A Ht P Ti T Ithf Approach to Patients with Fever

AhApproach to PPtiatient s with fever Pathogenesis

Pathogenเชื้อไวรัส เด็งกี่

สิ่งแวดลอม

Hostคน Environmentยุงลาย Pathogen

• Bacteria • Virus – AFI : Dengue infection, Chigunkunya virus, acute HIV – Infectious mononucleosis : EBV, CMV, HIV – Fever with rash : Measle, Rubella – Vesicular lesion : HSV, Chicken pox, HZV – Respiratory tract infection : Influenza virus, parainfluenza virus, RSV, adenovirus – Hepatitis : HAV, HBV, HCV – Encephalitis : Enterovirus, HSV, JE • Fungus : PJP, Candida, Cryptococcus • Parasite , Protozoa (Giardia lambia) Host defense system : ระบบการตอตานเชื้อของรางกาย

1.กลไกตอตานเชื้อโดยกําเนิด (Natural or innate defense) หรอกลไกตื อตานเชื้อไม จจาเพาะําเพาะ (non‐specific defense) หรหรอกลไกตอตานเชอทมอยอกลไกตื อต านเชื้อที่มีอยตลอดเวลาู (constitutive defense)

2.กลไกตอตานเชื้อที่เกิดขึ้นจากการปรบตั ัว (Adaptive defense) หรอกลไกตื อตานเชื้อชนดิ จําเพาะ (specific defense) หรอกลไกตื อตานเชื้อที่เกดจากการกระติ ุน (induced defense) Innate defense

1.โครงสรางทางกายวิภาคและสรีรวิทยา 1.1 ผิวหนัง 1.2 เยื่อเมือกบุผิว เชน น้ําตา, mucociliary apparatus ในทางเดินหายใจ, กรดในกระเพาะอาหาร, เชื้อประจาถํ ิ่นในลําไสใหญ  2. การตอบสนองตการตอบสนองตอภอภมูมคิคุมกมกนัน 2.1 เซลลในระบบภ ูมิคุมกัน : phagocyte แบงเปน 2 ชนิดคือ neutrophil และ macrophage 2.2 ระบบคอมพลีเมนต (complement system) มี 3 กลไกคอืื classical pathway, alternative pathway, lectin pathway 2.3 ปฏิกริ ิยาการอกเสบั (inflammatory response )จะเกิด การหลงั่ cytokine หลายชนิด 2.4 การสรางสารอื่น ๆ ที่มีบทบาทตอตานเชื้อ เชน ferritin Adaptive defense

• เกเกดหลงจากไดรบเชอเขาสดหลิ งจากไดั ร ับเชื้อเขาสรูรางกายและเกดตามหลงกลไกการตอตานเชอโดยธรรมชาตางกายและเกดตามหลิ ังกลไกการตอตานเชื้อโดยธรรมชาติ เซลล  phagocyte ที่จับกินเชื้อแปลกปลอมจะทําการยอยสลายเช ื้อภายในเซลลและนําสวนที่มี คุณสมบัติเปนแอนติเจนออกสผู ิวเซลล  จึงเรียกเซลลเม็ดเลอดขาวกลื ุมนวี้ า antigen‐ presenting cell ซึ่งจะรวมตัวในรูปสารเชิงซอนกบสารั major histocompatibility complex (MHC) ซึ่งแบงเปน class I และ class II ซึ่ง antigen presenting cell นี้จะกระตนระบบภุ ูมิิคมกนจุ ั ําเพาะได  2 กลไก Adaptive defense

1.Humoral‐mediated response : – การสรางสารน้ํา ไดแก แอนติบอดหรี อื immunoglobulin: Ig ซึ่งแบงเปน IgM, IgG, IgA โดยท ี่ IgM และ IgG ทําหนาที่ในการตอตานการติดเชื้อในกระแสเลอดและื เนื้อเยอื่ ในขณะท่ี IgA จะถูกหลงออกส่ั บรู ิเวณเยื่อเมอกบื ุผวและทิ ําหนาท่ีชวยปองก ันการบุก รกของเชุ ื้อแปลกปลอมจากภายนอก – การกระตุนระบบคอมพลนระบบคอมพลเมนตีเมนต  classical pathway

2. Cell‐mediated response : มักพบในการติดเชื้อกลมุ Intracellular pathogen

Approach to Patients with fever Confirm “Fever”

•Acute fever < 2 weeks •Prolong fever > 2 weeks

• Verification of fever and fever pattern Pattern of Fever

Malaria

Typhoid Pattern of Fever

Pel‐Ebstein pattern

BliiBorreliosis ((lrelapsi ng fever pattern) Fever patterns are neither sensitive nor specific enough for diagnosis of any disease. (possible exception of tertian and quartan malaria) Cause of Fever • Infectious disease • Non‐infectious disease – CNS: SAH, cerebral infarction/hemorrhage – RS: lung atelectasis, PE – GI: Pancreatitis, Ischemic bowel – Crystal induced arthritis, DVT,Hematoma, Phebitis – Neoplastic fever, Drug fever – Post transfusion, Postoperative fever (<48h) Approach : 1. Sign and Symptom

• Fever with specific organ involvement : Pneumonia, UTI

• Fever without specific organ involement – Undifferentiated fever – Multi‐organs involvement Approach : 1. Sign and Symptom

• Typical manifestation of a common disease • Atypical manifestation of a common disease

• Typical manifestation of a uncommon disease • Atypical manifestation of a uncommon disease AhApproach : 2. Host

• Infection in the Elderly (>65 year) • Infection in Neutropenia • Infection in Cirrhosis • Infection in Diabetes Mellitus • Infection in Thalassemia patients • Infection in SLE, RA • Infection in Transplant recipients Approach : 2. Host

• Fever in HIV infected patients • Fever in ICU • Fever in the returned traveler • Postoperative fever • Fever of unknown origin Approach : 3. Epidemiology, Exposure

•Race • Domicile, Region • Career • Hobby • Immunization •Travel Approach : Fever from Infectious disease

1. Sign & Symptoms – Specific organ syypmptom –Non specific organ symptoms : Undifferentiated / Multi‐organ involvement 2. Host 3. Epidemiology, Exposure Acute Undifferentiated Fever Case 1

• 30 year old healthy woman • CC: High fever with chill for 3 days •PI: 3 days PTA, High fever with chill, headache, muscle pain, diarrhea?(1‐2 times/d), no dysuria, no cough, no abnormal bleeding •PE: BT 38.5C BP 120/80 mmHg, PR 100 bpm, RR 18 /min, no stiffness of neck, others: WNL • Q&A: Acute Undifferentiated Fever

Acute systemic febrile illness, or AtAcute PUO, or StSystemi c ifinfec tion

Acute Fever ‐ No primary focus of infection ‐ Multi‐system involvement Acute Undifferentiated Fever (Systemic Febrile Illness)

Primary Bacteremia

Dengue Malaria: Infection Rickettsioses: Pf, Pv, Po, (Acute viral hepatitis, SbScrub thtyphus, Pm, Chikungunya, Acute Leptospirosis Typhus group, retroviral syndrome Spotted fever group P.knowlesi Infectious mononucleosis Approach to Patients with fever

• Confirm “Fever” • S/S : Undifferentiated fever •Host: Healthy • Epidemiology, Exposure : Race, Domicile, Career, Hobby, Immunization, Travel, Incubation period

•Investigation for diagnosis Sign & Symptoms Malaria‐ Sign & Symptoms

Asex ual deve l opme n t (Schizogony) •30 mins

• Exoerythrocytic cycle (5‐16 dayy)s)

• Erythrocytic cycle (48‐72 h) • Schizogony(merozoites) • gametocytogenesis (gametocyte) Sexual development (Sporogony) Viral Infection

• Dengue infection: Dengue fever, Dengue Hemorrhagic fever • Viral hemorrhagic fever: Hanta virus • Chikunggyunya infection • Infectious mononucleosis : EBV, CMV

Bacteremia

Pathogenic Leptospira High fever spp. HdhHeadche O. tsutsugamushi, R. Conjunctival injection typhi Myalgia etc.

Meningoencephalitis Jaundice, Abnormal LFT Hemoptysis, Pneumonitis Oliguria, renal failure Myocarditis etc. Clinical presentations: Leptospirosis and Rickettsioses

•Latent or subclinical infection • Acute uncomplicated or flu‐like febrile illness • Acute fever plus –hepatic dysfunction‐‐> acute acalculous cholecystitis – renal dysfunction‐‐> acute renal failure – interstitial pneumonitis ‐‐‐> lung hemorrhage‐‐> ARDS – aseptic meningoencephalitis – multiorgan dysfunction – hhihemorrhagic manifes ta tions Acute Undifferentiated Fever

• 1,663 adltdult patien ts presenting with AtAcute fever, withou t an obvious focus of infection, at 6 hospitals in Thailand • between October 2000‐ March 2003 – Leptospirosis 463 (27.8%) – Scrub typhus 268 (16.1%) –Murine typhus 28 (1.7%) – Leptospirosis and rickettsioses 82 (4.9%) – Spotted fever group rickettsioses 18 (1.1%) –Dengue infection 55 (3.3%) – Bacteremia 8 (0.5%) – Unknown 725 (43.6%) Anicteric Leptospirosis Icteric Leptospirosis Weil’s Syndrome ระยะแรก ระยะที่สอง ระยะแรก ระยะท่สองี 3-7 วัน 0-30 วัน 3-7 วัน 10-30 วัน SeptSepticemicicemic Immune Septicemic Immune อาการไข

Myalgia Meningitis Jaundice Headache Uveitis Hemorrhage Abdominal Rash Renal failure pain Fever Myocarditis Vomiting Conjunctival suffusion Fever Blood Blood CSF CSF Urin Urin e e CLINICAL PRESENTATIONS OF 540 PATIENTS WITH SUSPECTED SEVERE LEPTOSPIROSIS

Clinical Presentations N (%)

‐ Acute febrile illness 127 (23.5) ‐ Jaundice 154 (28.5) ‐ Renal dysfunction 182 (33.7) ‐ Lung involvement 111 (20.6) ‐ Hypotension 72 (13.3) ‐ Bldileeding complicati on 63 ()(11.7) ‐ Thrombocytopenia (<100,000) 189 (35.0)

Clinical Infectious Diseases, 20042004;; 3939:: 1417‐24 CLINICAL PRESENTATIONS OF 540 PATIENTS WITH SUSPECTED SEVERE LEPTOSPIROSIS : FINAL DIAGNOSIS Diagnosi s N (%) Leptospirosis Only 256 (47.4) Plus rickettsioses 62 (()11.5) Plus other bacteremia Rickettsioses 2 (0.04) Others 71 (()13.1) Other bacterial infection Viral infection 22 (0.4) Unknown 19 (0.3) 88 (16.3) Clinical Infectious Diseases, 2004; 39: 1417‐24 Rickettsioses‐ Sign & Symptoms

• Sepsis study at Maharat Nakhon Ratchasima Hospital • Between November 2001 to January 2002 • 18/51 (35.3%) of community‐acquired sepsis were caused by scrub typhus. •3 (16.7%) patients died

Thap LC, et al. Southeast Asian J Trop Med Public Health 2002 Case 1 : AFI

• อาชอาชพีพ: พนพนกงานขายหางโลตสกงานขายหั างโลตัส • ภูมิลําเนา :พักอยบู านหลังโลตัส รอบบานมีสวนขนาดเล็ก ไมมี สสตวเลยงัตวเลี้ยง • โสด ปฏิเสธประวัติมีเพศสัมพันธ ประจําเดือนมาปกต ิ LMP 20/09/54 • เดินทาง : 3 อาทตยิ กอนเด นทางไปเชิ ียงใหมอยูแตในเม องื ไมไดเขาปา ไปเชาเยนกล็ ับ ไมมีคนละแวกบานเปน ไขเลือดออก • วัคซนี : ไมเคยฉีดวัคซนปี องกันไขหวัดใหญ • งานอดิเรก : อานหนังสือ Investigation Case 1 : AFI‐ Initial investigation

• CBC • Urinary analysis • Hemoculture ? • Bun/Cr, LFT •CXR ? Malaria‐ Investigation for Diagnosis

• Uncomplicated malaria ‐ P. falciparum ‐ P. vivax ‐ P. ovale ‐ P. malariae ‐ P. knowlesi • Complicated or severe malaria ‐ P. flifalciparum ‐ P. vivax ‐ P. knowlesi Malaria‐ Investigation for Diagnosis

• Microscopy : "gold standard” –Thick smears are used for screening purposes‐ low parasitem ia –Thin smears are for morphological detail and species identification

•Rapid diagnostic tests (RDT) • Molecular technique ; especially for differentiate betaween P.m. & P.knowlesi Malaria‐ Investigation for Diagnosis

Parameter Microscopy PCR Fluorescence Dipstick Dipstick HRP-2 pLDH, Sensitivity 5-10 5 50 >100 >100 parasites/µl) PfP. f PfP. f only PfP. f and PvP. v Specificity All species All species good, others good difficult Parasite density Yes No No Crude Crude or estimation estimation parasitemia Time for 30–60 m in 24 h 30–60 m in 20 m in 20 m in result Skill level High High Moderate Low Low Equipment Microscope PCR QBC Kit only Kit only apparatus apparatus or microscope Cost/test Low High Moderate/low Moderate Moderate

Diagnosis? Malaria‐ Investigation for Diagnosis

PhkParacheck Test OptiMAL Assay • useful in detecting P.f. • detection of an intracellular infection only metabolic enzyme produced by •It is based on antibody malarial parasites in blood‐ recognition of the HRP‐2 LDeHydrogenase (pLDH) antigen of PfP.f. •Different iat ion between malillarial species is based on antigenic differences between pLDH isoforms Malaria‐Clue for suspected diagnosis of P. knowlesi

*Parasite morphology from blood smear is similar to P. malariae and with • high parasitemia • severe manifestation •coming from SSkaravak, MMlalays ia, SShouth of Tha ilan d

*Confirmative diagnosis by PCR or RDT (Animalaria™ test) Malaria‐Clue for suspected diagnosis of P. knowlesi Dengue Infection ‐ Investigation for Diagnosis

Direct evidence Viral isolation PCR ( Fever day1‐3) Indirect evidence: immunodiagnosis Antibody detection : Haeagglutination inhibition test (HI test) Antibody capture EIA Immunochromatographic test: Rapid Antibody test: Dengue duo (IgM, IgG, Ag) (IgM; false positive & false negative 10‐20%) AtiAntigen dtdetecti on : Non Struct ural protitein (NS1) Leptospirosis‐ Investigation for Diagnosis

Direct evidence Gram stain, AFB, Dark field microscopy Culture DNA detection Indirect evidence: immunodiagnosis Antibody detection : Serogroup specific :Microscopic agglutination test ((,MAT,Gold standard) Genus specific : IFA , Lepto‐dipstick test Antigen detection : Rapid Ag detection system (RDTS) autumnalis or pomona or icterohaemorrhagia tarassovi

hardjo or pomona Leptospira biflexa Leptospira interrogans 25 serogroups > 250 serovars

canilicola Leptospirosis‐ Investigation for Diagnosis

Slack A, 2010 ¾Antibody detection : detectable by the 6th to 10th day ,peaks within 3‐4 weeks ¾ gradually decreases but may remain detectable for years Leptospirosis : Diagnosis

WHO criteria Symptom &signs Risk factors Laboratory results

sensitivity 68% specificity 58% +ve predictive value 64% –ve predictive value 59% Rickettsioses z Orientia tsutsugamushi Æ Scrub typhus z Typhus group (TG) ‐ R. typhi Æ Murine typhus ‐ R. prowazakiiÆ Epidemic typhus z Spotted fever group (SFG) rickettsia ‐ R. rickettsiiÆ Rocky Mountain spotted fever ‐ R. conorii Æ Mediterranean spotted fever ‐ R. australis Æ Queenland tick typhus ‐ R. akari Æ rickettsial pox etc. Rickettsioses‐ Investigation for Diagnosis

Direct evidence Culture : extremely difficult Indirect evidence: immunodiagnosis AtibdAntibody dtdetec tion : IFA, IIP Rapid O. tsutsugamushi Ab test Antigen detection Rickettsioses‐ Investigation for Diagnosis

• Indirect immunofluorescent antibody test (IFAT) • Indirect immunoperoxidase test(IIP)

– Detection of both IgM and IgG – Standard diagnosis of rickettsial infection –High IFAT or IPP titer more than 1: 400 – A four‐fold rising of more than 1 : 200 Ricketsiosis‐ Investigation for Diagnosis

Primary Infection

Reinfection IFA Profile: ID Lab Siriraj Hospital ISO15189

Leptospires Orientia R.typhi Test -ve control +veCtlControl IgM IgG IgM IgG IgM IgG

[email protected] Phone: 02 4197203 O. tsutsugamushi Gilliam 11/46, 24% from Thai patients (2000‐2009)

Kato 1/46, 2%

TA763 8/46,17%

Karp 23/46, 50% Rickettsial infection : Weil-Felix test

Proteus vulgaris OX - 19 murine or epidemic typhus Proteus vulgaris OX- 2 spotted fever group Proteus mirabilis OX - K scrub typhus

Tests usually become +ve first 1-2 weeks of infection A four-fold rise in paired sera or suggestive of recent infection Sensitivity>1 : 320 and specificity < 50% have been abandoned in many countries Case 1 : AFI‐Investigation for Diagnosis

• Malaria : Thick film, Thin film, Rapid test • Dengue infection : Dengue PCR, NS1, IgM, IgG • Leptospirosis : MAT, IFA • Ricketsia : IFA for Scrub typhus, Murine typhus, Spotted fever group • Primary bacteremia : Hemoculture Treatment 2010

Dengue Infection ‐ Treatment

• StitttSupportive treatment Treatment : Leptospirosis , Rickettsioses

• Antimicrobial therapy shortens the course of the illness and its associitdated mortalit y • Doxycycline and azithromycin are effective antimicrobial treatment in mild cases Treatment – Severe Leptospirosis

• There remains uncertainty regarding the optimum antimicrobial therapy for severe leptospirosis • Choices of antimicrobial therapy are – Penicillin G sodium – Ceftriaxone or cefotaxime – Doxycycline • Neither high dose steroid nor desmopressin is effective as an adjunctive treatment of pulmonary hemorrhage associated with leptospirosis Fever with specific organ involvement Fever with specific organ involvement

•CNS infection: Meningitis, Encephalitis, Brain abscess •RS : URI, Tracheobronchitis, Pneumonia (CAP, HAP, VAP), Aspiration pneumonia,Infected bronchiectasis • GI : Diarrhea (Food poisoning, Infective diarrhea, Parasite infection, Toxin), Hepatobiliary tract infectio n, Peeoritonitis, hepatosp l eni c abscess •GU : UTI (upper, lower) (Complicated/uncomplicared) • SSTI : Furuncle, cellulitis, NF, Abscess, pyomyositis Case 1 : Acute Fever with Headache

A 34 year old man looked distress CC: Acute fever with headache for 2 days PE: Good conscious, BT 39 C, BP 130/90 mmHg, PR 100 bpm, RR 22 /min Stiffness of neck: positive, Others : WNL

Diagnosis : Acute meningitisÆ Bacteria Clinical of bacterial meningitis

Blood culture

Empirical ABO+/- steroid (Strep)

Indication for No emergency CT Yes ↓ ↓ Immediate LP CT No contraindiction ↓ ↓ CSF analysis Contraindication ↓ ↓ Adjust antibiotics Continue empirical Rx Acute bacterial meningitis

Host Usual pathogen Therapy

NlNormal addltult S. pneumoniae CftiCeftriaxone 2 g q 12 h N. meningitidis +/- Vancomycin 1 g q 12 h

Elderly >50 y. S. pneumoniae Ceftriaxone 2 g q 12 h + Pregnancy, GNB Ampicillin 2 g q 4 h Alcoholism, Listeria monocytogenes +/- Vancomycin 1 g q 12 h Steroid use Case 2 : Fever with dysuria

A 19 year old primigravida, GA 29 weeks CC: Fever and right flank pain for 2 days PI : 2 mo PTA, acute fever with dysuria, visited private clinicÆ oral ATB for 7 days and clinically improved 1 mo PTA, sam e symp t om s, took sam e abocantibiotic adand got better 2 d PTA, high grade fever and Rt. flank PE: BP 120/80 mmHg, BT 38.5 0C ,RR 24 /min, HR 108 bpm Abdomen: marked tenderness right flank Ix : UA :WBC 10‐20/HPF, numerous RBC

Dx: Acute pyelhiilonephritis, complicated Case Presentation : Ultrasound KUB (8 AUG 11) • RK showed large low echo lesion with internal septation diameter 5.4x5 cm in midpart with mild hydronephrosis

•LK showed marked hydronephrosis with turbid Case 2 : Management • Complicated UTI – Antibiotic (community onset): Ceftriaxone 2 g iv od – Drainage : Consulted UrologistÆ Close drainage – Bilateral hydronephrosis Physiologic change or Structural abnormalities ? Consulted UrologistÆ Plan to evaluate abnormality after delivery

• Preterm Labor : – Inhibited labor pain by medication Æ success Bacterial etiology of urinary tract infection % Uncomplicated %Complicateda

Gram-negative E.coli 70-95 21-54 P mirabilis 1-2 1-10 Klebsiella sp 1-2 2-17 Citrobacter sp <1 5 Enterobacter sp <1 2-10 P aeruginosa <1 2-19 Other <1 6-20 Gram-positive Coagulase-negative 5-10b 1-4 staphylococci 1-2 1-23 EtEnterococci <1 1-4 Group B streptococci <1 1-2 S. aureus <1 2

Other aData from Nicolle LE. A practical guide to the management of complicated urinary Tract infection. Drugs 1997;53”583-92.,also 2005 bS saprophyticus : Acute Pyelonephitis

Case 4: Fever with sore throat

• 30 year old healthy woman • CC: High fever with sore throat for 2 days •PI: 2 days PTA, fever with sore throat, sneezing, headache, no cough •PE: BT 38.0C BP 120/80 mmHg, PR 84 bpm, RR 16 /min, mild injected pharynx, lung clear, others: WNL Common cold

Acute Pharyngitis

Acute Laryngitis Common Cold : Sign & Symptom

•Sore throat, scratchy throat (resolve quickly ) followed closely by nasal obstruction and rhinorrhea •Cough 30% (begin after onset of nasal symptom) • Change in color is common diduring the course of illness and not indicative bacterial superinfection or siitiinusitis

• Nasal cavity : swollen, erythematous nasal turbinate Common Cold : Sign & Symptom

•Cold persist about 1 week, 25% last 2 weeks • Symptoms that persist > 10 days are more likely to be bacterial infection1,2

• Differential diagnosis : Allergic rhinitis

• Complication: Acute otitis media 30%, sinusitis 8%

Gwaltney, J Allergy Clin Immunol. 1992;90:457‐461;discuss 62. Wald ER,Pediatrics.1986;77:795‐800 Sinusitis

• Pathogenesis of sinusitis are similar to viral URI

•Acute community‐acquired bacterial sinusitis – Persistent nasal discharge or cough>10 days – Severe symptoms: fever, purulent nasal discharge – Worsening symptoms: new fever, increasing nasal discharge, congestion or daytime cough •Chronic sinusitis

Acute Pharyygngitis : Sign & Sypymptom

• TilTypicalÆTiTriad : sore throa t, f ever and pharyngeal inflammation Microbial Causes of Acute Pharyngitis Suggestive of Viral etiology Suggestive of GAS • Sudden onset • Conjunctivitis • Sore throat • Coryza • Fever • Cough •Headache • Diarrhea •Neusea, vomitting, abdominal •Discrete ulcerative lesions pain • Inflammation of ppyharynx and tonsils • Patchy discrete exudates • Tender, enlarge anterior cervilical nodes •Patients age 5‐15 years •Presentation in winter or early spring • His tory of exposure CID 2002;35:113‐125 Streptococcal Pharyngitis : Antibiotics

•To prevent poststreptococal sequelae – Acute rheumatic fever Æ Rheumatic heart disease

–Acute poststreptococcal glomerulonephritis (PSGN) Streptococcal Pharyngitis : Antibiotics

•To prevent suppurative complication – Peritonsillar abscess : adolescent, young adult – Retropharyngeal abscess : common in first few years – Sinusitis : very rare

•To reduce symptoms

•To prevent transmission : pediatrics Modified Centor Score

Upper Respiratory tract infection

• Acute epiglottitis : sore throat with odynophagia

• Acute Laryngitis: Horseness, Dry cough

• Acute laryngotracheobronchitis : Croup

• Acute Bronchiolitis TB

Laryngotracheobronchitis

COPD with exacerbate

Bronchiectasis

Acute Bronchitis

Acute Pneumonia Lower respiratory tract infection

• Acute Bronchitis : cough predominate – Productive cough> 2 weeksÆ R/O TB – Prolong cough> 4 weeks + poroxysmal vomitting Æ suggest Bordetella pertussis

• Asthmatic attack • COPD with exacerbate AECOPD Lower respiratory tract infection

• Bronchiectasis : Infected bronchiectasis • Acute Pneumonia – Symptoms: Fever,cough, dyspnea, pleuritis pain – Sign: CCiirepitation –CXR : Pulmonary infiltrate

• Tuberculosis Most common etiologies of CAP (2007 IDSA/ATS Consensus)

Fever of Unknown Origin

•40 year old helthy woman • CC: fever with chill 3 weeks, wt loss 6 kg/2 wks, no organ specific symptoms • PE: BT 38.5 c,BP 130/80 mmHg, PR 98 bpm, RR 16 /min • Mildly pale, no jaudice, Others: WNL • Initial investigation: CBC, UA, LFT, BUN/Cr, Anti HIV, CXR Approach : Fever of unknown origin

• Classical FUO •Infants and Children • Elderly Persons • Returned Travelers • Health Care‐Associated FUO • Postoperative patients • ICU patien ts • Stroke patients • Immune Deficient FUO • Neutropenic FUO •HIV related FUO

Subtle Physical Finding Having Special Significance in Patients with FUO

Rare Miscellaneous Causes of Fever Clinical Evaluation of Fever of unknown origin

•History :Comprehensive History is cornerstone • Physical Examination : Repeated PE • Laboratory Investigation : Noninvasive test ; CBC, UA, chemistry, culture, serology, BM exam • IiImaging Stu dies : CT, U/S, SiScanning with llbldabeled autologous leukocytes, Ga scan • Invasive Diagnostic Procedures : Histopathology ; excisional biopsy, needle biopsy or laparotomy

• Therapeutic Trials FUO : Therapeutic Trials

• Lim ita tions and riiksks of empiiirica l therapeuti c trials are obvious • Underlying disease may remit spontaneously • Naproxen test to differentiate malignant from nonmalignant remains unvalidated • Reserved for very few patients in whom all other approaches have failed or so seriously ill •In practice, most often in suspected TB Case 4 :FUO

• Classic FUO – Infection : IE, Hepppatosplenic abscess, TB, Melioidosis – Malignancy : • Hematologic: Lymphoma • Solid tumor: Renal cell CA, HCC or Liver metastasis – Autoimmune : SLE

• CXR: Hilar adenopathy

Melioidosis ‐ Sign & Symptoms

Thai : 686 pateints Australian : 252 pateints in 10 years Organ % Organ % • Septicemia 57.4 • Pulmonary 44.9 •Bacteremia 117 (46) •Skin & soft tissue 16.2 • Pneumonia 27 (50) • liver + spleen(7+2.3) 9.3 •Skin/soft tissue 42 (17) •UTI 7.4 • Genitourinary infection 37 (15) •Bone and joint 5.2 • Olii/iOsteomyelitis/septic arthhiiritis 9(4) •CNS 2.7 • Pericardium 2.4 •Neurological 10 (4) • LN 2.1 • Other 27 (11) •Parotid gland 1.9

Punyagupta S. Melioidosis 1989:217‐29 Currie BJ. CID 2000;31:981‐6 Melioidosis ‐ Sign & Symptoms

• Acute infection: – Direct inoculation during work – Inhalation during monsoon – Drowning • Reactivation : – Dormant intracellular after exposure – Relapse by the same strain

Direct IF stain Melioidosis – Risk Factors

• Age 42 yr. peak 40‐60 yr. • Seasonal Variation: Rainy • Risk factors OR (95%CI) Preexisting renal dz. 2.6 (1.5‐5.6) Thal assemi a 11.8 (2.5‐54.5) Malignancy 0.4 (0.1‐0.9) DM 4.8 (3.0‐7.7) Soil & water exposure 1.8 (0.6‐5.4) DM + Soil & water exposure 6.3 (3.8‐10.4) • Exposure to soil and water

Suputtamongkol Y. Intern J Epidemio 1994;23:1082‐90 Suputtamongkol Y.CID 1999;29:408‐13 Melioidosis ‐ Sign & Symptoms

• Lung involvement – Rapidly progressive community acquired pneumonia – Chronic pneumonia mimics TB –Mass lesion mimics malignancy • Intra‐abdominal abscess (Single > Multiple organs) –Single Abscess: Splenic > Liver > Kidney – MltilMultiple abscesses – Small abscesses < 3cm – Cart‐wheel or Swiss cheese –Prostatic abscess Melioidosis ‐ Investigation for Diagnosis

Direct evidence Gram stain Culture: (1‐4 days) Gold standard

Direct IF Ashdown’s agar stain Melioidosis ‐ Investigation for Diagnosis

Indirect evidence: immunodiagnosis Æ limited value Antibody detection : Melioid titer – In endemic areas : High background Ab in healthy – Cross reaction with other Gram negative infections – cut off 1: 160 sensitiv ity 80%, specific ity 80% –4‐ 4 rising of IHA titer??? AtiAntigen dtdetecti on –IF staining of clinical specimens –Latex agglutination for colony identification

– PCR specific for B. pseudomallei Direct IF stitain Melioidosis ‐ Treatment

• IiilInitial phase or IdInducti on phase – Severe cases to decrease mortality – Parenteral antimicrobial – ~ 2 week of treatment or defervescence • Maintenance phase – To ppeerevent reapseelapse –Oral antimicrobial – 12‐20 weeks of treatment

Direct IF stain RCT studies in acute phase treatment of melioidosis

Authors Regimen, dose No.patients Treatment Mortality per arm failure rate White et al Ceftazidime (120) vs TMP/SMX (10/50)+ 34 vs 31 37 vs 74* Doxycycline (4) + chloramphenicol (100) มนตเดช และ Ceftazidime (120)+ TMP/SMX (8/40) vs 27 vs 34 18.5 vs 47* คณะ TMP/SMX (8/40) + Doxycycline (4) + chlorampp(henicol (100) ยุพินและคณะ Ceftazidime (120) vs co-amoxyclav (120/40) 106 vs105 39 vs 51* 47 vs 47 Simpson et al Ceftazidime (120) vs imipenem (50) 106 vs 108 41 vs 20* 38 vs 36 เพลินจันทร และ Ceftazidime (100) TMP/SMX (8/40) vs 51 vs 51 14 vs 18 คณะ Cefoperazone – sulbactam (25/25)+ TMP/SMX (8/40) วิรงครองและคณะ Ceftazidime (120) vs Ceftazidime (120) 118 vs 123 26 vs 19 22 vs 20 TMP/SMX (10/50)

* Significant different Melioidosis – Induction Treatment

• Ceftazidime 120 MKD (2g IV 8 hourly) • Amoxycillin‐clavulanic acid 160 MKD (2.4g IV stat then 1.2gm IV 4 h) • IiImipenem 60mg/kg/d ay (1g IV 8 hl)hourly) • Cefoperazone/sulbactam 25mg/kg/day (1 g IV 8 h) + Trimethoprim‐ sulfamethoxazole

•Mean fever clearance ((y)days) – Imipenem 7.751 – Ceftazidime 9‐111,2 – Sulperazone 102

1. Simpson AH. Clin Infect Dis 1999;29:381‐7 2. Chetchotisakd P. Clin Infect Dis 2001;33:29‐34 RCT studies in maintenance phase treatment of melioidosis

AthAuthors RiRegimen, d ose mg/k g DtiDuration No. Relapse weeks patents rate(%) อดุลย Amoxicillin-clavulanate (60/15) vs 20 vs 20 49 vs 52 16 vs 4* [TRSTMH chloramphenicol (40), doxycycline (4), 1995] and TMP-SMX (10/50) วิภาดา Doxycycline (4) vs chloramphenicl (40), 20 vs 20 58 vs 58 26 vs 1* [CID 1999] doxycycline (4) and TMP-SMX (10/50) เพลเพลนจนทรินจันทร Azithromycin (8) and ciprofloxacin (8) vs 12 vs 20 36 vs 29 22 vs 3* [AJTMH 2001] doxycycline (4) TMP-SMX (10/50) วิภาดา Doxyyycycline ( 4) and TMP-SMX (10/50) vs 12-20 vs 89 vs 91 8 vs 10 [AAC2005] chloramphenicol (40), doxycycline (4), 12-20 and TMP-SMX

* Significant different Melioidosis ‐Maintenance phase for 12‐20 weeks

• Bactrim ((/)TMP/SMX): 8‐10mg/k g/d of TMP GFR > 30 mL/min GFR < 30 mL/min – BW >60 kg: 4 tab bid 3 tab bid – BW 40‐60 kg: 3 tab bid 2 tab bid – BW <40 kg: 2 tab bid 1 tab bid

• Coamoxyclav:30 MKD of amoxy (Cheng AC.Am J Trop Med Hyg 2008;78:208‐9) – BW < 60 kg • Coamoxyclav (375mg) 2 tab tid + amoxy 500mg tid or • Coamoxyclav (625mg) 2 tab tid x 20 wks – BW > 60 kg • ClCoamoxyclav 1500/375 TID • Coamoxycalv (625) 3 tab TID

11 Feb 2009 16 Feb 2009 Case 3: A 52‐year‐old man

• CC: Hig h fever 4 days

• Underlyyging: DM type2, NPDR last HbA1c 7.3% HT, dyslipidemia, CAD s/p PCI, BUN/Cr 27.6/1.7 •PI: 4days PTA, High fever with chill, severe hdhheadache, no nausea, vomiting, no dhdiarrhea, no cough, no dysuria • Q&A: Case 3: Physical Examination

•BT 37.5ºC, HR 80/min, RR 20/min BP 120/80 mmHg • HEENT: No icteric sclera, no pallor •CVS: High JVP, PMI at 5th ICS mid clavicular line, no hiheaving, no thr ill, no murmur • Lung :clear • Abdomen : Liver 2 cm below right costal margin, span 12 cm, no splenic dullness, no signs of chronic liver disease

Lab results on admission A B

C D Diagnosis?

mycoplasma Legionella Day3 Case : A 25‐year‐old man, BKK

• High fever with chill for 3 days • He has productive cough with yellowish sputum, severe muscle pain at both thigg,hs, nausea vomitin g, watery diarrhea 4-5 time/day for 1 day.

• Heavy alcoholic drink for 4-5 yrs • SkfSmoker for 8 year •No previous antibiotics Case : Physical Examination

• T 39ºC, HR 128/min, RR 32/min BP 131/63 mmHg • Mild icteric sclera, no pallor, no signs of chronic liver disease • High JVP, PMI at 6th ICS 2cm. lateral to mid clavicular line, no heaving, no thrill, syygstolic murmur grIII maximum at left parasternal border • Fine crepitation at right lung • Liver 4 cm below riggg,pht costal margin, span 18 cm. • No splenomegaly Initial Laboratory Investigations

5.3 313.1 90 61 114 1077 23.8 0.8 Urine Sp. gr . 1. 037 Protein 4+ WBC 0-1 What is your diagnosi s?

1. Severe community‐ acquired pneumonia 2. Severe leptospirosis 3. Severe scrub typhus 4. Commu nity‐acquired sepsis 5. Severe pneumonia with alcoholic hepatitis and cardiac beriberi Clinical Cou rse

• Sputum Gram stain: normal oropharyngeal floras • Blood culture : S. pneumoniae x II specimen Penicillin MIC 0.012 μg/ml Cefotaxime MIC 0.016 μg/ml • Echocardiogram: - Poor LV contraction, EF 28.7% generalized wall hypokinesia - Moderate to severe PR, mild MR • IFA for leptospirosis: IgG <1:50, IgM <1:50 Clinical Cou rse

•IFA for Orientia tsutsugamushi: IgG IgM 9 Feb 2009 1:400 1:100 12 Feb 2009 1:1600 1:100

• 11 Feb 2009: +ve PCR for O.tsutsugamushi

71‐ year old Thai female, Nakhon‐Pratom

• CC: Dyspnea 1 day •High fever and chill 5 days, generalized abdominal pain, no vomiting, no diarrhea • Oliguria and dyspnea 1 day • PE: Temp 39.30 C,P 114/min, R 22//,min, BP86/53 mmHg. fine crepitation both lungs No rash, no lymphadenopathy Problem list ‐ Fever 5 days. Eschar at lower abdomen ‐ History of abdominal pain ‐ Eschar ‐ Bilateral pneumonitis, hypoxemia ‐ Hypotension‐> sepsis Chest X-ray AP: on Admission Admission Lab CBC CCcaCouselinical Course

IFA for Scrub typhus 7/2/2008 12/2/2008 IgG 1:50 1:400 IgM 1: 400 1:3200 ชาย อายุ 41 ป อาชีพ ขายประกัน

CC: ไขสูง ตัวเหลือง 6 วัน กอนมารพ. PI: 4 ววนัน จกใตจุกใตชายโครงขวาชายโครงขวา ททองอดมากขนองอืดมากขึ้น ปปสสาวะออกนอยลงสสาวะออกนอยลง - 1 วันกอน เริ่มมีเหนื่อยมากขึ้น นอนราบไมได ขาบวม ไมเจ็บ หนาอกไปรพ. เอกชน ไดรบการวั ินิิจฉยวั า Fulminant hepatic failure with hepato-renal syndrome ไดรับการฟอกไต 1 ครั้งรวมกับยาปฏิชีวนะเขาเสน แลวสงตัวผูปวยมา PE: Temp 38.50C, P 100/min, R 28/min, BP 130/80 mmHg mildly pale , mod jaundice, pitting edema 2+, ascites +ve fine basal crepitation both lungs, JVP 6 cm above sternal angle, PMI at 5th ICS, no murmur CBC: Hct 26.6%, WBC 16,700, P84%, Plt 167,000 U/A: sp.gr 1.020, alb 4+ BUN 119, Cr 7.5, Na 139, K 4.2, HCO3 22 Direct Bili 28.2, AST 152, ALT 105, Alp 259 A/G 2.6/2.1 Blood Gas :pH: pH 7.49, pCO2342 34.8 pO2 59.1 O2 sat. 92.4

On admission and 1 week after admission IFA for - Leptospira spp. : negative - O. tsutsugamushi : negative - R. typhi : IgM 1:100Æ 1: 6400 IGIgG 1:100Æ 1:3200 Acute Undifferentiated Fever

Acute systemic febrile illness, or AtAcute PUO, or StSystemi c ifinfec tion

Acute Fever ‐ No primary focus of infection ‐ Multi‐system involvement Acute Undifferentiated Fever (Systemic Febrile Illness)

Primary Bacteremia

• Pulmonary involvement is more common in patients presented with other complications such as jaundice, renal failure, or thrombocytopenia. • Diffuse pulmonary lesions and cardiomegaly are common • Severe pulmonary involvement (ARDS or pulmonary hemorrhage) occurs in 1‐ 5%.

• Pulmonary hemorrhage and multiorgan failure are main causes of death in severe form of leptospirosis. Rickettsioses‐ Pulmonary Involvement

• Abnormal chest radiograp hy in 59% to 72%. • Bilateral reticulonodular infiltration, hilar LN enlargement, and septal line are common findings. •Air‐space nodules is relatively uncommon • In an autopsy stdtudy; int erstiti al pneumonitis (ith(with or withou t vasculitis) has been found in almost all patients. • Pulmonary involvement is a marker of disease severity Anicteric Leptospirosis Icteric Leptospirosis Weil’s Syndrome ระยะแรก ระยะที่สอง ระยะแรก ระยะท่สองี 3-7 วัน 0-30 วัน 3-7 วัน 10-30 วัน SeptSepticemicicemic Immune Septicemic Immune อาการไข

hardjo or pomona Leptospira biflexa Leptospira interrogans 25 serogroups > 250 serovars

canilicola Leptospirosis‐ Investigation for Diagnosis

Slack A, 2010 ¾Antibody detection : detectable by the 6th to 10th day ,peaks within 3‐4 weeks ¾ gradually decreases but may remain detectable for years Rickettsioses‐ Sign & Symptoms

Thap LC, et al. Southeast Asian J Trop Med Public Health 2002 Rickettsioses‐ Investigation for Diagnosis

• Indirect immunofluorescent antibody test (IFAT) • Indirect immunoperoxidase test(IIP)

– Detection of both IgM and IgG – Standard diagnosis of rickettsial infection –High IFAT or IPP titer more than 1: 400 – A four‐fold rising of more than 1 : 200 Rickettsial Diseases: Treatment

• Antimicrobial therapy shortens the course of the illness and its associated mortality

• Chloramphenicol, Doxyyycycline, Azithromycin, Levofloxacin are effective antimi crobi al treatment Doxycycline & Azithromycin Scrub typhus and Murine typhus

• Early recognition and appropriate treatment reduce morbidity and mortality • Rational antimicrobial therapy would be doxycycline in mild cases and a combination of either cefotaxime or ceftriaxone and doxyyycycline in severe cases. • Azithromycin could be considered as an alternative treatment when ever doxycycline allergy is suspected. • Failure to improve or defervesce within the next 48 hours would indicate the need to a thorough reevaluation of clinical findings and initial laboratory investigation results and a need to change antibiotic. Hospital Acquire Pneumonia Definitions

• HitlHospital‐acquidired pneumonia (HAP) – Pneumonia occurs ≥ 48 hrs after admission –Not incubating at the time of admission • VilVentilator‐associdiated pneumonia (VAP) – Pneumonia occurs ≥ 48‐72 hrs after endotracheal intubation – Not incubating at the time of intubation •Early v.s. Late onset (before or after 4 days of admission) Microbiology

• HAP, VAP in patients with no known risk factors for MDR‐pathogens, early onset – Streptococcus pneumoniae – Haemophilus influenzae – Methicillin‐sensitive Staphylococcus aureus – Antibiotic‐sensitive enteric GNB • Escherichia coli • Klebsiella pneumoniae

• Enterobacter spp. Am J Respir Crit Care Med 2005; 171: 388–416. Rotstein C, et al. Can J Infect Dis Med Microbiol 2008; 19: • Proteus spp. 19-53. Song JH, et al.Am J Infect Control 2008; 36: S83-92. Risk factors for MDR‐pathogens

• Antimicrobial therapy in preceding 90 days • Current hospitalization of 5 days or more •High frequency of resistance in the community or specific hospital unit • Presence of rikisk ftfactors for HCAP • Immunocompromised disease and/ or therapy

Am J Respir Crit Care Med 2005; 171: 388–416. Microbiology

•HAP, VAP, and HCAP, late onset, or risk factors for MDR‐pathogens – Pathogens listed previously and MDR‐pathogens ildiincluding – Pseudomonas aeruginosa – Klebsiella pneumoniae – Acinetobacter spp. – MRSA Am J Respir Crit Care Med 2005; 171: 388–416. Rotstein C, et al. Can J Infect Dis Med Microbiol 2008; 19: 19-53. Song JH, et al.Am J Infect Control 2008; 36: S83-92. Potential pathogens American Thoracic Society‐ 2005 Treatment Guidelines

Am J Respir Crit Care Med 2005; 171:388-416 Treatment Guidelines Early-onset, AND Recommended Regimens no rikisk o fMDRf MDR-pathogens • S. pneumoniae 1. Non‐pseudomonal 3rd • H. influenzae generation cephalosporin (cefotaxime, ceftriaxone) OR • MSSA • AtibitiAntibiotic‐sensitive enttieric 2. ß‐lactam/ ß‐lactamase gram‐negative bacilli e.g. inhibitor – E.coli, (amoxicillin/ clavulanic acid, – K. pneumoniae, ampicillin/ sulbactam) OR – Enterobacter spp. – Proteus spp. 3. Carbapenems (ertapenem) OR – Serratia spp. 4. Flu oroqu inolones (Levofloxacin/ moxifloxacin) Treatment Guidelines late-onset, OR Recommended Regimens no rikisk o fMDRf MDR-pathogens • MDR‐pathogens 1. Antipseudomonal cephalosporin – P. aeruginosa (ceftazidime, cefoperazone/ sulbactam, cefepime) OR – K. pneumoniae 2. Antipseudomonal penicillin – Acinetobacter spp. (piperacilllin/ tazobactam) OR 3. Antipseudomonal carbapenems (imipenem, meropenem) PLUS

1. Aminoglycosides (amikacin, netilmycin) OR 2. Fluoroquinolones (Ciprofloxacin/ levofloxacin) PLUS

–MRSA 1. Vancomycin or Linezolid Asian Guidelines ‐ 2008 Dosage