PUO in the TropicsHelen van der Plas

Outline

• Case Presentation

• Approach to fever in traveller

• Discussion of differential diagnosis

• Brief discussion of diagnosis

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

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

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

Past Travel

Short: ≤ 10 days

Intermediate: 10– 21 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 virusEbola virus (2-12 days)PlagueYellow fever (3-16 days)

Bacterial:BrucellosisEnteric fever (typhoid and paratyphoid)LeptospirosisQ fever (Coxiella burnetii)BartonellosisProtozoal:Malaria (P. falciparum)Trypanosoma (East African)Fungal:HistoplasmosisViral:VHF : YF,Marburg,Ebola,LassaHIV,EBV,CMVViral Hepatitis

Bacterial:BrucellosisTBFluke:Schistosomiasis (acute)Protozoal:Amoebic liver abscessMalaria (including P. falciparum, P malariae)Trypanosoma bruceigambiense (West African)Visceral leishmaniasisViral:HIV, viral hepatitisHepatitis B (A, C,E)

AmoebiasisBrucellosis Chronic schistosomiasis Trypanosomiasis FilariasisHIV MelioidosisSystemic fungal infections Rabies Tuberculosis

Causes of tropically acquired fever by incubation period

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

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

Empiric treatment ensued

Antibiotic exposure:

no response to

• 1st month • Ciprofloxacin x 5 days

• Cefuroxime x 5 days

• 3rd 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

Short: ≤ 10 days

Intermediate: 10– 21 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 virusEbola virus (2-12 days)PlagueYellow fever (3-16 days)

Bacterial:BrucellosisEnteric fever (typhoid and paratyphoid)LeptospirosisQ fever (Coxiella burnetii)BartonellosisProtozoal:Malaria (P. falciparum)Trypanosoma (East African)Fungal:HistoplasmosisViral:VHF : YF,Marburg,Ebola,LassaHIV,EBV,CMVViral Hepatitis

Bacterial:BrucellosisTBFluke:Schistosomiasis (acute)Protozoal:Amoebic liver abscessMalaria (including P. falciparum, P malariae)Trypanosoma bruceigambiense (West African)Visceral leishmaniasisViral:HIV, viral hepatitisHepatitis B (A, C,E)

AmoebiasisBrucellosis Chronic schistosomiasis Trypanosomiasis FilariasisHIV MelioidosisSystemic fungal infections Rabies Tuberculosis

Causes of tropically acquired fever by incubation period

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

Differential diagnosisOccult 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 rheumaticaAdult’s Still’s diseasePolyarteritis nodosa & VasculitisSarcoidosis

Haematological maligancye.g lymphoma, myeloma, leukemia,myelodysplastic syndromesRenal cell Ca or Hepatocellular Ca

Hemophagocytic lymphohistiocytosis

Atrial MyxomaMulticentric Castleman’s (HHV8)Thrombosis

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

Cultures remain sterile

• Blood• Bacterial, fungal, mycobacterial

• Urine

• Stool

• Sputum

Repeat lab workPancytopenia

Transamintits with raised canalicularenzymes

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

And the counts continue to drop…..

Head for tissue

Granulomatous hepatitis Special stains and TB PCR negativeFungal and TB cultures pending

Mildly hypercellularSeveral reactive lymphoid aggregates Special stains negativeTB, HHV8 and bartonella PCR negative

And the GI tract

Both investigations normal

Histology duodenum and colon normal

PCR for Tropheryma whipplei negative

C. difficile toxin negative

You have friends - always ask for help!!

Enterprising virologist

Visceral Leishmaniasis

Leishmaniasis: visceral,cutaneous,mucocutaneous

VL 95% fatality if left untreated

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 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)

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

Back to our vet…..

• Defervescence

• Overall feeling better

• Extensive mucocutaneous Herpes

• Blood counts recovered

• No relapse or complications

Thank you

• Lucille Blumberg and John Frean

• Wendy Spearman and Michael Locketz

• Craig Corcoran