Appendix 1. Prevalence of main aetiologies of acute undifferentiated febrile illnesses in geographic regions with low resource settings 1-4 Protozoal* Bacterial Rickettsial Spirochetal Viruses Helminthic Arboviruses Other viruses ASIA South and Malaria: PF, PV, & P. Enteric fever, Brucellosis, Scrub typhus, Murine Leptospirosis Dengue, Crimean-Congo Hemorrhagic Filariasis#, Acute South-East knowlesi Melioidosis Typhus Chikungunya, Zika Fever (CCHF), Kyasanur Forest schistosomiasis Asia Disease (S E Asia) East Asia Malaria (parts of China) Enteric fever, Brucellosis, Scrub typhus, Murine --- Dengue Hantavirus -Hemorrhagic fever Filariasis, Acute Melioidosis Typhus with renal syndrome (HFRS), schistosomiasis Australia, - Melioidosis Australian tick typhus, Leptospirosis Ross River virus, New Zealand Q fever Chikungunya Oceania Malaria in some Melioidosis - Leptospirosis Ross River virus, Filariasis countries Dengue, Zika, AFRICA North Limited risk of malaria Enteric Fever, Brucellosis, Murine typhus, ? Leptospirosis No yellow fever Filariasis, Acute Q fever Mediterranean risk, Limited risk of Schistosomiasis spotted fever other arboviral West Malaria: PF>PV, Acute Enteric Fever, Br ucellosis, Murine typhus Leptospirosis, Yellow fever, Other Viral Hemorrhagic fevers Filariasis, Acute African Trypanosomiasis Epidemic meningococcal ATBF Dengue, Zika, (Ebola, Lassa, CCHF) Schistosomiasis disease Chikungunya East Malaria: PF >PV, East En teric fever, Epidemic Murine typhus, ATBF Leptospirosis, Yellow fever, Other Hemorrhagic fevers (Rift Filariasis, Acute African trypanosomiasis meningococcal disease, Tick/louse- Dengue, valley fever, CCHF) Schistosomiasis Brucellosis borne Chikungunya Central Malaria: PF > PV, West Enteric fever, Epidemic Murine typhus, ATBF, Leptospirosis, Yellow fever, Other Viral hemorrhagic fever Filariasis, Acute African trypanosomiasis meningococcal disease, Epidemic Typhus Tick-borne Dengue, (Ebola, Marburg, CCHF) Schistosomiasis, Brucellosis relapsing fever Chikungunya, Zika Trichinosis South Malaria: PF > PV Enteric fever, Brucellosis Murine typhus, ATBF Leptospirosis Dengue, Filariasis, Acute Chikungunya Schistosomiasis, Trichinosis AMERICAS Latin Malaria risk (Limited): Enteric Fever, Oroya fever Rocky Mountain Leptospirosis, Dengue, HFRS, Hantavirus pulmonary Filariasis, Acute America and PV > PF, Acute American (Bartonellosis), Spotted Fever, Murine Tick-borne Chikungunya, Zika syndrome (HPS), Other viral Schistosomiasis, Caribbean trypanosomiasis (T. Brucellosis typhus, Scrub typhus, relapsing fever hemorrhagic fevers: Junin, Trichinosis cruzi) African tick bite fever Machupo, Sabia, Guanarito *Other protozoal causes of acute fever include H epatic amebiasis : This has wide distribution with high incidence in Asia (esp. India and Vietnam), tropical regions of Africa, Mexico, Venezuela and Colombia. # Acute filariasis usually has fever with localising features like tender adenopathy, lymphangitis or funiculitis, orchitis and epididymitis. Abbreviations: PF: Plasmodium falciparum; PV: Plasmodium vivax ; P. knowlesi : Plasmodium knowlesi ; ATBF: African Tick-Bite Fever; Appendix 2. Clinical features of the common and important causes of acute undifferentiated febrile illnesses 5 rs) -out -in undice Eschar Eschar Ja Conjunctiva l Suffusion Lymphaden opathy Muscle tenderness Spleen Dyspnoea Encephalop athy Renal Acute Failure Shock Bleeding White blood count cell Thrombocy (< topenia 150,000) Rule features (good predictors) Rule features (good exclude Disease Rash Uncomplicated 0 0 + 0 0 0 +++ 0 0 0 0 0 N +++ b Fever >40 degrees. 54 Rash and Splenomegaly, Lymphadenopathy Malaria Severe 0 0 +++ 0 0 0 +++ +a ++ +++ a ++ (+) H +++ b thrombocytopenia and suggest alternative hyperbilirubinemia 55 56 diagnosis.51 Uncomplicated +++ 0 0 ++ ++ + + 0 0 0 0 + N/L +++ Leukopenia and Fever >12 days, thrombcytopenia. 57 Positive combination of tourniquet test is a good normal tourniquet Dengue predictor of infection (OR: test & normal Severe +++ (+) ++ ++ ++ + (+) + + ++ +++ L +++ c 4.86) and ascites is a good leucocyte count.59 predictor of severe dengue (OR:13.91).58 Enteric fever uncomplicated (+) 0 0 0 (+) 0 +/++ d + 0 (+) 0 0 N/L 0 Fever in endemic areas > 3 (similar features days duration & presence of Generalised rash or in typhoid & abdominal tenderness (51) complicated (+) 0 ++ 0 (+) 0 +++ d + ++ (+) + ++ e H + lymphadenopathy paratyphoid fever) 52 Combination of suffusion, No reliable icterus and conjunctival. information Leptospirosis Mild (anicteric) + 0 0 +++ ++ ++ (+) ++ 0 0 0 0 N +++ hemorrhage is characteristic available of Leptospirosis. 49 A THAI- LEPTO score of > 5 useful f for suspecting diagnosis, Severe (icteric) + 0 +++ +++ ++ +++ + ++ ++ +++ ++ ++ H +++ especially severe Leptospirosis. 60 Scrub typhus Non-severe ++ +++ 0 ++ ++/+++ 0 + 0 L/N/ +++ h No information (see appendix 3 available Eschar is pathognomonic for for spotted Severe scrub typhus (OR 46).61 fever, and ++ +++ ++ ++ ++ +/++ +++ g ++ ++ ++ + H +++ i murine typhus) *Notes: a: ARDS and ARF are commoner in adults than children. b: Thrombocytopenia is frequent, but bleeding is uncommon in malaria. c: bleeding can occur in skin or in mucous membranes. d: splenomegaly may be absent in 1 st week of illness. e: Gastro-intestinal hemorrhages occur in around 10% of patients with severe enteric fever. f: Bleeding manifestations include severe pulmonary hemorrhage with ARDS. g¨ pneumonia is a common complication of scrub typhus in south Asia, and can progress rapidly to ARDS. h: thrombocytopenia frequent but mild in non-severe scrub typhus, i: severe scrub patients may have severe thrombocytopenia. Abbreviations: 0: does not occur/usually not associated with the disease; (+): Rare (frequency <5%); + Uncommon (frequency 6-10%);++: Occasional (10-30%); +++: Common (>30%); cut-offs are arbitrary; N: normal (4.0 -11.0 x 10 9/L); H: high (> 11.0 x 10 9/L); L: low (< 4.0 x 10 9/L); S: severe. TT: Tourniquet test; OR: Odds ratio;LR:;ARDS: Acute Respiratory Distress syndrome; ARF: Acute Renal Failure Appendix 3. Clinical features of some other important causes of AUFIs Disease Epidemiology Characteristic symptoms Systemic involvement Other features and points of discriminatory value Zika virus Vector borne (Aedes aegypti, albopictus Low grade Fever with 2 out of the GI and Liver: Transaminases ↑ Risk of fetal microcephaly, ocular in Americas), Other Aedes spp in following 3 features: Pruritic Lungs: Rare.Neurological Guillain-Barre abnormalities. Fever lesser than in dengue, Micronesia Also parenteral, maculopapular rash (90%), syndrome strongly associated (OR >34) post Arthralgia lesser than in Chikungunya transplacental and sexual arthralgia, Non-purulent Zika fever. Renal: Rare Conjunctivitis present. Rash is pruritic and conjunctivitis - cephalocaudal in distribution. Ebola virus disease Zoonoses. Fruit bats possible reservoirs History of being in an endemic area, GI and Liver: Abdominal pain, vomiting, Maculo-papular rash occasional. Secondary of virus. Person to person transmission and exposure to Ebola virus in past watery diarrhea between 3-10 days from infections by contact with body fluids. Outbreaks 21 days, in association with a febrile onset. GI bleeding late feature. Lungs: rare Features similar to other AUFIs. Fever, rash, seen. illness with myalgia, conjunctival involvement.CNS: Symptoms suggestive of conjunctival injection uncommon in cholera injection meningo-encephalitis typically after day 10. Confusion, seizures, hiccups. Acute renal failure due to hypovolemia Spotted fever group Vector borne (ticks) Zoonosis Fever with rash and eschars are No systemic complications in ATBF ATBF mild, non-fatal. Mediterranean spotted fever (MSF) - prominent findings in spotted GI and Liver: Transaminases ↑ In MSF serious complication seen in Rickettsia conorii ; African tick bite fevers. ATBF has prominent Lungs: Occasional pneumonia in MSF. presence of diabetes, alcoholism heart fever(ATBF) - Rickettsia africae ; Indian adenopathy & multiple eschars. Neurological: Very occasional encephalitis failure Tick Typhus(ITT)- Rickettsia conorii Rash commoner in MSF and ITT. in MSF/ITT indica Renal: ARF Reported in MSF/ITT Typhus group Vector borne, Fever with rash with no eschar or GI and Liver: Transaminase elevation Illness mild in murine typhus low mortality. Rat flea: Murine /Endemic typhus - adenopathy. Jaundice may be seen Serious CNS complications rare. Epidemic: (Rickettsia typhi ) Rash begins on trunk, centrifugal Lungs: Pneumonia in both epidemic and CNS complications prominent, high Body lice: Epidemic typhus ( Rickettsia spread to limbs sparing palms and endemic typhus, more prominent in murine mortality. Rash absent in 60% of epidemic prowazekii ) soles, face., commoner in epidemic typhus. Neurological: Confusion, coma may typhus in Africa Epidemic Potential typhus occur. Renal: ARF Reported in both Epidemic and endemic typhus Relapsing fever (RF) - TBRF –zoonoses caused by various Febrile episodes (3-10) of ~ 3-5 days Jaundice occasional in LBRF Louse borne relapsing fever seen usually in Tick borne relapsing species of Borrelia transmitted by soft & afebrile periods of ~7-10 days. Hepatosplenomegaly occasional. overcrowding and refugee populations. fever(TBRF) & Louse ticks Patients become tachycardic, Dry cough common Pneumonia unusual Relapsing fever should be considered if borne relapsing LBRF – humans are reservoir. Borrelia tachypneic in the chill phase and Confusion common Meningitis occasional patients has symptoms resembling