was etiology of intussuception is rarely established and available on the premises. The rule of three was is possible with lipomas, lymphadenopathy, and employed - three attempts being made with a abdominal metastatic disease. contrast (barium or non-ionic) reservoir suspended Another described finding is that of a rim at three feet above the fluoroscopy table, each shaped accumulation of oral contrast encircling the attempt being sustained for three minutes. Barium intussusceptum, due to contrast coating the opposing has since been replaced by water and air, which are walls of the bowel. Additional findings on CT are 274 Adult Intussusception: A Radiological Approach September 2007 small amounts of ascites and proximal obstruc t i o n [8 ] . made by the radiologist. Imaging by plain imaging, CT scanning has been found to be the most barium studies, sonography in children, and CT accurate, with ultrasound being the second most and MRI in adults hastens the detection of useful modality in the diagnosis of intussusception. intussusception thus preventing the dre a d e d complications of infarction, gangrene and perforation. Magnetic resonance Imaging (MRI) It also aids in surgical planning while also Recent developments in MRI with ultrafast demonstrating an underlying cause. multiplanar techniques now allow for rapid evaluation of bowel obstruction[9]. The multiplanar REFERENCES HASTE (half-fourier single shot turbo spin echo) is particularly useful in the diagnosis of intussusception, 1. G o re RM, Levine MS. Textbook of gastro i n t e s t i n a l radiology. Saunders, 1994; 1251-1256. since this sequence is motion insensitive. The high 2. Daneman A, Alton DJ. Intussusception. Issues and contrast resolution between the increased signal of controversies related to diagnosis and reduction. Radiol the trapped intraluminal fluid and the intermediate Clin North Am 1996; 34:743-756. to low signal of the bowel wall can clearly 3. Byrne AT, Goeghegan T, Govender P, Lyburn ID, Colhoun demonstrate the pathology. E, Torreggiani WC. The Imaging of intussusception. Clin Radiol 2005; 60:39-46. 4. D i F i o re JW. Intussusception. Semin Pediatr Surg 1999; Treatment 8:214-220. The optimal treatment of adult intussusception 5. Gayer G, Zissin R, Apter S, Papa M, Hertz M. Adult is mandatory laparotomy to identify the underlying intussusception-a CT Diagnosis. Br J Radiol 2002; 75:185- lead point [ 6 ]. Weilbacher et al established the 190. 6. Takeuchi K, Tsuzuki Y, Ando, et al. The diagnosis and principle of primary resection without reduction in treatment of adult intussusception. J Clin Gastroenterol ileo-colic, ileo-ceocolic, and colo-colic intussusception 2003; 36:18-21. in adults due to the high incidence of underlying 7. Verschelden P, Filiatrault D, Garel L. Intussusception in m a l i g n a n c y[ 1 0 ]. In patients with small bowel c h i l d ren: reliability of ultrasound in diagnosis-a intussusception, without evidence of ischemia, prospective study. Radiology 1992; 184:741-744. 8. Gayer G, Apter S, Hofmann C, et al. Intussusception in inflammation or malignancy, reduction can be adults: CT diagnosis. Clin Radiol 1998; 53:53-57. [11] initially attempted . 9. M a rcos HB, Semelka RC, Worawattanakul S. A d u l t intussusception: demonstration by current MR techniques. CONCLUSION Magn Reson Imaging 1997; 15:1095-1098. With the widespread use of imaging in the 10. Weilbaecher D, Bolin JA, Hearn D, et al. Intussusception in adults. Am J Surg 1971; 121:531-535. evaluation of non-specific abdominal pain the 11. Begos DG, Sander A, Modlin IM. The diagnosis and diagnosis of intussusception in adults is most often management of adult intussusception. Am J Surg 1997; 173:88-94. September 2007 KUWAIT MEDICAL JOURNAL
Case Report
A Female Infant with Severe Combined Immunodeficiency
Enamul Hoque, Mona Hussain Badawi, Zahra Qabazard Department of Pediatrics, Al- Adan Hospital, Kuwait
Kuwait Medical Journal 2007, 39 (3): 275-277 ABSTRACT
We report a case of a female infant with autosomal opportunistic infections and failure to thrive. This is a recessive severe combined immunodeficiency. She pres e n t e d serious life-threatening disorder. The child will die with early in life with re c u r rent severe chest infection, severe infection within two years of life, if left untreated.
KEY WORDS: bone marrow transplantation, gene therapy, severe combined immunodeficiency
INTRODUCTION infiltrate with no congenital anomalies. Severe combined immunodeficiency (SCID) is a As a result of low immunoglobulins the patient life-threatening disorder due to severe T and B cell was referred to immunologists who diagnosed the dysfunction[1]. Most patients present by the age of case as SCID, subclass MHC class II antigen three months with recurrent infections, diarrhea, deficiency and recommended daily oral antibiotic dermatitis and failure to thrive. It is an immunological prophylaxis and monthly i.v immunoglobulin until emergency as the patients’ life depends on early stem cell transplantation could be arranged . pr ecise diagnosis and team approach in management. One month later she was readmitted and Bone marrow transplantation is the specific transferred to ICU in poor general condition with treatment while gene therapy still under trial[1]. respiratory failure due to severe bro n c h o p n e u - Genetic counseling is an essential part in the monia (Fig. 1 and 2). During her stay in the ICU a management and prenatal diagnosis is available multidisciplinary team was involved in her th r ough chorionic villus sampling early in preg n a n c y . management (pediatrician, pulmonologist, immunologist, gastro e n t e rologist and infectious CASE REPORT disease control specialist). Arepeated septic profile A six-month-old Kuwaiti girl was admitted with including cultures from blood, urine, and broncho- severe bronchopneumonia. She was a product of alveolar lavage (BAL) showed: positive urine full term, normal vaginal delivery with a birth c u l t u re for Klebsiella pneumoni and multiple weight of 2.5 kg. She was the third child born to organisms in BAL including RSV, Pseudomonas and healthy first degree consanguineous parents with Pneumocyctitis carnii. She was ventilated and st a r t e d two healthy elder brothers. Her physical examination on total parenteral nutrition. She also re c e i v e d showed failure to thrive with weight and length fluconazole, trimethoprim/sulphamethoxazole, below the 3rd centile. She was toxic, febrile, having piperacillin/tazobactam (tazocin), ribavirin, cimetidine, tachycardia with signs of respiratory distress. m e t h y l p rednisolone and immunoglobulin. The routine hemogram and biochemical U n f o r t u n a t e l y, she died due to uncontro l l a b l e investigations were normal. Plain X-ray chest sepsis resulting multiorgan failure at eight months showed bronchopneumonia. Intravenous fluid and of age . antibiotic were started and she responded well and was discharged after seven days in good general DISCUSSION condition. She was readmitted after two days with SCID represents a group of rare, sometimes severe bronchopneumonia. Further investigations fatal, congenital disorders characterized by little or w e re done for re c u r rent pneumonia including no immune response and can occur in all races with barium-swallow which showed gastro-esophageal f requency of 1 in 100,000 births. This disease reflux. Sweat chloride was normal and seru m usually presents within the first three months of immunoglobulin showed panhypoglobulinemia life, as chronic diarrhea, failure to thrive, (Table 1). A CT chest showed bilateral pneumonic pneumonia and sepsis without specific
Address correspondence to: Dr. Mona Hussain Badawi, DCH, MRCP, Al-Adan Hospital, P.O. Box: 46969, Haedia-64020, Kuwait. Tel: 965-3941623, Fax: 9653941624, E- mail: [email protected] 276 A Female Infant with Severe Combined Immunodeficiency September 2007
Fig. 1 and 2: Showing bilateral diffuse parenchymal infiltrates of Pneumocystis carinii pneumonia. abnormalities on physical examination. The kinase (PTK) deficiency, reticular dysgenesis and defining feature of SCID is a defect in specialized Omenn syndrome. white blood cells (B and T lymphocytes) that Adenosine Diaminase (ADA) is the most defend us from infection by viruses, bacteria and common cause (20% of all SCID, 30-50% of f u n g i [ 1 ]. All forms of SCID are inherited. Almost autosomal recessive SCID) of SCID. The gene for 50% cases of SCID are linked to the X chromosome ADAis located on chromosome 20 q. Accumulation passed on by the mother. X linked SCID of adenosine and 2-deoxyadenosine and its lymphopenia occurs primarily from the absence of derivatives is toxic to lymphocytes[4]. T cells (CD3+) and natural killer (NK) cells[2]. X JAK3 deficiency is associated with lymphopenia linked SCID results from a mutation of the common due to absent or reduced T cells and NK cells. In gamma chain of the interleukin (IL) receptor for IL- PNP deficiency there is lymphopenia due to death 2, Il-4, IL-7, IL-9, IL-15 and this protein is encoded of T cells from accumulation of toxic metabolites in on the X chromosome. the purine savage pathway and differs from ADA Defective IL receptors and IL receptor pathways deficiency as there are circulating B cells that are p revent the proper development of T- unable to produce antibodies. In IL-2 deficiency T lymphocytes[3]. T-lymphocytes play a key role in cell numbers are rarely affected but fail to identifying invading agents as well as activating proliferate in vitro with mitogen stimulation unless and regulating other cells of the immune system (B IL-2 is added to the medium and is often associated cells). So in this condition no functional antibody is with other cytokine production defects; the produced. Autosomal recessive types are Adensine functional antibody production is reduced. In deaminase (ADA) deficiency, Janus associated Omenn syndrome there are normal or elevated T kinase 3 (JAK 3) deficiency, purine nucleoside cells of maternal origin, undetectable B cells[5], poor phosphorylase (PNP) deficiency, defective expres s i o n antibody production, eosinophilia, high immunoglobulin of major histocompatibility (MHC) complex E and TCR recombinase genes (Rag 1, Rag 2 genes) antigen, IL-2 deficiency, Zap-70 protein tyrosine are believed to be responsible. MHC deficiency is September 2007 KUWAIT MEDICAL JOURNAL 277
Table 1: Shows a summary of investigations and normal with repeated severe pneumonia needing frequent values admissions and panhypoglobulinemia on investigation. A diagnosis of agammaglobulinaemia was Investigations Results Normal values co n s i d e r ed. However, a flow cytometry immediately distinguishes between B cell deficiencies and lack Hematological: of mature T cells which supports the diagnosis of Hb 101 gm/l 105 - 120 gm/l SCID[8]. Our patient was investigated further by the Total WBC count 14.3 x 109/l 6 - 17x 109 /l Polymorphs 75% 32% pediatric immunologist and was found to have Lymphocytes 19.7% 60% MHC type II deficiency. She was started on daily Monocytes 4.9% 5% oral antibiotic prophylaxis, monthly IV Eosinophils 0.2% 3% immunoglobulin until stem-cell transplantation Basophils 0.2% 0 - 0.75% could be done. The hallmark of treatment of SCID Platelets 606 x 109/l 150 - 300x109/l Immunological: is either bone marrow or stem cell transplantation IgG < 0.33 g/l 2.85 - 7.6 g/l early in life to reconstitute the defective immune IgM < 0.07 g/l 0.14 - 0.76 g/l system. Patient needs stabilization with antibiotics, IgA 0.11 g/l 0.28 - 1.1 g/l antifungals, immunoglobulins and nutritional T-cell, B-cell function support prior to bone marrow transplantation. and detailed MHC class II immunological study deficiency Biochemical: ACKNOWLEDGEMENTS AST 28 IU/l 15 - 55 IU/l Our thanks are due to Dr Nashat and Dr Fawzia ALT 18 IU/l 5 - 45 IU/l from the pediatric department, Adan Hospital for Urea 2.2 mmol/l 1.8 - 6.4 mmol/l help in writing this case report. Creatinine 23 umol/l 18 - 35 umol/l Calcium 2.4 mmol/l 2.2 - 2.7 mmol/l REFERENCES associated with defective T and B cell immunity 1. Buckley RH. Primary immunodeficiency diseases due to and belongs to class I (HLA-A,-B,-C) and class II defects in lymphocytes. N Engl J Med 2000; 343:1313-1324. (HLA-DR,-DQ,-DP) antigen deficiency. Isolated 2. Buckley RH, Schiff RI, Schiff SE,. Human severe combined class I deficiency also known as bare lymphocyte immunodeficiency: genetic, phenotypic and functional syndrome can be milder and may present at a later diversity in one hundred eight infants. J Pediatr 1997; 130:378-387. age. MCH class II (the deficiency that our patient 3. Candotti F, Villa A, Notaraanglo LD. Severe combined was suffering from) can present in early infancy immunodeficiency due to defects of JAK 3 tyrosine kinase. with persistent diarrhea, pneumonia and septicemia In: Primary Immunodeficiency Diseases. Ochs HD, Smith due to virus, bacteria, Pneumocystis carinii, or CIE, Puck JM, editors. 1999. p 111-120. C a n d i d a. Lymphocytopenia if it occurs is only 4. Hirschhorn R. Immunodeficiency disease due to deficiency of adenosine deaminase. In: Immunodeficiency Diseases. moderate and has very low number of CD4+ T cells Ochs HD, Smith CIE, Puck JM, editors. 1999. p 121-139. with normal or even elevated CD8+ T cells[6]. The 5. Vill A, Santagata S, Bozzi F, et al. Omenn syndrome: a MHC class II antigens are undetectable on B c e l l s disorder of Rag 1 and Rag 2 gene . J Clin Immunol 1999; and monocytes and patients are hypoglobulinemic 19:87-97. due to impaired antigen-specific response caused 6 Klein C, Lisowska-Grospierre B, LeDeist F, et al. Major histocompatibility complex class II deficiency : Clinical by the absence of these antigen pre s e n t i n g manifestations, immunologic features, and outcome. J molecules. The thymus and other lymphoid organs Pediatr 1993; 123:921. are severely hypoplastic. 7. Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem- Without stem cell transplantation, death from cell transplantation for the treatment of severe combined infections usually occurs within the first two years im m u n o d e f i c i e n c y . N Eng J Med 1999; 340:508-516. 8. Hong R. Disorders of the T cell System. In: Stiehm ER, [7] of life . editor. Immunologic Disorders in infants and children. 4th The clinical features of our patient were typical ed. Philadelphia Pa: WB Saunders; 1996. p 339-408. of autosomal recessive SCID. She presented to us KUWAIT MEDICAL JOURNAL September 2007
Case Report Neonatal Presentation of Two Siblings with Pena-Shokeir Syndrome
Bhaskar Ramgopal Gupta Neonatal Intensive Care Unit, Khoula Hospital, Muscat, Sultanate of Oman
Kuwait Medical Journal 2007, 39 (3): 278-280 ABSTRACT
Pena-Shokeir phenotype is an autosomal re c e s s i v e the second sibling. The facial anomalies, pulmonary inherited disorder resulting from fetal akinesia or hypoplasia and bony ankylosis were similar to that seen hypokinesia. It is characterized by polyhydramnios, in the previous baby. This baby was ventilated soon after intrauterine growth ret a r dation, neurogenic arthogryposis, birth and skeletal survey, ultrasound, chro m o s o m a l facial anomalies, short umbilical cord and pulmonary analysis, dye studies and muscle biopsy could be done to hypoplasia. In this lethal disorder a significant number p rove the diagnosis. Since the clinical pre s e n t a t i o n of affected fetuses are born prematurely, 30% are still closely mimics Potter syndrome and Trisomy 18, this born and a majority die soon after birth. We report a case condition could be easily confused with these two disorde r s . where consecutive siblings have been affected by this Prenatal diagnosis and counseling could be offered to disorder, but the diagnosis could only be confirmed in such families with positive family history.
KEYWORDS: neruogenic arthrogryposis, Pena-Shokeir syndrome, pulmonary hypoplasia
INTRODUCTION The previous full term baby had multiple bony Pena-Shokeir syndrome is an autosomal ankylosis, pulmonary hypoplasia, deformed ears recessive disorder with clinical presentation of fetal and died soon after birth. No investigations could akinesia or hypokinesia sequence. This early lethal be done and the baby was diagnosed as Potter disorder involves multiple joint contractures, facial syndrome on the basis of clinical findings. abnormalities and pulmonary hypoplasia. Such This baby was born by spontaneous vaginal babies are usually misdiagnosed as either Trisomy delivery with an APGAR score of 6 at one minute 18 or Potter syndrome. Since most of them are still and 8 at five minutes. Since the baby had poor born or die soon after birth the definitive diagnosis respiratory effort soon after birth she was put on cannot be confirmed. The case presented here is to intermittent positive pressure ventilation, inotropic highlight the recurrence of similar manifestations support and monitoring in the special care baby in two siblings - the first who died soon after birth unit. All the investigations were done during this was diagnosed as Potter syndrome and the present period. The baby developed bilateral pneumothoraces case that was ventilated and investigated. The which were treated by intercostal drains. The baby diagnosis of Pena-Shokeir syndrome was proven expired at 44 hours of life. by definite clinical findings and muscle biopsy This baby was noted to have dysmorphic f e a t u res such as depressed nasal bridge, CASE REPORT hypertelorism, prominent eyes, epicanthic folds, A full-term female 2.5 kg baby with a head high arched palate and micrognathia, posteriorly circumference of 33 cms and length of 48 cms was placed bilaterally atretic ears with no external born at Khoula Hospital, Muscat, Sultanate of auditory meatus, soft skull bones with widely Oman to a 19-year-old Gravida 4 Para 1 mother separated sutures, short neck, narrowed thoracic with two early abortions at 10-12 weeks gestation, cavity and multiple skeletal anomalies. Both the and a history of consanguinity. Antenatal ultrasound legs were upturned, full rotation of hip, genu of the mother during this pregnancy at 29 weeks recurvatum, bilateral talipes equinovaru s , and 38 weeks revealed polyhydramnios with no camptodactyly with ulnar deviation of hands and other gross congenital anomaly. contractures of forearm (Fig. 1). There was absence
Address correspondence to: Dr. Bhaskar Ramgopal Gupta, M.D. (Pediatrics), Yiaco Apollo Medical Center, Amman Street, Salmiya, Kuwait. Tel: 5611706, 5648040, Mob: 9765011, Fax: 00965- 5646070, E-mail: [email protected] September 2007 KUWAIT MEDICAL JOURNAL 279
Fig. 1: Neonate with ocular hypertelorism, short nose with depressed Fig. 2: Neonate with camptodactyly, ulnar deviation of hand and absence nasal bridge, micrognathia, deformed low set atretic ears, short neck and of flexion creases on finger and palms severe contractures of hip, elbow, knee and ankles of flexion creases on finger and palms and sparse in first week of life. dermal ridges (Fig. 2). The umbilical cord was thin, Fetal movements were studied between 15-35 short and shriveled. The external genitalia was weeks of gestation by Mulder et al[5] and were found normal for female and no abdominal masses were to be quantitatively and qualitatively abnormal in felt. Auscultation of the heart did not reveal any babies affected by Pena-Shokeir syndrome. cardiac murmur. This prenatal onset degenerative disorder of Hemoglobin, WBC counts, platelets and electrol y t e s neurons leading to neurogenic muscular atrophy were within normal limits. Skeletal survey done with subsequent impairment of joint movement showed skull with soft thick swelling in the parietal leads to neurogenic arthrogryposis multiplex regions, poorly formed bones and the base of the congenita resulting in decreased fetal activity. Due skull looked dense. Chest X-ray re v e a l e d to failure of normal deglutition there is pulmonary hypoplasia with emphysematous polyhydramnios and neuromuscular deficiency in bullae in left upper lobe. X-ray of the spine showed diaphragmatic and intercostal muscle function spina bifida at the level of T5-T6. leads to pulmonary hypoplasia[6]. Termination of Ultrasound of abdomen revealed poor pregnancy can be offered before viability. For those visualisation of both kidneys. A dye study was who survive, supportive treatment and joint done which confirmed normal sized pro p e r l y mobilization can be done. functioning kidneys. Muscle biopsy revealed small This neonate had all the clinical features of bony individual muscle fibers with hyperc h ro m a t i c ankylosis along with pulmonary hypoplasia, dense nuclei - features suggestive of neurogenic malformed ears, micrognathia and a thin shriveled atrophy of muscle. The chromosomes were normal umbilical cord. The previous sibling was clinically 46XX. diagnosed as Potter syndrome as he died soon after birth and the diagnosis could not be confirmed. DISCUSSION This baby was ventilated and subsequently all the This syndrome of neurogenic arythrogryposis investigations were done. Ultrasound confirmed with pulmonary hypoplasia and hypertelorism the normal size of kidneys and dye studies showed described by Pena and Shokeir in 1974 is an properly functioning kidneys, thus excluding the autosomal recessive disorder with a frequency of diagnosis of Potter syndrome. 1:1200 births [1]. The prediction of recurrence risk is C h romosomes revealed 46XX excluding imprecise due to multi-factorial etiology and varies Trisomy 18 which could be easily confused with f rom 5-25% [ 2 ]. Familial re c u r rences have been Pena-Shokeir syndrome. The diagnosis was described earlier by Paldini et al[3] who reported confirmed by muscle biopsy which showed consecutive three pregnancies with Pena-Shokeir features consistent with neurogenic atrophy of the syndrome. Erdl et al reported two siblings with muscle. Muscle biopsy has been found to be Pena-Shokeir syndrome who had broad range of abnormal in 15 out of 17 babies with Pena-Shokeir deformities with associated cerebral malformations[4 ] . syndrome. Also spinal cord histology is abnormal Some of these babies are born prematurely and in five out of eight babies and cerebral abnormality those born at term are small for gestational age. seen in 11 out of 16 babies[6]. Since autopsy could About 30% are still born and a majority of live born not be done in our case we could not confirm these die of complications due to pulmonary hypoplasia abnormalities. 280 Neonatal Presentation of Two Siblings with Pena-Shokeir Syndrome September 2007
CONCLUSION REFERENCES Fetal akinesia sequence presents as neurogenic 1. Pena SDJ, Shokeir MHK. Syndrome of camptodactyly, arthrygryposis multiplex congenita and as most of multiple ankyloses facial anomalies and pulmonary hypoplasia: a lethal condition. J Pediatr 1974; 85:373-375. them are either still-born or die soon after birth, the 2. Hall JG. Analysis of Pena Shokeir phenotype. Am J Med definite diagnosis cannot be confirmed. This case Genet 1986; 25:99-117. reports of consecutive pregnancies with Pena- 3. Paldini D, Tartaglione A, Agangi A, Foglia S, Martinelli P, Shokeir syndrome where the diagnosis could not be Nappi C. Pena-Shokeir phenotype with variable onset in proven in the first baby and was proven in the three consecutive pregnancies. Ultrasound Obstet Gynecol 2001; 17:163-165. subsequent baby by chromosomal analysis, 4. Erdl R, Schmidtke K, Jakobeit M, Nerlich A, Schramm T. ultrasound and muscle biopsy. At present only Pena-Shokeir phenotype with major CNS-malformations: ultrasound guided paucity of fetal movement can clinicopathological report of two siblings. Clin Genet 1989; give a clue to the diagnosis. Prenatal diagnosis in 36:127-135. those with positive family history and treatment 5. Mulder EJ, Nikkels PG, Visser GH. Fetal akinesia deformation sequence: behavioral development in a case of may alter the management of Pena-Shokeir congenital myopathy. Ultrasound Obstet Gynecol 2001; syndrome in future. 18:253-257. 6. Jones KL. Pena-Shokeir phenotype. In: Smith’s recognizable patterns of human malformation. Philadelphia; WB Saunders Company: 1977; 174-175. September 2007 KUWAIT MEDICAL JOURNAL
Case Report Cholestatic Jaundice Induced by Carbimazole in Grave’s Disease
Ahmed AL Dousari, Saleh AL Enezi, Fahad AL Enezi Department of Internal Medicine, Farwania Hospital, Kuwait
Kuwait Medical Journal 2007, 39 (3): 281-283 ABSTRACT
Antithyroid medications are one of the treatment options occurrence of a granulocytosis and others. Hepatitis is for Grave’s disease. Carbimazole (the pro drug for another rare but serious side-effect. We report a methimazole) is widely used as the drug of choice, except p reviously healthy 65-year-old female patient with in pregnancy where propythiouracil is pre f e r red by Grave’s disease who developed cholestatic jaundice after m a n y. It is generally well-tolerated. Its side-eff e c t s carbimazole therapy. She made a full recovery after the include allergy, upper gastrointestinal upset, the rare drug was discontinued.
KEYWORDS: carbimazole, cholestatic jaundice, Grave’s, thyrotoxicosis
INTRODUCTION bilateral eye proptosis. In addition she gave history Grave’s disease is the most common cause of of palpitation, tremor and weight loss of seven hyperthyroidism. It accounts for approximately 80- kilograms over three months. She also admitted to 90% of cases. Treatment options include radioiodine, having frequent loose motions and heat antithyroid medications, and surgery. The former is intolerance. She was known to have chronic stable now considered the treatment of choice by most angina, and was taking atenolol and aspirin. There endocrinologists in the United States. Antithyroid was questionable history of iodine allergy. She had medications are still widely used in younger no history of liver disease. She was not a known patients with mild disease, pregnant or lactating diabetic or hypertensive. She was neither smoker patients. It is usually continued for about 12-24 nor an alcohol consumer. months. The chance of remission is around 40-50%. On physical examination, she had fine tremors It has several side effects; the majority is mild and of both hands. Her weight was 62 kg. Her pulse reversible such as allergic reaction, and upper GI rate was 120 beats/minute, regular and her blood disturbances. Other rare side effects include pre s s u r e was 150/70 mmHg. Eye examination showed agranulocytosis and vasculitis like re a c t i o n bilateral exophthalmos, with conjunctivitis and particularly with p ropylthiouracil. Hepatic periorbital edema. There was diplopia on looking toxicity is a rare but serious side effect with both to both sides indicating ophthalmoplegia. Thyroid methimazole (and its pro drug, carbimazole) and was soft and mildly diffusely enlarged. The liver propylthiouracil (PTU)[1-3]. Fatal cases have been and spleen were not palpable. Other systemic documented with both dru g s[ 4 ]. The hepato- examination was unremarkable. histopathological findings with PTU are toxic Her initial FT4 was 59.1 pmol/l (normal range = hepatitis with necrosis[5], whereas they resemble 12 - 22) and TSH < 0.005 uIU/ml (normal range = cholestatic hepatitis with methimazole (and 0.2 - 4.2). Other laboratory results are shown in carbimazole)[6]. We present a case of carbimazole Table 1. induced cholestatic hepatitis in a patient with She was diagnosed as Grave’s disease and Grave’s disease. We describe the clinical and started on propranolol with prednisolone for biochemical findings in this patient and review the Grave’s ophthalmopathy. Carbimazole was also relevant literature. initiated at a dose of 30 mg per day in three divided doses. She neither did thyroid scan nor took I 131 CASE REPORT because of concern with iodine allergy and A 65-year-old female patient was admitted to exacerbation of the eye manifestations respectively. the medical department with long standing Three weeks later, FT4 was normal at 16.9 pmol/l
Address correspondence to: Dr. Aldousari, Ahmed, Consultant Endocrinologist, Department of Internal Medicine, Farwania Hospital, Kuwait. Tel: 9642770 / 4891035 / 4888000 - 3413, E-mail: [email protected] 282 Cholestatic Jaundice Induced by Carbimazole in Grave’s Disease September 2007
Table 1: Showing date wise laboratory results (normal range)
Date-wise results Lab. test 03/01/05 31/01/05 08/02/05 09/03/05 30/03/05 25/04/05
Albumin g/l (34-50) 24.9 34 34 38 37 40 Alk.p u/l (50-136) 83 206 224 106 83 61 T.Bilirubin mmol/l (3-20) 2.3 135 413 48 16 18 D.Bilirubin mmol/l (0-5) 230 20 Gamma GT u/l (5-85) 29 399 79 145 ALT u/l (30-65) 32 165 164 159 117 41 AST u/l (10-42) 67 69 92 40 31 and TSH < 0.03 uIU/ml. She complained of blue without evidence of hepatic necrosis on liver discoloration of the sclera, associated with nausea b i o p s y[ 2 , 6 , 11 ]. Most patients recover on dru g and vomiting. Results of the liver function tests discontinuation. Nevertheless, there are occasional were as shown in Table 1. The laboratory findings reports of severe and fatal cases with methimazole were consistent with cholestatic jaundice. She had induced liver disease[12]. Review of the literature marked elevation of bilirubin and alkaline revealed around 22 cases of cholestatic jaundice phosphatase. Aspartate and alanine amino due to both methimazole and carbimazole[11]. The transferase were less markedly elevated. mean time of onset after starting treatment is 36 Prothrombin time was within normal limits. Test d a y s[ 1 ]. The majority of patients are female, for antinuclear antibodies was negative. reflecting the predominance of thyrotoxicosis in Abdominal ultrasound showed normal liver size female sex. The proposed mechanism of and texture. Intrahepatic biliary ducts were normal carbimazole-induced cholestasis is not fully and no obstruction was detected. Hepatitis serol o g y understood but is thought to be an allerg i c was negative for hepatitis A, B and C. Patient re a c t i o n[ 1 3 ]. Cross reaction between PTU and refused to do liver biopsy. Carbimazole was carbimazole is still a concern when a switch from stopped and she received radio active iodine under one to another is considered, in spite of some the cover of prednisolone to minimize risk of eye reports to the contrary[6]. The hepatotoxic effect is signs deterioration. Her liver functions normalized dose-independent[14]. within two months. She developed post-radioiodine Our patient developed significant hyperbilirub i n e m i a h y p o t h y roidism and was started on thyro x i n within three weeks of starting carbimazole, despite therapy. She was seen again after four and six normalization of thyroxin level. It continued to rise months and her liver functions were still normal. for one more week after stopping the offending d rug, until complete normalization over two DISCUSSION months. Aminotransferase level was mildly Hyperthyroidism per se can affect liver function elevated, reaching 2-3 times the normal. tests. It causes mild elevation in liver enzymes that Although she received steroid from the start for normalizes with treatment[7]. In addition, cholestatic reasons discussed above, it did not affect the course jaundice can happen solely due to severe of the liver disease. In fact, previous reports of hy p e r t h y ro i d i s m [8 ] . All antithyroid drugs (methimazole, using steroid in methimazole induced hepatitis did [15] carbimazole and propylthiouracil) can affect the not show any benefit . This coincides with the fact liver on rare occasions. A cohort study on 50 that most patients recover once the drug is stopped. patients by Liaw found that subclinical liver injury Our patient showed a good response to dru g is common during PTU treatment[5]. Thirty percent withdrawal. She received radioiodine with no patients had transient, asymptomatic rise in significant complications of the eyes. aminotransferase level with no elevation in b i l i rubin after two months of therapy. Despite CONCLUSION continuation of PTU, liver enzymes normalized in Hepatic toxicity is a rare but serious side effect most patients within five months. He suggested of antithyroid medications. Doctors dealing with t h y roid patients should be aware of such cautious continuation of PTU in the absence of complication. Routine liver function test during symptoms and hyperbilirubinemia. Despite this, therapy is not cost effective, but should be done PTU induced liver disease can be severe and when this complication is suspected. The drug f a t a l[ 9 , 1 0 ]. Carbimazole and methimazole, on the should be withdrawn immediately and alternative other hand have been typically associated with therapy for hyperthyroidism such as radioiodine cholestatic jaundice (mainly hyperbiliru b i n e m i a ) must be considered. September 2007 KUWAIT MEDICAL JOURNAL 283
REFFERENCES 8. Yao JD, Gross JB, Ludwig J, Purnell DC. Cholestatic jaundice in hyperthyroidism. Am J Med 1989; 86:619-620. 1. Woeber KA. Methimazole-induced hepatotoxicity. Endocr 9. Ruiz JK, Rossi GV, Vallejos HA, Brenet RW, Lopez IB, Pract 2002; 8:222-224. Escribono AA. Fulminant hepatic failure associated with 2. Ozenne G, Manchon ND, Doucet J, Memet J, Schrub JC, propylthiouracil. Ann Pharmacother 2003; 37:224-228. Bercoff E. Carbimazole -induced acute cholestatic hepatitis. 10. Limaye A, Ruffolo PR. Propylthiouracil-induced fatal J Clin Gastroenterol 1989; 11:95-97. hepatic necrosis. Am J Gastroenterol 1987; 82:152-154. 3. Westphal SA. Hepatotoxicity from propylthiouracil. South 11. Mikhail NE. Methimazole induced cholestatic jaundice. Med J 1994; 87:943-947. Southern Med J 2004; 97:178-182. 4. Williams KV, Nayak S, Becker D, Reyes J, Burmeister LA. 12. Backer B, Shapiro B, Fig LM, Woodbury D, Sisson JC, Fifty years of experience with propylthiouracil-associated Beierwaltes WM. Unusual complications of antithyroid hepatotoxicity: what have we learned? J Clin Endocrinol drug therapy: four cases reports and review of literature. Metab 1997; 82:1727-1733. Thyroidology 1989; 1:17-26. 5. Liaw YF, Huang MJ, Fan KD, Liki, Wu SS, Chen TJ. Hepatic 13. Blom H, Stolk J, Schreuder HB, Von Blomberg-Vander Flier injury during propylthiouracil therapy in patients with M. A case of carbimazole induced intrahepatic cholestasis. h y p e r t h y roidism. Cohort Study Ann Intern Med 1993; An immune-mediated reaction? Arch Intern Med 1985; 118:424-428. 145:1513-1515. 6. Arab DM, Malatjalian DA, Rittmaster RS. Severe cholestatic 14. Ozenirler S, Tuncer C, Boztepe U. Propylthiouracil-induced jaundice in uncomplicated hyperthyroidism treated with hepatic damage. Ann Pharmacother 1996; 30:960-963. methimazole. J Clin Endocrinol Metab 1995; 80:1083-1085. 15. Becker CF, Gorden P, Robbins J. Hepatitis from methimazole 7. Fong TL, McHutchinson JG, Reynolds TB. Hyperthyroi d i s m during adrenal steroid therapy for malignant exophthalmos. and hepatic dysfunction. J Clin Gastroenterol 1992; 14:240- JAMA1968; 206:1787-1789. 244. KUWAIT MEDICAL JOURNAL September 2007
Case Report Always Look Beyond the Stones: Hyperoxaluria Overlooked
Khalid Al- Ibrahim, Sherif A Sadek Department of Pediatrics, Al - Sabah Hospital, Kuwait
Kuwait Medical Journal 2007, 39 (3): 284-286 ABSTRACT
We report a case of hyperoxaluria type I in a nine-year- pyridoxine and crystallization inhibitors. He will require old boy with nephrolithiasis. His initial management a liver transplant to cure his primary hyperoxaluria. included multiple percutaneous nephrolithomies and Clinical clues of primary hyperoxaluria type I are l i t h o t r i p s y. Metabolic screening was not undertaken positive family history or presentation with several renal i n i t i a l l y. Hyperoxaluria was finally diagnosed by stones. Irrespective of the above, all patients with first elevated urine oxalate (1.363 mmol/24h). A diagnosis of presentation of renal calculi should undergo metabolic hyperoxaluria type I was confirmed by liver biopsy. His screening including urinary oxalate level determination. kidney function was nearly normal and he was started on
KEYWORDS: glomerular filtration rate, hyperoxaluria, renal stone
INTRODUCTION kidney function. On examination, he looked well- Primary hyperoxaluria type I is an autosomal grown and healthy without anemia or jaundice. His recessive inborn error of metabolism, which is the weight was 21.3 kg and height 119 centimeters. The result of endogenous overproduction of oxalate pulse was 80 / minute regular and the blood and glycolate. The disease is due to low or absent pressure was 100 / 55 mmHg. Neither kidney was activity of liver specific peroxisomal enzyme palpable. There was no hepatosplenomegaly. Initial alanine glyoxylate aminotransferase (AGT). This laboratory studies revealed a serum Na 137 leads to recurrent urolithiasis, nephrocalcinosis and mmol/l, K 4.6 mmol/l, Cl 103 mmol/l, HCO3 21 accumulation of insoluble oxalate throughout the mmol/l, serum creatinine 50 umol/l, Ca 2.41 body. Although the clinical course is highly variable mmol/l, phosphate 1.69 mmol/l, urate 222 as to when and if end stage renal failure (ESRF) will mmol/l. The estimated GFR was 95 ml / minute / result, about 50% of patients will reach ESRF before 1.73 m2. the age of 25 years. Plain abdominal X-ray showed multiple stones A high degree of clinical suspicion coupled with in both kidneys and bladder (Fig. 1). elevated urinary oxalate, points strongly to this Ultrasound of KUB revealed calcification of the condition. Liver biopsy demonstrating A G T cortico-medullary junction and renal calculi with deficiency remains the diagnostic gold standard. mild bilateral renal pelvic and ureteric dilatation. The right kidney measured 7 cm and the left kidney 7.6 cm in length (Fig. 2). CASE REPORT The MAG3 scan showed marginal impairment A 9-year old Kuwaiti boy presented at the age of of left sided renal function at 43% of total GFR but three years with abdominal pain and retention of no evidence of urinary obstruction. urine due to renal calculi and a bladder stone. Further biochemical analysis showed urinary Subsequently percutaneous lithotripsy and oxalate excretion 1.363 mmol / 24h (normal range p e rcutaneous nephrolithotomy were performed. = 0.1 - 0.46), urinary oxalate: creatinine ratio 340 He continues to pass stones per urethra on a regular (normal range = 1 - 38) and urine calcium 0.8 mmol basis, approximately one every one to two months. /24h (normal range = 2.5 - 7.5 mmol / 24h). Stone He has not had any further episodes of urinary analysis revealed calcium oxalate. obstruction. His parents are non-consanguineous A liver biopsy showed normal liver but and he has two older sisters (19 and 17 years old) confirmed the diagnosis of primary oxaluria with a who also pass stones in the urine but have good level of alanine glyoxylate aminotransferase (AGT)
Address correspondence to: Dr. Sherif ASadek, P.O. Box 1940, Al Ardyia 92400, Kuwait. Tel: 907 7495, E-mail: [email protected] September 2007 KUWAIT MEDICAL JOURNAL 285
Fig. 2: Ultrasound of KUB showing multiple renal stones in both kidneys with bilateral renal pelvic and ureteric dilatation.
hydration[2]. The natural history of the condition is such that a therapeutic window of opportunity exists only if the diagnosis is made before renal Fig. 1: Abdominal X-Ray showing multiple stones in both kidneys and function deteriorates significantly. If treatment is bladder delayed, deterioration of GFR inevitably leads to d e c reased urinary excretion of oxalate and activity of 3.7 umol/h/mg protein (normal range = accelerated increase of oxalate burden, even in the 19.1 - 47.9). Chromium EDTA GFR was mildly face of pyridoxine therapy. Neither hemodialysis reduced at 81 mls / min/ 1.73 m2 (normal range = nor peritoneal dialysis is able to keep pace with the 80-130 mls/min/1.73m2). He was commenced on endogenous production of oxalate in these pyridoxine 50 mg daily and polycitra (sodium + patients[3]. Survival on dialysis is poor, principally potassium citrate) 10 ml/bd. Flexible ure t e ro - due to progressive tissue oxalate accumulation and renoscopy was performed to remove all the stones deposition. within the collecting system. He was followed up in Isolated renal transplantation is complicated by the pediatric department of Al Sabah Hospital since acute oxalate nephrop a t h y . Recurrent nephroc a l c i n o s i s the age of four years. His current condition remains and stone formation are expected, except among e x t remely stable but he will re q u i re a liver those who are pyridoxine responsive. The results of transplant to cure his primary hyperoxaluria. isolated cadaveric kidney transplant performed in Europe in the 1980s were very poor with 3 - year DISCUSSION survival rate of 20% for grafts and 74% for patients. Primary hyperoxaluria type I is an autosomal The cause of graft loss was related to rejection in recessive inherited metabolic disease in which 33% of patients and recurrence of stone disease in excessive oxalate is formed in the liver and excreted 31%[4]. Isolated liver transplantation might be the by the kidneys. It manifests as a wide spectrum of first-choice treatment in selected patients before an phenotypes ranging from renal failure in infancy to advanced stage of chronic renal failure occurs, i.e., renal stones in adulthood. Medical tre a t m e n t while the GFR is between 60 mls/min/1.73 m2 and centers on high fluid intake and pyridoxine. 40 mls/min/1.73 m2 [ 5 ]. Once significant re n a l Pyridoxal phosphate is an essential co-factor for insufficiency has developed, combined liver and alanine - glyoxalate aminotransferase (AGT) and at renal transplants appear to offer the best chance for a dose of 5-20 mg/kg /day can significantly long term survival (i.e., while GFR ranges between decrease hyperoxaluria in 30% of those affected. 20 - 40 mls/min /1.73 m2) because at this level Pyridoxine responsiveness may prevent or delay [6] [1] oxalate retention increases rapidly . Survival rates the progression to ESRF . The patients most likely of 80% for patients at five years with combined to respond are those with residual AGT activity. transplant have been reported. Despite the potential Other measures are directed towards decreasing risks to the grafted kidney due to oxalate release the formation of calcium oxalate crystals in urine from body stores, kidney survival is about 95% at with potassium citrate, magnesium and adequate three years after transplantation. Renal function 286 Always Look Beyond the Stones: Hyperoxaluria Overlooked September 2007 remained stable with a creatinine clearance of 40 - Nephrol Dial Transplant 1999; 14:301-303. 60 mls/min/1.73m2 after five years [7]. Whatever the 2. Leumann E, Hoppe B. The primary hyperoxalurias. J Am Soc Nephrol 2001; 12:1986-1993. transplantation strategy, the kidney must be 3. Hoppe B, Graft D, Offner G, et al. Oxalate elimination via protected against the damage that can be induced hemodialysis or peritoneal dialysis in children with chronic by heavy oxalate load suddenly released fro m renal failure. Pediatric Nephrol 1996; 10:488-492. tissue. Forced fluid intake of 5 l/1.73 m2/ d a y 4. B royer M, Burnner FP, Brynger H, et al. Kidney supported by diuretics and use of crystallization transplantation in primary oxalosis: data from the EDTA Registry. Nephrol Dial Transplant 1990; 5:332-336. inhibitors, is the most important strategy. 5. Cochat P, Basmaison O. Current approaches to the Appropriate initial assessment of all stone formers management of primary hyperoxaluria. Arch Dis Child at first presentation will minimize the chance of 1993; 82:470-473. accelerated morbidity in this dangerous condition. 6. Scheinman JI, Najarian JS, Mauer SM. Successful strategies for renal transplantation in primary oxalosis: Kidney Int REFERENCES 1991; 25:804-811. 7. Jamieson NV. The result of combined liver/kidney 1. Marangella M. Transplantation strategies in type I primary transplantation for primary hyperoxaluria 1984-1997. The h y p e roxaluria: the issue of pyridoxine re s p o n s i v e n e s s . European PH1 Transplant registry report. European pH1 Transplantation Study Group. J Nephrol 1998; (Suppl I) :36-41. September 2007 KUWAIT MEDICAL JOURNAL
Case Report
Severe Hypereosinophilia in an Asthmatic Young Female
Jehan A Qassem, Najat Ashour, Puthusseril P Boby Department of Medicine, Al-Amiri Hospital, Kuwait
Kuwait Medical Journal 2007, 39 (3): 287-289 ABSTRACT We present a case of a young asthmatic lady who of Churg-Strauss syndrome. She was treated with pr esented with multiple systemic manifestations associated corticosteroids only. She made a complete recovery and with severe eosinophilia. She proved to be a classical case does not show any signs of relapse to date. KEYWORDS: asthma, Churg-Strauss syndrome, hypereosinophilia, necrotizing vasculitis
INTRODUCTION 101 iu/ml), perinuclear antineutrophil cytoplasmic Churg-Strauss Syndrome (CSS) is a very rare antibodies (P-ANCA = 63 u/ml), IgE level (2312 systemic disease with clinico-pathological features iu/ml), low albumin level (28 g/dl), proteinuria that overlap with those of polyarteritis nodosa and and microscopic hematuria. Her electrocardiogram Wegener’s granulomatosis. It makes up to 20% of showed sinus tachycardia with T wave inversion in systematic vasculitis with an incidence of 30% of leads V1 to V3 that normalized later on while her that estimated for Wegener’s granulomatosis (5.3 chest X-ray showed right upper lobe fibrosis and per one million patients per year)[ 1 , 2 ]. It occurs left lower lobe pneumonitis with mild pleural almost exclusively in patients with asthma or e ffusion. Her pulmonary function test showed history of allergy. moderately severe bronchial asthma as her forced expiratory volume in first second (FEV1) was 1.59 CASE REPORT liters (51% of predicted), forced vital capacity A 31-year-old Kuwaiti lady was admitted to our (FVC) was 2.24 liters (62% of pre d i c t e d ) , medical ward in March 2004 with a two weeks FEV1/FVC ratio was 71%, residual volume (RV) history of malaise, myalgia, neck pain and plantar was 3.2 liters (219% of predicted) while her FEV1 fasciitis followed by one week history of productive after bronchodilators was 1.8 liter. Her lower limb cough and yellowish sputum. Soon after admission nerve conduction study showed a picture of early her cough improved while other symptoms sensory neuropathy. A high resolution computed persisted. Four days later she started developing tomography (HRCT) chest revealed scattere d skin lesions on her fingers, toes and elbows pulmonary infiltrations while her echocardi o g r a p h y associated with arthralgia in addition to bilateral was normal (Fig. 1). Skin lesion biopsy showed feet numbness. The patient was a known case of p i c t u re of leukocytoclastic vasculitis while her bronchial asthma, sinusitis and otitis media with kidney biopsy revealed no abnormality. Finally, a several surgeries for the latter two conditions over video assisted thoracoscopic lung biopsy showed the last eight years. Her asthma had gotten worse evidence of necrotizing vasculitis with intensive over the last three years with fre q u e n t eosinophil infiltration with granuloma (Fig. 2). exacerbations that needed short courses of steroid Her other investigations (including hemoglobin for control. Clinical examination initially was level, platelets count, renal, liver and thyro i d unremarkable but later showed vasculitic rash on function test, stool for parasites, serum Troponin previously mentioned areas. levels, antinuclear antibodies, cytoplasmic(c)ANCA Her investigations showed leukocytosis with and blood for aspergillus antibodies) were all severe eosinophilia (WBC = 16 x 109, eosinophils normal. count 8.7 x 109, 53.8%), high erythro c y t e The diagnosis of CSS was made and she was sedimentation rate (ESR = 107 mm/h), C-reactive started on prednisolone 60 mg daily. She showed protein (CRP = 71.6 mg/l), rheumatoid factor (RF = immediate dramatic response with disappearance
Address correspondence to: Dr.Jehan A Qassem, Department of Medicine, Al-Amiri Hospital, P.O. Box::4077, Safat- Code :13041, Kuwait. Tel: 4881257(R), (M )9704001, (P) 9165900, E-mail:[email protected] 288 Severe Hypereosinophilia in an Asthmatic Young Female September 2007
Fig. 1: High resolution CT chest shows scattered peripheral pulmonary Fig. 2: Section from lung biopsy shows evidence of necrotizing vasculitis infiltrations with intense eosinophil infiltration of all symptoms, normalization of eosinophil count, Peripheral nerve involvement is typical of ESR and HRCT chest picture. She remained in mononeuritis multiplex while cranial nerve palsies remission while her prednisolone dose was tapered are infrequent and when the former is seen in over the next 16 months and then discontinued. asthmatic patient with eosinophilia the diagnosis of Currently she is under close follow-up clinically, CSS is almost certain[2,4]. Skin lesions can occur in biochemically and radiologically for any possible any form but palpable purpura is the most frequent relapse. form[2,7]. Cardiac and gastro-intestinal involvement a re the two major causes of morbidity and DISCUSSION mortality with the former being responsible for 48% CSS is a necrotizing systemic vasculitis, which of deaths in one series[1,2,7]. On the other hand, renal involves small vessels and is distinguished by involvement which is a major and serious feature in asthma, hypereosinophilia and extra-vascular other types of vasculitis occurs only in 20% of cases, granuloma[1]. Its prevalence varies in the general commonly as mild hematuria with albuminuria population with a frequency of 2.4 - 6.8 per one and focal segmental glomerulonephritis while renal million patients per year. It is global in distribution failure occurs in only 9% of cases[3,7]. Laboratory with no significant gender predilection. It occurs in features including high ESR, CRP and IGE level are all age groups but is most common in third to fifth non-specific while severe peripheral eosinophilia is decade of life[3,4]. The exact etiology is still unknown the hallmark of CSS. ANCA, mainly perinuclear on but allergic or immuno-pathogenesis was the other hand is only positive in 50 to 75% of cases suggested[2,3]. CSS was also described in association and so can be a valuable adjunct in supporting the with macrolides and leukotrine re c e p t o r s diagnosis[1,7]. antagonists although evidence points clearly to Radiologically 27 to 93% of cases will show s t e roids withdrawal unmasking the disease[ 3 - 6 ]. abnormality on chest radiograph (72% - non- Clinically it has three distinct consecutive phases: segmental air space disease, 40% - transient (1) prodromal phase that may persist for many L o ff l e r’s pneumonia, 67% - patchy multifocal years consisting of asthma often preceeded by peripheral consolidation) while thin section CT, allergic rhinitis, which is often the first evidence of which is abnormal in 88% to 100% of cases often disease, (2) second phase of marked peripheral shows subpleural consolidation with lobular eosinophilia with tissue infiltration and (3) life- distribution, centrilobular perivascular densities, threatening vasculitis phase. Because of this, it may and bronchial wall thickening[2]. be difficult for non-specialists to recognize the Although CSS can be readily diagnosed on di s o rd e r [1 , 2 ] . Asthma usually precedes the development clinical grounds, histological confirmation should of vasculitis by period of weeks to years (0 to 30 always be sought whenever possible by biopsy of years with an average of 6 years); it is often any involved organ to confirm the presence of an p ro g ressively severe and re q u i res steroids for eosinophilic infiltration or vasculitis [2-4]. In our case, adequate control[1,3]. although the patient had a classical presentation of The disease most frequently involves the lungs CSS and the skin biopsy showed evidence of (100%), nerves (75%), skin (81%), heart (37.5%) and vasculitis which was enough to make diagnosis, ga s t r o-intestinal system. The pulmonary involvement open lung biopsy (which is not needed for all cases) is universal and manifests as transient pulmonary was still done mainly to rule out other types of infiltration that antedate vasculitis in 40% cases[2,7]. necrotizing vasculitis that have different prognoses September 2007 KUWAIT MEDICAL JOURNAL 289 and response to treatment. In conclusion, recognition of CSS as separate Accurate diagnosis remains problematic as none disease entity is important because of it’s of the features are pathognomonic and because distinctive natural history, frequent rapid response asthma itself might be associated with sinusitis and to treatment and good prognosis that suggests a pulmonary infiltration[3,4]. For this reason, in 1990 pathogenic mechanism diff e rent in nature and the American College of Rheumatology developed degree from other forms of vasculitis[3]. All of the six criteria, four or more of which are required for available classifications and definitions have diagnosis. Although they were not designed for obvious limitations especially in mild and limited this purpose, they are still widely used (sensitivity disease or those who have already started steroid and specificity of 85 and 99% respectively). They therapy. The difficulties highlight our need for includes asthma, eosinophilia > 10%, neuropathy, better understanding of the underlying pathogenesis non-fixed pulmonary infiltration, paranasal sinus for purpose of diagnosis and other therapeutic abnormality and biopsy containing extravascular interventions for some of the patients as currently eosinophil infiltration[7]. case reports are plentiful but without evidence Treatment remains an unresolved pro b l e m support. given the rarity of the disease with no established protocol whose efficacy has been documented in REFERENCES trials[1]. 40% of cases are treated with steroids alone for 12-18 months while immune suppressive agents 1. Rosa D, Baldini C, Tavoni A. Churg-Strauss Syndrome clinical and serological features of 19 patients from a single are added only in life-threatening conditions such Italian centre. Rheumatology 2002, 41:1286-1294. as severe CNS, cardiac and gastro - i n t e s t i n a l 2. Hichoi Y, Junggi IM, Bukyung H. Thoracic Manifestations involvement or in those cases who do not respond of Churg-Strauss Syndrome: Radiological and clinical adequately to steroids[4-7]. Some authors recommend findings. Chest 2002; 117:117-124. routine use of cyclophosphamide in all cases 3. Eustace JA, Nadasdy T, Chol M. The Churg Strauss Syndrome. J Am Soc Nephrol 1999, 10:2048-2055. although this did not show improvement in 10 year 4. Noth I, Estrk M, Rleff A. Churg-Strauss Syndrome. The survival rate and increased the rate of infection by Lancet 2003; 361:587-594. 10%[3-4]. Use of plasmapheresis alone did not offer 5. Mario J, Alonso J, Crespo F. More about Churg-Strauss additional benefit whereas when it was combined S y n d rome and Montelukast Treatment. Chest 2001; with intravenous immunoglobulin therapy a 120:2116. [8] 6. Wechsler ME, Finnd R, Gunawardena D. Churg-Strauss benefit was demonstrated in several case reports . Syndrome in patients receiving Montelukast as treatment M o re o v e r, preliminary observations suggest for asthma. Chest 2001; 117:708-713. efficiency of high dose alpha interferon in treating 7. Solans R, Bosch T, Bacanegra C. Churg-Strauss Syndrome: patients with incomplete response to steroids or Outcome and long term follow up of 32 patients. infection complications[9]. Rheumatology 2001; 40:63-771. 8. Danieli MG, Malcangi MG. Long term effectiveness of intra Overall, remission in CSS is 81 to 92% with a venous Immunoglobulin in Churg-Strauss Syndrome. Ann relapse rate of 26 to 28%. It could be 40% in first Rheum Dis 2004; 63: 1649-1654. year but is much rare afterwards. The blood 9. Stratios Tatsis EF, Schnabel A. Interferon alpha treatment of eosinophil count is the only sensitive indicator for four patients with the Churg-Strauss Syndrome. Ann Int activity or relapse as relapses are always preceeded Med 1998; 129:370-374. [ 4 , 7 , 9 ] 10. Keogh KA, Specksu CD. Churg-Strauss Syndrome: clinical by an increase in the count . The overall presentation, anti neutrophil cytoplasmic antibodies and p rognosis is good with low mortality rate leuko Triene receptor antagonists. Am J Med 2003; 115:284- compared to other forms of vasculitis[10]. 290. KUWAIT MEDICAL JOURNAL September 2007
Selected Abstracts of Articles Published Elsewhere by Authors in Kuwait
Kuwait Medical Journal 2007, 39 (3): 290-291
Injuries to the Major Airway after Blunt Thoracic Trauma in Children: Review of 2 Cases
Jamal-Eddine H, Ayed AK, Peri_ M, Ben-Nakih ME. Thoracic Surgical Department, Chest Diseases Hospital, Kuwait City, Safat 13041, Kuwait
J Pediatr Surg 2007; 42:719-721
Tracheobronchial injuries in children occur rarely. Their diagnosis is often very difficult and needs a high degree of suspicion, with in-depth knowledge of the anatomy of and radiological findings for the chest. With proper surgical management, even a delayed diagnosis can result in normal lung function. We discuss 2 cases of major airway injuries with successful outcomes and present some interesting surgical maneuvers.
Relative Contribution of Digital Rectal Examination and Transrectal Ultrasonography in Interpreting Serum Prostate-Specific Antigen Values for Screening Prostate Cancer in Arab Men
Sheikh M, Sinan T, Kehinde EO, Hussein AY, Anim JT, Al-Hunayan AA Department of Radiology, Faculty of Medicine, Kuwait University P.O. Box 24923, Safat, 13110 Kuwait. E-mail: [email protected]
Ann Saudi Med. 2007; 27:73-78
Background: This study was conducted to determine the utility of digital rectal examination (DRE), transrectal ultrasonography (TRUS) and serum prostate-specific antigen (PSA) in the diagnosis of prostate cancer in men in Arabia, an are of the world with a relatively low incidence of this disease. Patients And Methods: 329 patients suspected of having prostate cancer on account of raised serum PSA level (>4 ng/ml), DRE or TRUS findings, underwent TRUS-guided prostate biopsy. Raised PSA individually as well as combined, or a lesion suspicious of carcinoma on DRE or TRUS was recorded as PSA(+), DRE(+) or TRUS(+), respectively. The contribution of DRE, TRUS and serum PSA to the diagnosis of prostate cancer was analysed. Results: Of the 329 patients who had prostate biopsies 109 cases (33.1%) had PCa. Of these 109 patients 56 (51%) had DRE(+), 77 (42%) had TRUS(+) and 49 (66%) had both DRE(+) and TRUS(+). Statistical analysis revealed that DRE(+) tripled the probability for cancer. PSA over a range of 10-50 ng/mL demonstrated an increasing cancer probability ranging from 2 to 3 fold. TRUS(+) was only significantly associated with cancer risk if PSA was elevated. The presence of all three factors increased the cancer probability by 6 to 7 fold. Conclusion: TRUS findings are dependent on PSAfor interpretation while DRE(+) with elevated PSA makes PCa more likely. September 2007 KUWAIT MEDICAL JOURNAL 291
Different Responses to Angiotensin-(1-7) in Young, Aged and Diabetic Rabbit Corpus Cavernosum
Yousif MH, Kehinde EO, Benter IF Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Kuwait.
Pharmacol Res 2007; Jun 19: [Epub ahead of print]
We evaluated the ability of angiotensin-(1-7) [Ang-(1-7)] to produce relaxation of the corpus cavernosum of New Zealand White rabbits. The reactivity of corpus cavernosal strips isolated from young rabbits (8-10 months old) was assessed in organ-bath chambers. Cumulative concentration response curves for Ang-(1-7), angiotensin II (Ang II), carbachol and sodium nitroprusside (SNP) were established. Ang-(1-7) (10(-12) to 10(-5)M) produced a concentration-dependent relaxation of the corpus cavernosal strips with a pD(2) value of 9.8+/-0.3. Ang-(1-7)-induced maximal relaxant response was reduced by 48+/-2%, 57+/-3% and 76+/-2% in the presence of A-779 (10(-6)M), a selective Ang-(1-7) receptor (AT(1-7)) antagonist, nitro-l-arginine methyl ester (l-NAME) (10(-4)M), an inhibitor of nitric oxide (NO) synthase, or iberiotoxin (5x10(-8)M), an inhibitor of calcium-activated potassium (BK) channels, respectively. In contrast, Ang II-induced contraction was increased in the presence of A-779. Carbachol-, SNP- and Ang-(1-7)-induced relaxations were significantly reduced whereas Ang-II induced contraction was significantly increased in the cavernosum strips from older (18-24 months old) and diabetic rabbits compared to the young. Pre-incubation of the cavernosum strips obtained from young, older or diabetic rabbits with Ang-(1-7) resulted in a significant attenuation of Ang II-induced contraction. In conclusion, these results demonstrate that Ang-(1-7) can produce nitric oxide-dependent relaxation of the corpus cavernosum through activation of AT(1-7) and BK channels. Older and diabetic animals showed impaired Ang-(1-7)-mediated relaxation suggesting that aging and diabetes related erectile dysfunction (ED) may be partly due to decreased Ang-(1-7)-mediated relaxation of the corpus cavernosum. Acute pre-incubation with Ang-(1-7) was effective in attenuating Ang II-induced contraction of rabbit corpus cavernosum suggesting that the possible role of Ang-(1-7) in treatment of ED should be investigated.
Factors Influencing Engraftment in Autologous Pperipheral Stem Cell Transplantation. The experience of a Local Kuwaiti Transplantation Center
Alshemmari SH, Ameen RM, Gyrafas J, Alqallaf DA, Sajnani KP. Department of Medicine, Faculty of Allied Health Sciences, Kuwait University, State of Kuwait, PO Box 24923, Safat 13110, Kuwait. E-mail: [email protected]
Saudi Med J 2007; 28:1080-1085
Objective: To assess factors affecting engraftment among patients with lymphoproliferative disorders treated with high dose-chemotherapy and autologous peripheral blood stem cell transplantation. Methods: Fifty-four patients with lymphoproliferative disorders were treated from March 2000 to April 2006, at the Hamid Al-Essa Multiorgan Transplant Center, Kuwait. There were 37 males and 17 females, with a median age of 43 years (range 12-60). The cohort included 13 Hodgkin’s lymphoma, 31 non-Hodgkin’s lymphoma, and 10 multiple myeloma cases. Results: The median number of infused CD34+ cells was 1.7x10(6) per kg (0.38-15). The medians for absolute neutrophil count (ANC) and platelet (PLT) engraftment were 12 days (10-15) and 11 days (6- 33). The CD34+ cell dose and timing of granulocyte-colony stimulating growth factor administration had no significant influence on ANC engraftment (p=0.3 and p=0.05). Conclusion: The results imply that the CD34+ cell dose is the most important predictor of hematopoietic engraftment, namely PLT engraftment. The other factors studied had no clear influence on engraftment kinetics in this cohort. KUWAIT MEDICAL JOURNAL September 2007
Forthcoming Conferences and Meetings
Compiled and edited by Babichan K Chandy
Kuwait Medical Journal 2007, 39 (3): 292-297
Mayo Clinic Gastroenterology & Hepatology Interventional Ultrasound in new Millenium-2007 Board Review Sep 15 - 16, 2007 Sep 06-09, 2007 Kiev, Ukraine Chicago, IL, United States Contact: Meeting Organiser Contact: Mayo Clinic - Mayo School of Continuing Tel: 00-38-0-632-776-465 Fax:00-38-0-445-331-270 Medical Education E-mail: [email protected] Tel: 800-323-2688 E-mail: [email protected] International Workshop on Regulation of Pathology & Laboratory Coding & Transport Phenomena in Biological Systems Reimbursement Confere nce Sep 16-19, 2007 Sep 09-11, 2007 Antalya, Turkey Orlando, FL, United States Contact: Meeting Organiser Contact: Lacy Tel: 90-3-122-105-214 Fax:90-3-122-101-429 Tel: 1-866-251-3060 E-mail: [email protected] / [email protected]
th 8 World Congress of Perinatal Medicine AOCOG 2007: The XX Asian and Oceanic Sep 09-13, 2007 Congress of Obstetrics and Gynecology Florence, Italy Sep 21-25, 2007 Contact: MCA Events - Roberto Caflisch Tokyo, Japan Tel: 39-0-234-934-404; Fax: 39-0-234-934-397 E-mail: [email protected] Contact: Secretariat of AOCOG 2007, c/o ICS Convention Design, lnc. Sumitomo Corp. Jinbocho On Ovulation Induction 2007 Bldg, 3-24, Kanda-Nishikicho, Chiyoda-ku, Tokyo Sep 13-15, 2007 101-8449, JAPAN Rome, Italy Tel: 81-3-3219-3541; Fax: 81-3-3292-1811 Contact: Emanuela Ruggeri E-mail: [email protected] Tel: 00-39-0-51-223-260; Fax: 00-39-0-51-222-101 E-mail: [email protected] Obesity Treatment-2007 Sep 22-23, 2007 Women’s Health Kiev, Ukraine Sep 15-22, 2007 Contact: Meeting Organiser Honolulu, HI, United States Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 Contact: Sandra Barnhart Tel: 1-800-422-0711; Fax: 727-527-3228 E-mail: [email protected] E-mail: [email protected] 3rd International Clinical Trials Symposium Interventional Ultrasound in new Millenium-2007 Sep 23-26, 2007 Sep 15-16, 2007 Sydney, NSW, Australia Kiev, Ukraine Contact: Sandra Ibrahim Contact: Meeting Organiser Tel: 61-29-545-000; Fax: 61-292-513-552 Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 E-mail: [email protected] E-mail: [email protected] Update in Clinical Cardiology The 46th National Congress of Cardiology of the Sep 26-28, 2007 Romanian Society of Cardiology United States Sep 15-18, 2007 Boston, MA, Sinaia, Romania Contact:Harvard Medical School CME Office Contact: Meeting Organiser Tel: 617-384-8600 Fax:617-384-8686 E-mail: [email protected] E-mail: [email protected] September 2007 KUWAIT MEDICAL JOURNAL 293
61st High Blood Pressure Research Conference XVI International Symposium on Drugs Affecting 2007 Lipid Metabolism Sep 26-29, 2007 Oct 04 - 07, 2007 Tucson, AZ, United States New York, NY, United States Contact: Anita Lara Contact: Ann Jackson Tel: 214-706-1773 Tel: 713-797-0401 Fax: 713-796-8853 E-mail: [email protected] E-mail: [email protected] Reproductive Health 2007 Controversies and Advances in the Treatment of Sep 26-28, 2007 Cardiovascular Disease: The Seventh in the Series Minneapolis, MN, United States Contact: Carole Berke Oct 04 - 05, 2007 Tel: 202-466-3825; Fax: 202-466-3826 Beverly Hills, CA, United States E-mail: [email protected] Contact: Laurel Steigerwald Tel: 760-720-2263 Fax: 760-720-6263 2007 Cardiometabolic Health Congress E-mail: [email protected] Sep 27 - 29, 2007 Boston, MA, United States Clinical Update in Thrombosis and Contact: Dina Kouveliotes Anticoagulation Tel: 877-571-4700 Fax: 866-218-9168 Oct 04 - 05, 2007 E-mail: [email protected] Rochester, MN, United States Contact: Connie Levell Mammography Update 2007 Tel: 507-538-6253/800-533-1710 Fax: 507-284-8016 Sep 27-28, 2007 E-mail: [email protected] Madison, WI, United States Contact: Terese Bailey Plastic, Reconstructive and Aesthetic Surgery- Tel: 608-240-2141; Fax: 608-240-2151 2007 E-mail: [email protected] Oct 06-07, 2007 Kiev, Ukraine 8th International Meeting “AICT 2007 - Athens Interventional Cardiovascular Therapeutics VIII” Contact: Meeting Organiser Sep 28 - 29, 2007 Tel: 00-38-0-632-776-465; Fax: 00-38-0-4-453-331-270 Athens, Greece E-mail: [email protected] Contact: Mrs. Penelope Mitroyianni Tel: 302-107-257-693 Fax: 302-107-257-532 Cardiology, Radiology, & Oncology Coding & E-mail: [email protected] Reimbursement Conference Oct 07 - 10, 2007 Emergency Medicine -2007 Naples, FL, United States Sep 29-30, 2007 Contact: Lacy Kiev, Ukraine Tel: 1-866-251-3060 Contact: Meeting Organiser Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 7th International Congress on Coronary Artery E-mail: [email protected] Disease Oct 07 - 10, 2007 Bleeding Complications in the treatment of Acute Venice, Italy Coronary Syndrome Contact: Meeting Organiser Oct 03 - 05, 2007 Lund, Sweden Tel: 41-229-080-488 Fax: 41-227-322-850 Contact: Meeting Organiser E-mail: [email protected] E-mail: [email protected] 17th World Congress on Ultrasound in Obstetrics Coronary Interventions and Gynecology Oct 03 - 05, 2007 Oct 07-11, 2007 San Diego, CA, United States Florence, Italy Contact: Gretchen Ploen Contact: IUSOG Secretariat Tel: 858-587-4404 Fax: 858-587-4438 Tel: 44-0-2-074-719-955; Fax: 44-0-2-074-719-959 E-mail: [email protected] E-mail: [email protected] 294 Forthcoming Conferences and Meetings September 2007
Cancer and Cardiology in Primary Care 27th Annual Current Concepts in Primary Care Oct 11 - 13, 2007 Cardiology & EKG Course Asheville, NC, United States Oct 17 - 20, 2007 Contact: Registrar Big Island of Hawaii, HI, United States Tel: 800-462-9633 Fax: 904-953-2954 Contact: Continuing Medical Education Office, E-mail: [email protected] 3560 Business Drive, Suite 130, Sacramento, CA 95820 5th Annual World Congress on the Insulin Tel: 916-734-5390 / 866-263-4338 / 866-CME-4EDU Resistance Syndrome E-mail: [email protected] Oct 11 - 13, 2007 th Menopause & Newton, MA, United States 4 International Congress on Osteoporosis Contact: Nava Mekel Oct 17-21, 2007 Tel: 818-342-1889 Antalya, Turkey Contact: Erhan Senol European Conference on Myocardial and Tel: 90-2-123-684-795; Fax: 90-2-122-306-425 Pericardial Diseases with Focus on Heart Diseases E-mail: [email protected] in Women Oct 11 - 14, 2007 21st Century Treatment of Heart Failure: Marburg, Germany Synchronizing Surgical and Medical Therapies Contact: Meeting Organiser for Better Outcomes E-mail: [email protected] Oct 18 - 20, 2007 Cleveland, OH, United States 23rd IUSTI (International Union against Sexually Contact: Heart House, 2400 N Street NW, Transmitted Infections) Europe Conference on Washington DC, 20037 Sexually Transmitted Infections and HIV/AIDS Tel: 202-375-6000 Fax: 202-375-7000 Oct 11-14, 2007 Dubrovnik, Croatia The VII-th Congress of Angiology and Contact: Prof. Mihael Skerlev, M.D., Ph.D, Ambulatory Medicine Conference President Oct 18 - 20, 2007 Tel: 385-1-4862-600 Timisoara, Romania E-mail: [email protected] Contact: President Prof.Dr.Avram J. Tel: 00-4-0-74-526-200 Fax: 00-4-0-256-489-628 Thoracic Surgery -2007 E-mail: [email protected] Oct 13-14, 2007 CHEST 2007 Kiev, Ukraine October 20 - 25, 2007 Contact: Meeting Organiser Chicago, IL, United States Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 Contact: American College of Chest Physicians, E-mail: [email protected] 3300 Dundee Road, Northbrook, Illinois 60062- 2348 rd 3 NRITLD-ERS Joint International Conference on Tel: 847-498-1400 Fax: 800-343-2227 Pulmonary Disease, Intensive Care and TB Oct 15-18, 2007 Pain and Headache -2007 Tehran, Iran Oct 20-21, 2007 Contact: Hamideh Rastegari Kiev, Ukraine Tel: 00-982-120-109-677; Fax: 00-982-120-109-484 Contact: Meeting Organiser E-mail: [email protected] Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 E-mail: [email protected] STD Intensive Oct 16 - 18, 2007 2007 Transcatheter Cardiovascular Therapeutics Denver, CO, United States Oct 22 - 26, 2007 Contact: CME Office Washington, DC, United States Tel: 1-800-207-9399 / 513-558-7277 Fax: 513-558- Contact: Cardiovascular Reasearch Foundation 1708 / 513-558-1756 Tel: 212-851-9137 Fax: 212-851-9397 E-mail: [email protected] E-mail: [email protected] September 2007 KUWAIT MEDICAL JOURNAL 295
2nd International Saudi German HEART Pacific ASCLEPIOS Gynaecology Obstetrics Conference Perinatology Paediatrics & Midwives Oct 22 - 24, 2007 International Congress Dubai, United Arab Emirates Oct 31-Nov 02, 2007 Contact: Ms. Kaye Salas, Mr. Mohamed Abdel- Noumea, New Caledonia Maksoud Contact: Dr Kamel BARGAOUI Tel: 33-607-686-118; Fax: 33-143-839-985 Tel: 00-96-626-398-815 Fax: 00-96-626-398-816 E-mail: [email protected] E-mail: [email protected] The 8th biennial meeting of the Syrian th 24 Annual Symposium Cardiology for the Cardiovascular Association Practitioner Nov 01 - 03, 2007 Oct 22 - 24, 2007 Damascus, Syria Yosemite, CA, United States Contact: Meeting Organiser Contact: UCSF Office of Continuing Medical E-mail: [email protected] Education, 3333 California Street, Room 450, San Francisco, CA 9411 Building Palliative Care Programs in Hospitals: Tel: 415-476-4251 / 415-476-5808 Fax: 415-476-0318 Tools and Strategies for Success / 415-502-1795 Nov 01 - 03, 2007 E-mail: [email protected] San Francisco, CA, United States Contact: Hallia Baker Tel: 212-201-2680 Fetal Echocardiography E-mail: [email protected] Oct 25-26, 2007 Philadelphia, PA, United States Limited OB/GYN Ultrasound Contact: Office of CME, 1020 Locust Street, Suite Nov 01-03, 2007 M5, Philadelphia, PA 19107-6799 Tel: 1-888-JEFF- Philadelphia, PA, United States CME / 215-955-6992; Fax: 215-923-3212 Contact: Office of CME, 1020 Locust Street, Suite E-mail: [email protected] M5, Philadelphia, PA 19107-6799 Tel: 1-888-JEFF- CME / 215-955-6992; Fax: 215-923-3212 An International Symposium on Ventricular E-mail: [email protected] Arrhythmias: Pathophysiology & Therapy Oct 26 - 27, 2007 Breast Imaging Philadelphia, PA, United States Nov 05-09, 2007 United States Contact: Office of Continuing Medical Education, Palm Springs, CA, Contact: UCSF Office of Continuing Medical University of Pennsylvania School of Medicine, Education, 3333 California Street, Room 450, San 333 Blockley Hall, 423 Guardian Drive, Francisco, CA9411 Philadelphia, PA 19104-6021 / Belinda Rose Tel: Tel: 415-476-4251 / 415-476-5808; Fax: 415-476-0318 215-898-8006 / 215-898-8005 / 415-502-1795 E-mail: [email protected] / E-mail: [email protected] [email protected] Dermatological Care For All: A Basic Human International Vascular Conference-2007 Right Oct 27-28, 2007 Nov 06-09, 2007 Kiev, Ukraine Addis Ababa, Mekele, Ethiopia Contact: Meeting Organiser Contact: Loredana Bonazzoli Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 Tel: 39-658-543-780; Fax: 39-658-543-686 E-mail: [email protected] E-mail: [email protected] 8th Annual Pharmaceutical Regulatory and AIDS Medicine: An Intensive Case-Based Course Compliance Congress Oct 29 - 31, 2007 Nov 07 - 09, 2007 Boston, MA, United States Washington, DC, United States Contact: Harvard Medical School CME Office Contact: Paul Tunnecliff Tel: 617-384-8600 Fax: 617-384-8686 Tel: 800-684-4549 Fax: 760-418-8084 E-mail: [email protected] E-mail: [email protected] 296 Forthcoming Conferences and Meetings September 2007
2nd SGI International Summit: Reporductive Asthma, Pulmonary Hypertension-2007 Medicine International Conference Nov 08-10, 2007 Nov 10-11, 2007 Valencia, Spain Kiev, Ukraine Contact: Amparo Martinez Contact: Meeting Organiser Tel: 00-34-961-974-670; Fax: 00-34-961-974-598 Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 E-mail: [email protected] E-mail: [email protected]
nd The 2 Asia Pacific Congress on Controversies in STD Intensive Obstetrics, Gynecology & Infertility (COGI) Nov 13 - 15, 2007 Nov 08-11, 2007 Denver, CO, United States Shanghai, China Contact: CME Office Contact: Ms. Ruthi Yahav Tel: 1-800-207-9399 / 513-558-7277 Fax: 513-558- Tel: 972-3-566-6166; Fax: 972- 3-566-6177 1708 / 513-558-1756 E-mail: [email protected] E-mail: [email protected] 38th Union World Conference on Lung Health Nov 8-12, 2007 Obstetrics and Gynecology-Core Course Cape Town International Convention Centre, Cape Nov 13-17, 2007 Town, South Africa Philadelphia, PA, United States Contact: International Union Against Tuberculosis Contact: Office of CME, 1020 Locust Street, Suite and Lung Disease (The Union), 68, boulevard M5, Philadelphia, PA 19107-6799 Tel: 1-888-JEFF- Saint-Michel, 75006 Paris - FRANCE CME / 215-955-6992; Fax: 215-923-3212 Tel: (+33) 1 44 32 03 60; Fax : (+33) 1 53 10 85 54 / E-mail: [email protected] (+33) 1 43 29 45 10 www.worldlunghealth.org Cardio Lipid 2007 Egypt E-mail: [email protected] Nov 15 - 17, 2007 Ain Sokhna - Red Sea, Egypt Selective Sentinel Lymphadenectomy and Breast Contact: El Asdekaa building (1) - Masged El Ultrasound Asdekaa st. Garden city Smouha - Alexandria - Nov 09-10, 2007 Egypt San Francisco, CA, United States Tel: 203- 420-48-49 / 20-10-122-48-49 / 20-12-248- Contact: UCSF Office of Continuing Medical 02-06 Education, 3333 California Street, Room 450, San E-mail: [email protected] Francisco, CA 9411 Tel: 415-476-4251 / 415-476-5808; Fax: 415-476-0318 5th International Meeting on Antimicrobial / 415-502-1795 Chemotherapy in Clinical Practice (ACCP) E-mail: [email protected] Nov 15-17, 2007 Santa Margherita, Italy th 7 International Congress on Obstetrics and Contact: Bassetti Gynecology Tel: 39-0-105-555-132; Fax: 39-0-103-537-680 Nov 09-13, 2007 E-mail: [email protected] Tehran, Iran Contact: Maryam Kashanian 5th World Congress of the World Society for Tel: 98-21-88-309-564-6; Fax: 98-21-88-309-567 Pediatric Infectious Diseases - WSPID E-mail: [email protected] / Nov 15 - 18, 2007 [email protected] Bangkok, Thailand Hepatocellular Carcinoma: Multi-Disciplinary Contact: Meeting Organiser Management 2007 Tel: 41-229-080-488 Fax: 41-227-322-850 Nov 10, 2007 E-mail:[email protected] Los Angeles, CA, United States Contact: Office of Continuing Medical Education, Primary Care Pulmonology David Geffen School of Medicine at UCLA , 10920 Nov 18 - 25, 2007 Wilshire Blvd., Suite 1060, Los Angeles, CA 90024- Miami, FL, United States 6512 Contact: Eileen Tener Tel: 310-794-2620; Fax: 310-794-2624 Tel: 813-333-6878 E-mail: [email protected] E-mail: [email protected] September 2007 KUWAIT MEDICAL JOURNAL 297 Turkish Sleep Society 1st Sleep Disorders Course Antibiotics in Pediatrics-2007 Nov 19 - 23, 2007 Nov 29-30, 2007 Ankara, Turkey Kiev, Ukraine Contact: Professor Oguz Kokturk, MD Contact: Meeting Organiser Tel: 905-323-263-757 Fax: 903-122-129-019 Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 E-mail: [email protected] E-mail: [email protected]
Genetics and Mechanisms of Susceptability to Practical Obstetrics and Gynecology Infectious Diseases Nov 29-Dec 01, 2007 Nov 21-24, 2007 New York, NY, United States Paris, France Contact: American College of Obstetricians and Contact: Caroline Louvet Gynecologists, 409 12th St., S.W., PO Box 96920, Fax: 33-140-613-721 Washington, D.C. 20090-6920 E-mail: [email protected] Tel: 202-638-5577 E-mail: [email protected] International Meeting: The Endothelium: Regulation and Regeneration ICCA2007 - 7th International Course on Carotid Nov 22 - 23, 2007 Angioplasty and Other Cerebrovascular Padova, Italy Interventions Contact: Prof. A. Avogaro Nov 29 - Dec 01, 2007 Tel: 39-0-498-212-178 Fax: 39-0-498-754-179 Frankfurt am Main, Germany E-mail: [email protected] Contact: Nadine Koebke Tel: 49-61-062-867-880 Fax: 49-61-062-867-882 Rheumatology for the Primary Care Physician E-mail: [email protected] Nov 24 - Dec 01, 2007 Miami, FL, United States ISN Nexus Symposium - Hypertension and the Contact: Eileen Tener Kidney Tel: 813-333-6878 . Nov 29 - Dec 02, 2007 E-mail: [email protected] Vienna, Austria Contact: Meeting Organiser Medical Biology and Biochemistry-2007 Tel: 32-27-431-546 Fax: 32-27-431-550 Nov 24-25, 2007 E-mail: [email protected] Kiev, Ukraine Contact: Meeting Organiser DVD - Pediatric Emergency Medicine: An Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 Evidence-Based Approach E-mail: [email protected] Dec 01 - 31, 2007 Sarasota, FL, United States Medicinal Chemistry 2007 Contact: Eva or Cristina Nov 26-29, 2007 Tel: 1-866-267-4263 (toll free), 1-941-388-1766 Fax: Kololi, Gambia 1-941-365-7073 Contact: Anthony F. England, Ph.D. E-mail: [email protected] Tel: 31-302-145-715; Fax: 31-302-145-715 E-mail: [email protected] Women’s Health-2007 Dec 01 - 02, 2007 Asian Intensive Care: Problems & Solutions Kiev, Ukraine Nov 28 - 30, 2007 Contact: Meeting Organiser Hong Kong, China Tel: 00-38-0-632-776-465 Fax: 00-38-0-445-331-270 Contact: Rebecca Luk E-mail: [email protected] Tel: 85-226-322-734 E-mail: [email protected] Minimally Invasive Techniques in Gynaecology Dec 03-06, 2007 Influenza, Respiratory Viruses 2007 Norderstedt, Germany Nov 29-30, 2007 Contact: European Surgical Institute, Kiev, Ukraine Hummelsbuetteler Steindamm 71, D-22851 Contact: Meeting Organiser Norderstedt, Germany Tel: 00-38-0-632-776-465; Fax: 00-38-0-445-331-270 Tel: 49-0-4-052-973-200; Fax: 49-0-4-052-973-209 E-mail: [email protected] E-mail: [email protected] KUWAIT MEDICAL JOURNAL September 2007
WHO-Facts Sheet
1. Recent Food Scares Prove Weaknesses in Food Safety Systems Around the World - FAO and WHO Urge for More Vigilance 2. Battle against Chagas the “Kissing Bug” Disease - Strategy Set Out to Eliminate Disease 3. Safe Blood for Safe Motherhood: Global Facts on Blood Safety and Donation 4. New WHO Online Tool to Improve Clinical Trial Transparency
Compiled and edited by Babichan K Chandy
Kuwait Medical Journal 2007, 39 (3): 298-302
1. RECENT FOOD SCARES PROVE “Countries are only able to keep their shares in WEAKNESSES IN FOOD SAFETY SYSTEMS globalized food markets and the trust of AROUND THE WORLD - FAO AND WHO consumers, if they apply internationally agreed URGE FOR MORE VIGILANCE food quality and safety standards,” said Ezzeddine Boutrif, Director of FAO’s Nutrition and Consumer The Food and Agriculture Organization (FAO) Protection Division. “Consumers have a right to be and the World Health Organization (WHO) urge all informed about potential hazards in food and to be countries to strengthen their food safety systems protected against them.” and to be far more vigilant with food producers and traders. Inadequate food safety systems Recent food safety incidents, like the discovery Weak food safety systems can lead to a higher of the industrial chemical melamine in animal and incidence of food safety problems and diseases fish feed, or the unauthorized use of certain caused by micro- o r ganisms such as Salmonella, E. coli, veterinary drugs in intense aquaculture, can affect Ca m p y l o b a c t e r , and Li s t e r i a , by residues of agricultural health and often lead to rejections of food products chemicals (pesticides, veterinary drugs, etc) and by in international trade. the use of unauthorized food additives. Diarrhoeal Such food safety incidents are often caused by diseases alone, mainly due to unsafe food and lack of knowledge of food safety requirements and water, kill 1.8 million children every year. of their implications, or by the illegal or fraudulent Food production systems in developing use of ingredients including unauthorised food countries are facing a series of challenges: additives or veterinary drugs. population growth and urbanization, changing During the last 12 months, an average of up to dietary patterns, intensification and industrialization 200 food safety incidents per month have been of food and agricultural production. Climate investigated by WHO and FAO to determine their conditions, poor sanitation and weak public public health impact. Information about food safety infrastructure compound these difficulties. Food incidents of international significance was shared safety legislation in many developing countries is with countries through the International Food often incomplete or obsolete or not in line with Safety Authorities Network (INFOSAN). international requirements. Responsibility for food “Food safety is an issue for every country and safety and control tends to be dispersed across ultimately every food consumer. All countries can many institutions. Laboratories lack essential benefit from taking stronger measures to fill safety equipment and supplies. gaps in the sometimes considerable journey food Many developed countries are in similar takes from the farm to the table,” said Dr Jørgen situations with fragmented food safety systems that Schlundt, Director of WHO’s Department of Food often do not include or cover primary production Safety, Zoonoses and Food borne Diseases. w h e re many food safety issues originate. For
Address correspondence to: Office of the Spokesperson, WHO, Geneva. Tel.: (+41 22) 791 2599; Fax (+41 22) 791 4858; E-mail: [email protected]; Web site: http://www.who.int/ September 2007 KUWAIT MEDICAL JOURNAL 299 example the spread in recent years of new fatigue, swollen glands and heart pain, but in later Salmonella strains in poultry originated in years the infection can lead to chronic debilitation developed countries and was spread globally caused by progressive destruction of the heart through trade. muscle. It occurs mainly in Latin America where, In order to ensure safe food production for their during the 1980s, over 20 million people were own consumers and to meet international sanitary thought to be infected. Since then, Latin American and phytosanitary requirements for food exports, countries have made enormous efforts to control national food safety authorities should be more the infection, such that current estimates suggest vigilant. Producers and traders should be held that less than eight million people remain infected. accountable for safe food production throughout However, the infection is no longer confined to the the food chain. Americas because of blood transmission and organ The rules of the World Trade Org a n i z a t i o n transplantation. Cases have been identified in non- stipulate that developed countries help exporting endemic countries in Europe, and in Canada and developing countries to achieve the necessary high the United States. level of food safety for international trade. This Although remarkable success has been achieved assistance should contribute to building or in the Region of the Americas in eliminating s t rengthening integrated national food safety vectorial transmission of Chagas, much remains to systems covering the entire food chain. This often be done, to reduce the risk of transmission to requires long-term multi-billion dollar investments recipients of blood or blood products obtained and technical advice. from migrants from Chagas endemic areas, and to e n s u re screening and diagnosis of congenital For more information contact: FAO: Erwin Chagas disease. Northoff, Media Relations, FAO, Tel:(+39) 06 570 The parasite that causes Chagas disease is called 53105, Mobile: (+39) 348 252 3616, Email: T. cruzi and is mainly transmitted by large blood- [email protected]. sucking insects, sometimes known as ‘kissing WHO: Christine McNab, Communications bugs’, that often colonise the homes of poorer rural department, WHO, Tel: (+41) 22 791 4688, Mobile: communities in Latin America. But the parasite can (+41) 79 254 6815, Email: [email protected]. also be transmitted by blood transfusion or organ transplant from infected donors, and occasionally 2. BATTLE AGAINST CHAGAS THE “KISSING by transplacental passage from infected mother to BUG” DISEASE - STRATEGY SET OUT TO new-born baby. In some regions, particularly in the ELIMINATE DISEASE southern cone countries of South America, the c h ronic infection can also give rise to severe A new effort to eliminate Chagas disease by intestinal problems requiring complex corrective 2010 was launched at a World Health Organization surgery. (WHO) meeting of disease experts and partners, in The WHO Global Network will focus on several July 2007. The strategy was designed to answer key key aspects of the Chagas problem including: questions about the treatment and control of l st r engthening epidemiological surveillance Chagas disease, and to coordinate global efforts and information systems; toward the prevention of transmission through a l pr eventing transmission by blood transfusion new Global Network for Chagas Elimination. and organ transplantation in endemic and “The establishment of the WHO Global non-endemic countries; Network to combat Chagas disease occurs in the l identifying a diagnostic test(s) for scree n i n g b roader context of the WHO’s renewed fight and diagnosis of infections; against neglected tropical diseases. The prospects l expanding secondary prevention of congenital for reducing the burden caused by these diseases transmission and case management of have changed dramatically in the past few years. congenital and non-congenital infections; While Chagas disease is controlled in many and countries in the Americas, commitment must be l promoting a consensus on adequate case strengthened as elimination of the disease is now management attainable. Cases identified in non-endemic In keeping with the goal of eliminating Chagas countries have demonstrated the need to globalize disease by 2010, the WHO Global Network plans to our efforts. “said Dr Marg a ret Chan, WHO develop a five pillar strategy before the end of this Director- general. year. Chagas disease is a serious, potentially life- Earlier this year, WHO together with partners threatening illness caused by a protozoan parasite f rom across the public, private and non- called T. cruzi. Early symptoms can include fever, governmental sectors, launched a campaign to 300 WHO-Facts Sheet September 2007 a d d ress neglected diseases. An estimated one requiring transfusion do not have timely access to billion people are affected by one or more of these safe blood. Despite advances in medical science, it diseases and very often, the victims are among the will be many years before artificial blood poorest populations. substitutes can routinely replace the need for the donation of human blood. Every country needs to For more information contact:John Rainford, avoid blood shortages and ensure that blood Communications Officer, Pandemic and Outbreak supplies are free from HIV, hepatitis viruses and Communications, WHO, Geneva, Tel: +41 22 791 other life-threatening infections that can be 3982, Mobile: +41 79 516 3709, Email: transmitted through unsafe transfusion. [email protected] OR Daniel Epstein, Information Officer, PAHO/WHO, Tel: +1.202.974-3459 office, Blood supply: While the need for blood is Mobile: +1.202 316-5679, Email: [email protected] universal, there is a major imbalance between developing and industrialized countries in access to safe blood. 3. SAFE BLOOD FOR SAFE MOTHERHOOD: l Only 45% of the global blood supply is GLOBAL FACTS ON BLOOD SAFETY AND collected in developing countries, which DONATION are home to more than 80% of the world’s population Safe Blood for Safe Motherhood l In sub-Saharan Africa, fewer than three Globally, more than half a million women die million units of blood are collected each each year during pregnancy, childbirth or in the year for a population of more than 700 postpartum period - 99% of them in the developing million people world. An estimated 25% of those deaths are l Out of 80 countries that have donation caused by severe bleeding. rates of less than 1% of the population l Of the 20 countries with the highest (fewer than 10 donations per thousand maternal mortality ratios, 19 are in sub- people), 79 are in developing regions; it is Saharan Africa where the lifetime risk of generally recommended that 1-3% of the maternal death is one in 16, compared with population give blood to meet a country’s one in 2800 in rich countries. needs l Severe bleeding during delivery or after l The average number of blood donations childbirth is the commonest cause of per 1,000 population is 11 times higher in maternal mortality and contributes to high-income countries than in low-income around 34% of maternal deaths in Africa, countries. 31% in Asia and 21% in Latin America and the Caribbean. Types of blood donation: The safest blood is donated by the safest blood Postpartum bleeding is unpredictable and the donors. The prevalence of HIV, hepatitis viruses quickest of maternal killers. It can kill even a and other blood-borne infections is lowest among healthy woman within two hours, if unattended. voluntary unpaid blood donors who give blood Blood transfusion has been identified as one of the purely for altruistic reasons. Higher infection rates eight key life-saving functions that should be are found among family or family replacement available in healthcare facilities pro v i d i n g donors who give blood only when it is required by comprehensive emergency obstetric care. Access to a member of the patient’s family or community. a safe and sufficient blood supply could help to Worldwide, the highest rate of infection is found p revent the deaths of a significant number of among donors who give blood for money or other mothers and their newborn children each year. form of payment. Adequate stocks of safe blood can The impact that access to safe blood can have on only be assured by regular donation by voluntary health outcomes for pregnant women with severe unpaid blood donors. bleeding is illustrated by Malawi. In 2003, the The 2004 data reveal some tangible improv e m e n t s country established the Malawi Blood Transfusion since 2001-2002, but family/replacement donors Service. In 2005, the maternal mortality rate due to and paid donors still remain a significant source of severe blood loss had fallen by more than 50%. blood for transfusion in many developing and transitional countries. Global data: WHO has collected data from 172 l A total of 60 countries reported an increase countries, covering 95% of the world’s population, in the percentage of blood donated by based on 2004 figures. Blood transfusion saves lives voluntary unpaid blood donors and a and improves health, but millions of patients further 41 countries maintained the same September 2007 KUWAIT MEDICAL JOURNAL 301
level; 37 countries showed a decline in the infections and is not affordable or cost-effective in percentage of blood donations from unpaid most developing and transitional countries. voluntary blood donors. l Fourtyone out of 148 countries (28%) that l In 2002, 39 countries had achieved 100% provided data on screening for transfusion- unpaid voluntary blood donation, of which transmissible infections including HIV, five were developing countries. By 2004, hepatitis B and C, and syphilis were not this had risen to 50 countries. Out of the 11 able to screen all donated blood for one or new countries that achieved this, thre e more of these infections. were least developed countries. l However, globally, the number of tests not l Ministries of health in three countries performed for the markers for four main reported very significant strides in infections (HIV, HBV, HCV and syphilis) achieving 100% voluntary unpaid decreased from six million in 2002 to 1.5 donation. These are Central A f r i c a n million in 2004. The most marked Republic (where the proportion increased reduction was seen in the African region from 25% to 100%), Egypt (from 15% to where the number of tests not performed 100%) and Uruguay (28% to 100%). was reduced from more than one million in l M o re and more countries are moving 2001-02 to 380 000 in 2004. towards voluntary blood donation. In 2002, l In 2004, the following countries achieved 63 countries were collecting less than 25% universal screening for all four of their blood from voluntary unpaid recommended markers of transfusion- donors; by 2004, this had fallen to 46 transmissible infections: Benin, Buru n d i , countries. Chile, Democratic Republic of Congo, l Particularly striking was the increase from E c u a d o r, Guinea-Bissau, Honduras, 25% to 47% in the proportion of total Mauritania, Uzbekistan and Democratic donations collected from voluntary non- Republic of Korea remunerated blood donors in developing l Out of 40 countries in sub-Saharan Africa, and transitional countries. 28 countries have yet to implement l The number of units donated in national quality systems in their blood transitional countries has increased from 29 transfusion services. million in 2002 to 36 million in 2004. l 92% of donations in developed countries Blood usage a re from voluntary unpaid donors as Data on blood utilization are limited, but studies compared to about 67% in developing and suggest that transfusions are often given transitional countries. This means that unnecessarily when simpler, less expensive family/replacement donors still remain a treatments can provide equal or greater benefit. Not significant source of blood for transfusion only is this wasteful of a scarce resource, it also in low HDI and medium HDI countries. exposes patients unnecessarily to the risk of serious l M o re than 2.2 million units were still adverse transfusion reactions or transfusion- collected from paid blood donors in 2004 in transmitted infections. which the level is the same as compared to the last survey. The majority of these (94%) For more information contact: Daniela Bagozzi, were collected in medium HDI countries. Communications Officer, Health Technology and Pharmaceuticals, WHO, Geneva, Tel: +41 22 791 4544, Blood screening Mobile: +41 79 475 5490, Email: [email protected]. WHO recommends that, at minimum, all blood for transfusions should be screened for HIV, 4. NEW WHO ONLINE TOOL TO IMPROVE hepatitis B, hepatitis C and syphilis. Complete and CLINICAL TRIAL TRANSPARENCY accurate data on the testing of donated blood are not available in the majority of developing The World Health Organization (WHO) countries, particularly in those where blood launched this year, a new web site that will enable services are fragmented, but many do not yet have re s e a rchers, health practitioners, consumers, reliable systems for testing because of staff journal editors and reporters to search more easily shortages, poor quality test kits or irre g u l a r and quickly for information on clinical trials. The supplies, and lack of basic laboratory quality site works as an entry point or portal into multiple, systems. The advanced technology used in many high quality clinical trial registers with a global developed countries is unable to detect very recent search function. 302 WHO-Facts Sheet September 2007
For a doctor or a patient, identifying all clinical through the ever increasing number of registers trials relevant to a decision to receive a specific that now exist, and knowing which re g i s t e r s treatment option is a difficult task, made easier if provide information that is accurate and reliable. the results have been reported in the published The quality of information accessible through l i t e r a t u re. However, a significant proportion of the WHO portal is assured as registers providing re s e a rch is never published and, even if it is data to the search portal are all collaborators in the published, it is possible that only part of the story is WHO Network of Collaborating Clinical Tr i a l told in the publication. Relying on information registers, also announced today. The Network will p rovided only by published trial re s e a rch is p rovide a forum for registers to exchange t h e re f o re, unreliable and leads to inadequately information and work together to establish best informed treatment decisions. practice for clinical trial registration. Registers in The only way to ensure the availability of the Network that contribute data to the search complete and accurate information about clinical portal have agreed to prospectively register trials, trials is for all trials to be registered before any are able to collect all 20 items in the WHO Trial participants are recruited. WHO believes that the Registration Data Set and have mechanisms in registration of clinical trials is a scientific, ethical place to ensure the optimal quality of the data and moral responsibility. p rovided. They are also re q u i red to publicly “The Clinical Trial Search Portal is a disclose their ownership, governance structure and collaborative international initiative led by WHO for-profit status. Details of registers meeting the that facilitates the identification of all clinical trials, required standards are available on the web site. re g a rdless of whether or not they have been “The WHO search portal is a big step forward to published. For health care researchers, funders, making it possible to search for all relevant trials in policy makers and consumers, the Portal represents a given research area. The onus now lies with all an enormous step towards greater access, investigators to be sure that their work is fully and transparency and accountability of health research meaningfully re g i s t e red in a WHO compatible globally.” Tim Evans, Assistant Director General, database,” said Jeff Drazen, Editor-in-Chief of the Information Evidence and Research, WHO. New England Journal of Medicine Clinical trial registries have now become widely accepted as an essential part of an overall strategy The WHO Clinical Trial Search Portal may be accessed for improving health outcomes. The challenge now at http://www.who.int/trialsearch/ For more facing those wanting to identify clinical trials information on the WHO International Clinical Trials research is knowing how to navigate their way Registry Platform go to http://www.who.int/ictrp.