Jay S. Keystone MD Medisys Travel / Edward C. Keystone MD ...

Diagnostic approach to fever, respiratory infections and eosinophilia in returned

travellers

Jay S. Keystone MD Medisys Travel /Edward C. Keystone MD RDU Mt.Sinai

Tuesday, June 23, 15

Fever in returned travellerCATMAT statement CCDR 2011;37.AC3 (11 studies)

Infection percent Infection percent

malaria 20-30 skin and soft tissue 2-11

travellers diarrhea 10-20 rickettsiosis (ATBF) 3

respiratory tract 10-15 urinary tract & STI 2-3

dengue 5 viral hepatitis 3

enteric fever 2-7 mono/viral-like syndrome 4-25

http://www.phac-aspc.gc.ca/tmp-pmv/catmat-ccmtmv


Evaluation“It is difficult to make a diagnosis

if you don’t know what to look for!”

• pre-travel preparations: vaccines, prophylaxis

• travel itinerary: urban/rural, ‘first’ vs ‘no’ class

• exposure hx: food,water,bites,B&B,animal contact etc

• clinical: -fever pattern: periodic,con’t, saddle back-incubation period: short ,intermediate, long -duration of fever:


Evaluation: it is difficult to make a diagnosis if you don’t know what to look for!

Fever more than 2 weeks usually rules out dengue and CHIKFever onset < week of arrival in tropics is not malariaFever > 2 weeks on return after malaria is ruled out is often typhoid


Evaluation of fever in the returning travellerStep 1.Hx of travel: i. pre-travel preparations


Evaluation of fever in the returning traveller ii. specific travel itinerary


Evaluation of fever in the returning traveller iii.exposure history


STEP 2: Hx of fever & clinical features: i.fever pattern

Evaluation of fever in the returning traveller


6STEP 2: History of fever and clinical features

ii. Incubation period


iii.Fever duration at visit


Initial investigations

• CBC + diff, LFT,creatinine,electrolytes

• malaria smears x 3 + RDT over 24-48hrs

• blood cultures x 2

• urinalysis (urine culture)

Primary laboratory investigations after Hx and Px examination (malarious area)


Primary investigations cont’d

• stool C&S + C.diff ag if indicated

• Chest Xray

• Stool O&P (protozoa)

• serology (RDT):dengue,CHIK,hepatitis etc. if indicated

• acute serology saved for pairing with convalesence.( CYA retrospective)

Supplementary tests : based on Hx & Epi


The WBC and differential.*

disease Hbg WBC ** Platelets CRP*

dengue N or 70-90% 52-70% N

malaria N or N or 60-80%

typhoid N or N or N 10%

*Leder,JTM.14, McKenzie JID.05, Kain,CID 08, Taylor Malaria J.08

** i.atypical lymphocytosis (EBV) ii. eosinophilia iii. bands

*** < 10% *** <10% >10,000/cumm

***


Rapid diagnostic tests falciparum malariaantigen detection

Test % sensitivity % specificity

HRP2 95 95

pLDH 93 98

*expert microscopy 96 98

Abba, Cochrane database of systematic reviews 2011; *Kain CID 98


Clinical Infectious Diseases 2009; 49:908–13


Prospective study 95/852 tests malaria cases:2003-6; Binax Now;pcr confirmation

Pf (74) RDT sens 100% vs 88% films (p=.003) Pv (21) RDT sens 86% vs 74% films

Clinical Infectious Diseases 2009; 49:908–13


Culture everything!


Typhoid fever diagnostic tests

Test % Sensitivityblood culture (x3+) 40-80 (73-97)stool culture 30-40bone marrow culture 98urine culture 25-30enteric juice /string test 50blood pcr 88

Hoffman S. JID.84 Gilman R. Lancet .75 Brusch J. Medscape.15


Typhoid fever diagnostic tests

Test % Sensitivityblood culture (x3+) 40-80 (73-97)stool culture 30-40bone marrow culture 98urine culture 25-30enteric juice /string test 50blood pcr 88

Hoffman S. JID.84 Gilman R. Lancet .75 Brusch J. Medscape.15

Culture everything!


Fever and Diarrhea

• Stool C&S x1: 60-80% bacterial pathogens

• Stool C.diff toxin: EIA (GDH) 85% sens; RT-pcr 86% sens.;cytotoxin assay 70-100% sens*

• Stool 0&P x3:protozoa incl.coccidia

* Kufelnicka AM. Clin Infect Dis. 2011


Dengue Laboratory diagnosis

Test % sensitivity % specificity

IgM MAC ELISA >day 5IgG ELISA

9099

9896

RT-PCR day 1-5 80-90 95

NS1 Assay day 1-7 86 100

CDC.gov/dengue/clinical/lab Hermann L. PLoS NTD.14


Dengue diagnosis


Emerging Infectious Diseases 2008 ; 14, No. 3

2006: 720 samples from 680 returned travellers from Indian Ocean

RT-PCR: sens.100% from day1 ; none > day 7IgM: sens 40% before day 4;100% day 5


Elevated bilirubin & liver enzymesViral hepatitis

• Hepatitis A,B,(C,D),E: Hep A: IgM,Hep B:HBsAg, IGM anti-HBc

• EBV: atypical lymphocytosis;inceased WBC

• -North America Heterophile Ab : false neg early: 25% wk 1, 5-10% wk 2 ;5% wk 3

• -Europe VCAb: IgM 99% sens, 94% spec

• CMV IgM and paired IgG 2-4 weeks apart


Additional testing based on exposure basis

ActivityActionRisk

DietUnpasteurized cheeseb


J Travel Med 2003; 10 Suppl 2:S25–S00.


J Travel Med 2003; 10 Suppl 2:S25–S00.

www.fevertravel.ch


http://www.fevertravel.ch

http://www.fevertravel.ch

• Fever from the tropics often not tropical but is malaria and a medical emergency until proven otherwise

• Low platelets: think malaria & dengue

• Malaria: 3 thick & thin films or 2 RDT’s;

• RDT’s very sensitive vs microscopy but you still need film for parasite count

What have we learned?


• Typhoid: cultures good but suboptimal

• Dengue/Chik: RDT’s early; serology late (>5ds)

• Hepatitis: don’t forget HepC, EBV and CMV

• Diarrhea: 1 stool C&S only ; remember C.difficle



Infectious causes of eosinophilia

• Parasites : - HELMINTHS - ectoparasites - protozoa

• Non-parasite: cocci, TB,HIV


Eosinophilia may be travel related or NOT!

Etiologic category Examples

vascular Eosinophilic granulomatosis

inflammatory IBD ,sarcoid

metabolic Addison’s neoplastic Hodgkins lymphoma

allergic drugs

dermatologic pemphigus

misc kimurasTuesday, June 23, 15

Exposure history is every thing!

• fresh water schistomiasis

• bare foot, sandals strongyloidiasis

• short stay < 1mo filariasis


Parasites:Fever and eosinophilia• migratory larvae: strongyloides, ascaris,

hookworm

• filariasis

• trichinosis

• toxocariasis

• liver fluke: fascioliasis

• lung fluke: paragonimiasis

• blood fluke: schistosomiasis (acute)

• hydatid disease:echinococcosis


Eosinophilia diagnostic tests

• stool O&P x 3 or ag./pcr detection

• serology : schisto., strongy., filaria

• agar plate for strongyloides

• urine O&P (schistosomiasis)


Acute schistosomiasis (Katayama)

• Clinical onset usually 4-8 weeks after exposure to parasite in fresh water.

• Ova not excreted for almost 2 months

• Serology often takes ~ 2mo.to be positive

• 4 case series of acute schisto with serology:n=13,27, 79, 50 .Serology pos :,69%, 68% 86%, 94% respectively

Lambertucci JR CID 2013; Leshem E. CID .08; Jaureguiberry JTM 2011; Logan S. AJTMH 2013


Tests for strongyloidiasis

- direct wet mount x1 30-50% - concentration techniques:60-70+% • formalin ether acetate• Baermann• Harada-Mori

- agar plate culture > 95%*

*Am. J.Trop Med. Hyg 1991;45:518-521Tuesday, June 23, 15

Tests for strongyloidiasis

- stool pcr 92%- copro antigen ?- duodenal aspirate (string)76%


Strongyloides serology

• CDC USA ELISA: crude extract of L3 filariform larvae : 93% sens 98% spec;(spec 76% if other parasites included..? undetected Ss)

• NRCP CDN ELISA (NIE..recombinant ag) 100% sens 88% spec.

• CTD Italy IFAT: 98% sens 98% spec

• Potential cross reactions: filariaisis,schistosomiasis,hookworm etc


Filariasis

• Loa Loa day bloods for mf

• Onchocerciasis skin snips

• W. Bancrofti night bloods


Serology filariasis

• NIH: IgG & IgG4 LIPS assay : sens/spec Wb 100%; Loa, Onco,Bm sens 98-100% spec 98-100% IgG4

• NRCP: filaria : 90% sens; x-reaction with nematodes

Thttp://www.cliniquesantevoyage.com/wp-content/uploads/2012/03/12-Colloque-Bleu-NRCP.pdfextKubofcik J.PLoSNTD.2012 6(12) e1930

“Never do a test you don’t want to know the results of!”


http://www.cliniquesantevoyage.com/wp-content/uploads/2012/03/12-Colloque-Bleu-NRCP.pdfext




Serology filariasis

• NIH: IgG & IgG4 LIPS assay : sens/spec Wb 100%; Loa, Onco,Bm sens 98-100% spec 98-100% IgG4

• NRCP: filaria : 90% sens; x-reaction with nematodes

Thttp://www.cliniquesantevoyage.com/wp-content/uploads/2012/03/12-Colloque-Bleu-NRCP.pdfextKubofcik J.PLoSNTD.2012 6(12) e1930

“Never do a test you don’t want to know the results of!”

If serology is positive . mf are neg and now what?..measure filaria antigen in blood






A case

34 yr Canadian seen after 3 week trip in SEA returns with 1 week hx cough, diarrhea and eosinophilia. 3 stools neg O&P , schistosoma, strongyloides & filaria serologies are negative.


Which of the following parasites has probably been ruled out?

A. schistosomiasisB. strongyloidiasisC. filariasisD. none of the above




6-8 weeks




6-8 weeks 4-6 weeks




6-8 weeks 4-6 weeks 2 weeks-6mo


Timing is everything!• Egg excretion takes weeks to

months

• Seropositivity takes weeks to months

• Consider repetition of samples


Timing is everything!• Egg excretion takes weeks to

months

• Seropositivity takes weeks to months

• Consider repetition of samples

Consider presumptive treatment


Predictive value of eosinophilia for travel-related infections?

CID 2002;34:407



CID 2002;34:407

1995-99: 14,298 travelers screened:4.8% had eosinophilia

36% had helminthiasis 38% of helminthiases had eosinophilia



CID 1993;17:353



CID 1993;17:353

1981-87:1605 travellers screenedSensitivity of eosinophilia to Dx schisto. filariasis and strongy = 38%PPV for any helminthic infection = 9%


•Investigations depend on travel and exposure history

•“If the epidemiology doesn’t fit...try another diagnosis”

•Early Dx not possible in some because of long pre-patent period (egg detection) & late onset of serology

•Low yield of diagnostic tests!



Number of patients reported in the GeoSentinel surveillance network by respiratory diagnosis.

URTI N=1110

Sinusitis 1.6Acute otitis media 2.2Pharyngitis 13.2Tonsillitis or abscess 4.1Pertussis <1Nonspecific URTI 47.2

LRTI N=680

Bronchitis 20.3 Pneumonia 13.5 Influenza 5.6 Legionnaires disease <1 Pleurisy <1

Leder K Clinical Infectious Diseases 2003; 36:399–406

% %


Respiratory tract infections diagnosis

• CBC:high WBC suggests pneumonitis

• CXR: esp ill & and elderly patients

• Legionella ag in urine:(L.pneum.type 1) sens.70-80% : spec 99%

• Influenza RDT: sens 50-70%;spec 90-95% RT-PCR sens 95%; cultures sens 91%*

www.cdc.gov/flu/professionals/diagnosis/

*Peaper DR, Clin Lab Med. 2014


http://www.cdc.gov/professionals/diagnosis/

http://www.cdc.gov/professionals/diagnosis/

•Respiratory infections:•pneumonia is uncommon but think

elderly!•specific diagnoses uncommon• testing: good but not great sensitivity



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