Developing diagnostic guidance for persistent fever:

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Aubrie Morris
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1 Developing diagnostic guidance for persistent fever: the NIDIAG study François Chappuis Geneva University Hospitals on behalf of NIDIAG partners

2 What is NIDIAG? Objective: improve diagnostic approaches for different clinical syndromes in resource limited settings where NID are frequent EU funded project (FP7) Divided into WPs Epidemio clinical studies Development of new tools Quality assurance Translation into policies Clinical syndromes Neurological disorders Persistent digestive disorders Persistent fever

4 Diagnostic algorithm for primary VL [in East Africa]

5 Limitations of VL diagnostic algorithms

6 Limitations of VL diagnostic algorithms [in East Africa]

7 Limitations of VL diagnostic algorithms

8 Objectives of the epidemio clinical studies [persistent fever] Determine the prevalence of NIDs and other diseases in patients who present to heath care facilities with persistent ( 7d) fever Identify clinical and laboratory predictors of NIDs and other relevant conditions Assess diagnostic performance of available RDTs and novel assays developed in NIDIAG Incorporate acquired epidemiological and clinical knowledge and field designed diagnostic tests into diagnostic guidance tools, and assess their operational performance and feasibility

9 Study setting [Sudan] Tabarakallah

10 Inclusion exclusion criteria Inclusion criteria Patients presenting with fever for 7 days Age 5 years Exclusion criteria Unwillingness or inability to give consent Inability to comply with study requirement Presence of an existing laboratory confirmed diagnosis Patient in need of immediate intensive care (e.g. shock)

11 Targeted conditions Visceral leishmaniasis Enteric fever Malaria Brucellosis Tuberculosis Amoebic liver abscess Relapsing fever HIV & opportunistic infections Rickettsial diseases Leptospirosis Reference tests: On site DAT & LN/BM puncture Malaria smears & RDTs Sputum examination. In national reference laboratories Leishmania culture Blood cultures PCR for M. tuberculosis Serology brucellosis In international laboratories (Uni Méditerranée, ITM Antwerp) Leptospirosis: PCR + serology Rickettsiosis: PCR + serology Borreliosis: PCR

12 Case definitions Case definitions Target conditions: pre defined in study protocol Other conditions: Defined at time of e CRF review standardized Not single source (WHO, CDC, international societies...) Adapted to diagnostic tools available on site Diagnosis stratified into confirmed probable ( possible)

13 Results 670 patients recruited (end: June 2014) 667 patients analyzed (3 excluded as no investigation done) Demographic data Variable Value Count (n=) Proportion Season Dry % Age <15y % 15 45y % >45y % Sex Female %

14 Target conditions a Prevalence of diseases (1) Variable Value Count (n=) Proportion VL All (C/P) 65 (57/8) 9.4% Malaria Confirmed % Brucellosis All (C/P) 28 (15/13) 4.2% Enteric fever Confirmed % Tuberculosis (lung) All (C/P) 8 (7/1) 1.2% Borreliosis Confirmed 7 1% HIV Confirmed 7 1% Rickettsiosis Confirmed 1 0.2% Any target condition All (patients) % Mixed infections b All 19 (/158) 12% a Serologies for Leptospira missing b Target conditions only : VL M: n=6; VL HIV: n=3; VL EF: n=2; VL RF: n=2; M RF: n=1; VL B: n=1; TB M: n=1; B EF VL: n=1; other: n=2

15 Other conditions Prevalence of diseases (2) Variable Value Count (n=) Proportion Respiratory Pneumonia % Tonsillitis % Other RTI % Digestive Gastro entero colitis % Gyneco urinary UTI % PID % Bone & joints Acute arthritis 7 1% Other Various conditions % Undefined All %

16 Discussion VL, malaria and brucellosis are the prominent target conditions found in Gedaref Province, Sudan Few patients recruited in rainy season malaria underestimated Prevalence leptospirosis not yet defined 46% patients remain with an undefined diagnosis Limited # tests on site (and difficult referral to 3 ary hospital) No death High proportion received 1 antibiotic(s) +/ antimalarials Some patients may have leptospirosis Overdiagnosis of UTI/PID? But high % urinary schistosomiasis? Mixed infections are frequent (target and non target diagnosis)

17 Formats for diagnostic guidance Algorithm Score Other format

18 Diagnostic panorama Borreliosis Brucellosis VL Malaria Enteric fever Leptospirosis HIV TB Pneumonia Tonsillitis Other RTI Persistent fever Entero colitis Rickettsiosis UTI PID Others Undefined

19 Pre test probabilities Brucellosis VL Malaria Borreliosis 1% 4% 9% 8% 2% Enteric fever Leptospirosis HIV TB Pneumonia 1% 1% Tonsillitis 3% 4% Other RTI Persistent fever 5% 2% Entero colitis 0.2% Rickettsiosis 11% 5% Others UTI PID Undefined

20 Diagnostic predictors & LR+/LR Identification of features associated with each priority diagnosis Patients with mixed target conditions not included Calculation of LR+/LR according to standard formulas LR+ Confirming power; LR Excluding power To be done: calculation of post test probabilities (Bayes theorem) identification of independent predictors by logistic regression

21 Diagnostic predictors & LR+/LR

22 Febrile patient with splenomegaly How likely is VL? Pre-test Likelihood ratio Post-test Odds = 65/602 = 0.11 VL splenomegaly Odds = 0.11 x 5.4 = 0.6 Probability = 65/667 10% Se/(1-Sp) = 5.4 Probability 38%

23 Diagnostic guidance [Patient with 7d fever in Tabarakallah] INITIAL EVALUATION for all patients: History Physical examination Laboratory - Hb count - WBC count - Urine stick Diagnostic tests - rk39 RDT, if -: DAT - Malaria RDT - Brucella RDT - Typhoid RDT? Respiratory features - Chest X-Ray - Sputum examination

24 Diagnostic guidance [Patient with 7d fever in Tabarakallah] RDT + [Smear +] Malaria Enteric fever RDT +? Rainy season RDT? Diarrhoea Brucellosis RDT + Skin/soft tissue RDT infection Leptospirosis RDT [Smear -] Rickettsiosis LN asp + rk39 RDT + DAT + Splenomegaly Adenopathy Hb <10 VL DAT rk39 RDT LN asp - Fever 7 days Tuberculosis Sputum + CXRay + rk39 RDT + H/O unboiled milk CXRay + Cough Urine stick + Loin/suprapubic pain Suprapubic pain Vaginal discharge CXRay Sputum AFB - Pneumonia PID UTI CXRay - No abdominal pain Urine stix Borreliosis Others Other RTI Font size and intensity correlate with positive / negative likelihood ratio

25 SHCH Final diagnosis Target conditions a Cambodia Diagnosis Level of certainty Count (n=) Proportion Tuberculosis (all types) All (C/P) 75 (53/22) 19.8% Melioidosis All (C/P) 16 (14/2) 4.2% Leptospirosis a Confirmed (PCR) 15 4% Rickettsiosis (R. typhi) All (C/P) 8 (6/2) 2.1% Enteric fever Confirmed 6 1.6% Malaria (P. vivax) Confirmed 4 1.1% Scrub typhus a All (C/P) 2 (2/0) 0.5% Relapsing fever Confirmed 1 0.3% VL All (C/P) 0 0% Brucellosis All 0 0% Any target condition All % a Serologies for Leptospira & PCR scrub typhus awaited

26 SHCH Final diagnosis Cambodia Other conditions System Diagnosis Count (n=) Proportion Respiratory Pneumonia/lung abscess 102 (98/4) 27% Tonsillitis/pharyngitis 1 0.3% Other RTI 4 1.1% Urinary UTI % Cancer Leukemia/lymphoma 4 0.9% Digestive Liver abscess % Skin/soft tissue Skin/soft tissue infection % General Sepsis % Other (defined) % Mixed infections % Undefined 53 a 14% a 41/53 (77%) have suspicion of enteric fever +/ other condition; 7 death (13%); Proportion of Abx used: 89%

27 Discussion Large differential diagnosis with various frequencies (0.1 30%) Nepal: please see/hear K. Koirala et al. poster this afternoon No/few predictors for the conditions most difficult to diagnose: leptospirosis, rickettsiosis, scrub typhus, borreliosis, brucellosis NIDIAG revealed their presence Malaria & enteric fever (much) less frequent than expected Undefined conditions: 14 48%; >75% diagnosed as enteric fever Developing ASSURED RDTs for above conditions AND enteric fever (top research priority in tropical medicine)

28 Next steps Complete the data analysis and prototypes of diagnostic guidance Assess operational performance and feasibility of the diagnostic guidance in > 1 site/country Develop referral criteria for PHC level Development of smartphone application?

29 Acknowledgments Marleen Boelaert Sayda el Safi Kruy Lim, Thong Phe, Long Leng Pascal Lutumba, Deby Mukendi Suman Rijal, Pralhad Karki, Kanika Koirala.and research teams!

30 Thank you for your attention!

PROJECT FINAL REPORT

PROJECT FINAL REPORT Grant Agreement number: 260260 Project acronym: NIDIAG Project title: Syndromic approach to Neglected Infectious Diseases (NID) at primary health care level: an international collaboration