Causes of persistent febrile illnesses in eastern Nepal *Kanika Deshpande Koirala1,2,3, Basudha Khanal1, Nisha Keshary Bhatta1, Narayan Raj Bhattarai1, Kristien Verdonck2, Marleen Boelaert2, Francois Chappuis3, Suman Rijal1 *Email: kanikadeshpande@gmail.com 1B P Koirala Institute of Health Sciences (BPKIHS), Dharan, Nepal; 2Institute of Tropical Medicine, Antwerp, Belgium; 3University of Geneva, Geneva, Switzerland

Introduction

Nepal Area: 800 kilometres (497 mi) long and 200 kilometres (124 mi) wide, area of 147,181 km2 (56,827 sq mi) Population: approx 27 million

Introduction Persistent (>7 days) febrile illnesses (PFIs) represent a difficult and common presentation to healthcare Part of a EU funded multi-country NIDIAG study

Introduction We studied the differential diagnosis and associated clinical and laboratory predictors in patients with PFIs in eastern Nepal

Methods Inclusion: Patients ≥5 years old Fever > 7 days Study duration: January 2013 - Oct 2014 Study site: District & tertiary hospital, Eastern Nepal

Methods Case report forms maintained Medical history, physical examination, and laboratory investigations noted Follow up in 1 month Follow up blood sample taken

Tests performed Haemoglobin White blood cell count Kidney function tests Liver function tests Blood cultures Urine routine and culture Malaria RDT HIV serology

Other investigations Chest X-ray Abdominal ultrasound Sputum examination

Testing of samples National reference labs International reference labs

Target conditions Malaria HIV Tuberculosis Brucellosis Leptospirosis Rickettsial diseases Relapsing Enteric fever Visceral Leishmaniasis

Formulating Diagnosis Final case-ascertainment by experienced physicians based on pre-specified case-definitions

Results 578 patients recruited (427 BPKIHS, 151 Dhankuta)

Target conditions (BPKIHS)

BPKIHS - Final diagnosis Target conditionsa Diagnosis Count (n=) Proportion VL 54 12.7% Tuberculosis (all types) 23 5.4% Rickettsiosis 17 4% Scrub typhusa 12 2.8% Leptospirosisa 10 2.4% Enteric fever 7 1.6% HIV 4 0.9% Relapsing fever Brucellosis 0% Malaria Any target condition 131 30.8% a Serologies for Leptospira & PCR scrub typhus awaited

Other conditions (BPKIHS)

BPKIHS - Final diagnosis Other conditions System Diagnosis Count (n=) Proportion Respiratory Pneumonia 13 3.1% Tonsillitis/pharyngitis 7 1.6% Other RTI 24 5.6% Urinary UTI 31 7.3% Cancer Leukemia 4 0.9% Solid tumor 2 0.5% Other (defined) 17 4% Mixed infections Undefined 205a 48.2% a 129/205 (63%) have suspicion of enteric fever +/- other condition; 6 death (CFR: 2.9%); 173 (84%) received Abx

Target conditions (Dhankuta)

Dhankuta - Final diagnosis Target conditionsa Diagnosis Count (n=) Proportion VL 0% Tuberculosis (all types) 5 3.3% Rickettsiosis Scrub typhusa 1 0.7% Leptospirosisa Enteric fever HIV Relapsing fever Brucellosis Malaria Any target condition 9 6% a Serologies for Leptospira & PCR scrub typhus awaited

Other conditions (Dhankuta)

Dhankuta - Final diagnosis Other conditions System Diagnosis Count (n=) Proportion Respiratory Pneumonia 8 5.3% Tonsillitis/pharyngitis 16 10.7% Other RTI 32 21.3% Urinary UTI 4 2.7% Other (defined) 0% Mixed infections 1 0.7% Undefined 82a 54.7% a 70/82 (85%) have suspicion of enteric fever +/- other condition(s); 0 death; 91% received Abx

Way forward Development of a diagnostic guideline to assist healthcare workers in improving diagnosis of PFIs at primary healthcare centres

Fever > 7 days LP KalaAzar (VL) Tuberculosis Rickettsiosis History taking Duration of fever H/O VL Pallor/Jaundice H/O Travel Cough, bloody sputum, SOB Abdominal complaints Family H/o TB/VL On examination Hepatosplenomegaly Vital signs Skin examination Lung auscultation Abdominal palpation Stiff neck Lab WBC/HB ASAT/ALAT Malaria if H/O travel Blood culture Urine analysis Using dipstick Chest Xray Respiratory symptoms RDT rK39 (if no H/O VL and splenomegaly Abdominal Ultrasound Abominal tenderness LP Signs of meningitis KalaAzar (VL) Tuberculosis Rickettsiosis + - Splenomegaly RDT - Hb<10 RDT + BM + Fever > 2wks Pneumonia + - AFB+ Genexpert - Genexpert+ Abnormal Chest Xray Fever > 2 wks Scrub typhus + - Abnormal Chest Xray Normal Chest Xray Respiratory signs /symptoms Blood culture+ + - Eschar+ Fever > 7 days Enteric fever Leptospirosis + - Blood culture + Abdominal tenderness Acute Leukaemia Urinary tract infection Intra-abdominal infections Liver abcess /Cholelithiasis/Appendicitis + - WBC Bone marrow Meningitis + - Lumbar puncture Meningeal signs + - Urine analysis + Urine routine , culture +

Conclusion Common causes of PFIs in the eastern part of Nepal differed from those in parts of Nepal non-endemic for Visceral Leishmaniasis This is the first study to report the causes of PFIs in a VL-endemic region of Nepal