PUO in the Tropics. Helen van der Plas

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Colleen Beasley
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1 PUO in the Tropics Helen van der Plas

2 Outline Case Presentation Approach to fever in traveller Discussion of differential diagnosis Brief discussion of diagnosis

4 72 yr old Namibian Vet Fever for 3 months Fever 39.8 C Sweats Lassitude Weight loss No significant clinical findings No focal source of infection

5 Diagnosing the tropical traveller with fever Symptoms - nature, onset, duration Travel departure and return dates Region of travel Rural/urban/forest/mountains - nature of terrain Duration of visit - risk increases with length of stay Purpose of travel: healthcare workers, adventure travel Behaviour and lifestyle of traveller fresh water exposure Degree of contact with the local population Known disease contacts Known insect or animal bites, scratches or licks Unprotected intercourse Diet whilst travelling Vaccination history Malarial prophylaxis and compliance Injuries or illnesses during travel

6 72 year old vet with undifferentiated fever Past Medical History Past prostate Cancer prostatectomy 10 yrs ago Dyslipidemia Hypertension Asymptomatic diverticulosis Surgery Tonsillectomy & adenoidectomy Appendectomy ORIF of clavicle Ankle ligament repair Medication Atorvastatin Perindopril/HCTZ Vaccinations Yellow fever Hepatits A & B Typhoid Rabies

8 Past Travel

9 Causes of tropically acquired fever by incubation period Short: 10 days Intermediate: days Long: > 3 weeks Variable: Weeks to years Arboviral infections (dengue, chikungunya, Zika, West Nile Virus) Rickettsial infection Gastroenteritis, acute (bacterial, viral) Relapsing fever (borrelia) Respiratory infection (bacterial, viral) Malaria (P falciparum, 6-90 days, usually <30 days) VHF: Lassa fever, Marburg virus Ebola virus (2-12 days) Plague Yellow fever (3-16 days) Bacterial: Brucellosis Enteric fever (typhoid and paratyphoid) Leptospirosis Q fever (Coxiella burnetii) Bartonellosis Protozoal: Malaria (P. falciparum) Trypanosoma (East African) Fungal: Histoplasmosis Viral: VHF : YF,Marburg,Ebola,Lassa HIV,EBV,CMV Viral Hepatitis Bacterial: Brucellosis TB Fluke: Schistosomiasis (acute) Protozoal: Amoebic liver abscess Malaria (including P. falciparum, P malariae) Trypanosoma brucei gambiense (West African) Visceral leishmaniasis Viral: HIV, viral hepatitis Hepatitis B (A, C,E) Amoebiasis Brucellosis Chronic schistosomiasis Trypanosomiasis Filariasis HIV Melioidosis Systemic fungal infections Rabies Tuberculosis

Initial evaluation Examination: Fever 39C Imaging : CXR & Abdominal US normal Initial lab investigations HB 14.7 WCC 3.6 neutropenia PL 147 ALT 125 ALP 157 tbr25 cbr 6 CRP 32 ESR 48 PCT 0.

10 Initial evaluation Examination: Fever 39C Imaging : CXR & Abdominal US normal Initial lab investigations HB 14.7 WCC 3.6 neutropenia PL 147 ALT 125 ALP 157 tbr25 cbr 6 CRP 32 ESR 48 PCT 0.5 Malaria smear and Ag test negative x2 Ricketsia PCR and AB s negative Brucellosis IgM neg IgG pos Borrelia recurrentis smear negative Coxiella Antibodies neg Hepatitis ABC neg Microbiology: Stool Urine Blood

11 WBC differential in fever of returning travellers Leucopenia Leucocytosis Eosinophilia Malaria* Malaria* Schistosomiasis Typhoid Fever Amoebiasis Filariasis Arboviruses Pyogenic Hydatid Disease Rickettsiosis Leptospirosis Strongyloidiasis Brucellosis Borreliosis Trichinosis

12 Empiric treatment ensued Antibiotic exposure: no response to 1 st month Ciprofloxacin x 5 days Cefuroxime x 5 days 3 rd Month Doxy x 3 weeks Genta x 1 week Bone marrow trephine Normal trilineage haematopoeisis No blasts or dysplasia One small granuloma with lymphoid aggregates Stains negative for fungi and TB

13 Causes of tropically acquired fever by incubation period Short: 10 days Intermediate: days Long: > 3 weeks Variable: Weeks to years Arboviral infections (dengue, chikungunya, Zika, West Nile Virus) Rickettsial infection Gastroenteritis, acute (bacterial, viral) Relapsing fever (borrelia) Respiratory infection (bacterial, viral) Malaria (P falciparum, 6-90 days, usually <30 days) VHF: Lassa fever, Marburg virus Ebola virus (2-12 days) Plague Yellow fever (3-16 days) Bacterial: Brucellosis Enteric fever (typhoid and paratyphoid) Leptospirosis Q fever (Coxiella burnetii) Bartonellosis Protozoal: Malaria (P. falciparum) Trypanosoma (East African) Fungal: Histoplasmosis Viral: VHF : YF,Marburg,Ebola,Lassa HIV,EBV,CMV Viral Hepatitis Bacterial: Brucellosis TB Fluke: Schistosomiasis (acute) Protozoal: Amoebic liver abscess Malaria (including P. falciparum, P malariae) Trypanosoma brucei gambiense (West African) Visceral leishmaniasis Viral: HIV, viral hepatitis Hepatitis B (A, C,E) Amoebiasis Brucellosis Chronic schistosomiasis Trypanosomiasis Filariasis HIV Melioidosis Systemic fungal infections Rabies Tuberculosis

14 Upon review in Cape Town 3 months into illness His main symptoms: ongoing daily fevers, sweats, lassitude, weight loss new symptoms: dry cough and watery diarrhoea Clinical findings hepatomegaly tip of spleen palpable few ecchymoses NO adenopathy

15 Differential diagnosis Occult abscess abdomen, bone Subacute endocarditis Typhoid Brucellosis, Q-fever, leptospirosis, bartonella Tuberculosis Atypical mycobacterial infection Fungal infection: histoplasmosis, cryptococcosis Viral: HIV, EBV, CMV Visceral Leishmaniasis Malaria Temporal Arteritis Polymyalgia rheumatica Adult s Still s disease Polyarteritis nodosa & Vasculitis Sarcoidosis Haematological maligancy e.g lymphoma, myeloma, leukemia, myelodysplastic syndromes Renal cell Ca or Hepatocellular Ca Hemophagocytic lymphohistiocytosis Atrial Myxoma Multicentric Castleman s (HHV8) Thrombosis

16 Imaging CXR normal CT Sinuses: normal CT chest: normal CT abdomen and pelvis Splenomegaly Echocardiogram No vegetations 10 days later CT chest abdomen, pelvis No adenopathy Spleen bigger

17 Cultures remain sterile Blood Bacterial, fungal, mycobacterial Urine Stool Sputum

18 Repeat lab work Pancytopenia Transamintits with raised canalicular enzymes Hyponatremia ESR and CRP both ~100 now Ferritin ~6500. CK normal SEP - inflammatory Renal function & TFT normal HIV neg Hepatitis ABC neg Malaria smear & PCR negative Brucellosis IgG pos only x2 Coxiella negative Toxoplasma negative EBV,CMV neg Rickettsia negative Serum BD glucan and Clat negative Syphilis negative Autoimmune markers incl. ANCA negative S-ACE normal

19 And the counts continue to drop..

Mildly hypercellular Several reactive lymphoid

20 Head for tissue Granulomatous hepatitis Special stains and TB PCR negative Fungal and TB cultures pending Mildly hypercellular Several reactive lymphoid aggregates Special stains negative TB, HHV8 and bartonella PCR negative

22 And the GI tract Both investigations normal Histology duodenum and colon normal PCR for Tropheryma whipplei negative C. difficile toxin negative

23 You have friends - always ask for help!!

24 Enterprising virologist

25 Visceral Leishmaniasis

26 Leishmaniasis: visceral,cutaneous,mucocutaneous VL 95% fatality if left untreated

29 Clinical manifestation Incubation period is usually 2-6 months (few weeks to several years). Insidious onset Visceral leishmaniasis (kala-azar): fever, weight loss, hepatosplenomegaly, pancytopenia, hypergammaglobulinemia Viscerotropic leishmaniasis: Nonspecific abdominal tenderness; fever, rigors, fatigue, malaise, nonproductive cough, intermittent diarrhea, headache, arthralgias, myalgias, nausea, adenopathy, transient hepatosplenomegaly

Diagnosis Challenging particularly in under-resourced regions Can be made clinically Gold Standard visualisation of Leishmanial parasites in tissue biopsy, culture or smear CL: skin biopsy VL: bone

30 Diagnosis Challenging particularly in under-resourced regions Can be made clinically Gold Standard visualisation of Leishmanial parasites in tissue biopsy, culture or smear CL: skin biopsy VL: bone marrow or splenic biopsy Alternative methods RDT: rk39 rapid diagnostic test (IT-Leish, Bio-Rad laboratories, USA) Anti-Leishmanial antibody serology (IFA, ELISA) PCR of Leishmania DNA from biopsy Urine Antigen (low sensitivity)

31 Treatment Liposomal Amphotericin B 3mg/kg/day infusion Day 1-5 Day 14 Day 21 Alternatives Miltefosine orally 100mg/d x 28 days Sodium Stibogluconate 20mg/kg/day x 30 days

32 Back to our vet.. Defervescence Overall feeling better Extensive mucocutaneous Herpes Blood counts recovered No relapse or complications

33 Thank you Lucille Blumberg and John Frean Wendy Spearman and Michael Locketz Craig Corcoran

Post Travel Fever. Dr. Eyal Leshem. Center for Geographic Medicine Sheba Medical Center Tel Hashomer, Israel

Post Travel Fever. Dr. Eyal Leshem. Center for Geographic Medicine Sheba Medical Center Tel Hashomer, Israel Post Travel Fever Dr. Eyal Leshem Center for Geographic Medicine Sheba Medical Center Tel Hashomer, Israel Introduction Fever in returned traveler: Trivial vs. life threatening infections Tropical and