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Home , Melioidosis, Murine typhus, Rickettsia typhi, Scrub typhus, Spotted fever, Typhus

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 , , Scrub , Murine Dengue, Crimean-Congo Hemorrhagic Filariasis#, Acute South-East knowlesi Typhus Chikungunya, Zika Fever (CCHF), Kyasanur Forest schistosomiasis Asia Disease (S E Asia) East Asia Malaria (parts of China) Enteric fever, Brucellosis, , Murine --- Dengue Hantavirus -Hemorrhagic fever Filariasis, Acute Melioidosis Typhus with renal syndrome (HFRS), schistosomiasis , - Melioidosis Australian typhus, Leptospirosis Ross River virus, New Zealand Chikungunya Malaria in some Melioidosis - Leptospirosis Ross River virus, Filariasis countries Dengue, Zika, AFRICA North Limited risk of malaria Enteric Fever, Brucellosis, , ? Leptospirosis No yellow fever Filariasis, Acute Q fever Mediterranean risk, Limited risk of Schistosomiasis other arboviral West Malaria: PF>PV, Acute Enteric Fever, Br ucellosis, Murine typhus Leptospirosis, Yellow fever, Other Viral Hemorrhagic Filariasis, Acute African Trypanosomiasis meningococcal ATBF Dengue, Zika, (, 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 , Tick/- 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, Tick-borne Dengue, (Ebola, Marburg, CCHF) Schistosomiasis, Brucellosis 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 (), 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) 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, 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

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undice Eschar Ja Conjunctiva l Suffusion Lymphaden opathy Muscle tenderness Spleen Dyspnoea Encephalop athy Renal Acute Failure Shock White blood count cell Thrombocy (< topenia 150,000) Rule features (good predictors) Rule features (good exclude Disease Uncomplicated 0 0 + 0 0 0 +++ 0 0 0 0 0 N +++ b Fever >40 degrees. 54 Rash and , 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 +++ and Fever >12 days, thrombcytopenia. 57 Positive combination of tourniquet test is a good normal tourniquet Dengue predictor of (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 areas > 3 (similar features days duration & presence of Generalised rash or in typhoid & abdominal tenderness (51) complicated (+) 0 ++ 0 (+) 0 +++ d + ++ (+) + ++ e H + lymphadenopathy ) 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¨ is a common 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 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 : Rare.Neurological Guillain-Barre abnormalities. Fever lesser than in dengue, Micronesia Also parenteral, maculopapular rash (90%), syndrome strongly associated (OR >34) post 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, , 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 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 , conjunctival involvement.CNS: Symptoms suggestive of conjunctival injection uncommon in injection meningo- typically after day 10. . Confusion, seizures, hiccups. Acute renal failure due to hypovolemia Spotted fever group Vector borne () Fever with rash and 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 conorii ; African tick bite fevers. ATBF has prominent Lungs: Occasional pneumonia in MSF. presence of , heart fever(ATBF) - ; Indian adenopathy & multiple eschars. Neurological: Very occasional encephalitis failure Tick Typhus(ITT)- 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. : Murine /Endemic typhus - adenopathy. Jaundice may be seen Serious CNS complications rare. Epidemic: ( ) 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 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 common Pneumonia unusual Relapsing fever should be considered if borne relapsing LBRF – are reservoir. Borrelia tachypneic in the chill phase and Confusion common Meningitis occasional patients has symptoms resembling malaria fever(LBRF) recurrentis transmitted by . may have hypotension when fever but is persistently smear negative. . subsides Melioidosis Vehicle borne disease caused by Variable presentations but may GI and Liver: in liver, spleen may May mimic pyogenic infection with pseudomallei present as a community acquired be seen in acute and chronic forms of abscesses, Gram negative & TB Moist soil, water, fruits, vegetables. pneumonia or septicemic along melioidosis (Swiss cheese appearance on (upper lobe cavities) Rainy season. with abscesses in skin, parotid and USG). Commonest cause of splenic May mimic pulmonary TB (chronic fever, DM, COPD, alcohol put at risk. . in . Lungs: Pneumonia commonest upper lobe cavities) variable, and disease presentation. Multiple nodules, patchy may occur years after exposure. alveolar opacities which coalesce. Neurological: Meningo-encephalitis, Brain abscesses. Acute renal failure may occur Brucellosis Consumption of unpasteurised milk Acute mono-arthritis of hip or knee Transaminases ↑. Hepatosplenic abscesses Lumbar vertebra affected; with late discal products Contact with livestock Brucella in a young child. in a small proportion. involvement. Cord compress-ion is unusual, abortus Brucella melitensis commonest Vertebral in an older Pneumonia. May present as compared with which may person bronchopneumonia or even with miliary affect the lower thoracic vertebrae, with lesions. early discal involvement and result in cord (Rare) compression. - Vector borne (Rat flea) Zoonosis : commonest form. Abscesses in liver, spleen in septicemic Adenopathy in plague occurs as part of a Outbreak may follow an outbreak and Fever with enlarged very painful, plague. rapidly progressive illness, with no deaths in populations (epizootic) tender lymph nodes in any region. Pneumonia- in plague may be bilateral lymphangitis or (bubonic) or segmental progressing to bilateral alveolar(pneumonic) Occasional meningitis seen. ARF may occur as part of multi-organ failure African Vector borne disease due to 2 T.b. rhodesiense Intermittent high GI and Liver disease T.b. rhodesiense infections have an acute Trypanosomiasis subspecies of Trypanosoma brucei. (T.b) fevers →afebrile periods. Hepatosplenomegaly occasional onset with fever, rapid progression (HAT) Transmitted by bites of tsetse flies Painful at site of bite in half CNS: In Stage II disease -Daytime resembling malaria/sepsis. Chancre T.b. gambiense HAT: predominant form, of T.b. rhodesiense infections. Less somnolence, ataxia frequent. Death can occur in acute stage Stage I (haemo- prevalent in Central and West. often in T.b. gambiense Cardiac: Persistent tachycardia, arrhythmias due to cardiac failure. lymphatic) may T.b. rhodesiense HAT can present as Posterior cervical node enlargement CHF in T.b, rhodesiense T.b. gambiense infections are slower in present as an AUFI: AUFI in east and south Africa in T.b. gambiense - Winterbottom onset and progression, and may present sign with CNS symptoms. Abbreviations: GI: Gastrointestinal: Acute renal failure; CNS: Central Nervous system ; MSF: Mediterranean spotted fever; ATBF: African Tick Bite fever; ITT: Indian Tick Typhus; TBRF: Tick-borne relapsing fever; LBRF: Louse-borne relapsing fever; HAT: Human African Trypanosomiasis; T.b.: Trypanosoma brucei 1. Brunette GW, ed. CDC Yellow Book 2018: Health Information for International Travel . Centers for Disease Control and Prevention, 2017.

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