Prof Anurag Bhargava

1. Approach to acute febrile illness in tropical regions:
Focus on acute undifferentiated febrile illnesses
(AUFI)
Dr. Anurag Bhargava, M.D., M.Sc.(Epidemiology)
Professor of Medicine, Department of Medicine
Head, Center for Nutrition Studies, Yenepoya (Deemed to be University) , Mangalore
Adjunct Professor, Department of Medicine, McGill University, Montreal
Belur Temple 1117 A.D Yenepoya University

2. Life is short, and Art long,
opportunity fleeting,
experiment perilous,
decision difficult -
-Hippocrates
Mankind has but
three great enemies: fever,
famine and war; of these by far
the greatest, by far the most
terrible, is fever. – Sir William
Osler

3. “In the beginning of the malady, it is easy to cure but difficult to detect,
but in the course of time, it becomes easy to detect, but difficult to
cure “
– Niccolo Machiavelli in The Prince.

5. Acute febrile
illness
Acute localised
infections
Acute
undifferentiated
febrile
illness(AUFI)

6. AUFI
Fever of <14 days which is not associated with any organ specific symptoms at
its onset.
Many tropical infections present as AUFI.
May occur as outbreaks, epidemics.
Epidemiological, clinical and laboratory features often overlap.
May evolve rapidly into life-threatening illness.

7. Acute
undifferentiated
febrile illness
Malaria
Non-malarial
AUFI
Proportion of fevers due to Falciparum malaria decreased from 44% to 22% in Africa over
1990-2010.
Non-malarial AUFIs account for 20-50% of all fevers in South Asia.
D’Acremont V. Malaria J 2010. D’Acremont 2013.

9. 1564 patients > 5 years of age during April- November 2012 in
six states of India:
• Malaria : 17% of patients: 54% had P.falciparum.
• Dengue: 16% of patients.
• Scrub typhus: 10% of patients.
• Bacteremia : 8% of patients. 3% had Enteric fever.
• Leptospirosis: 7% of patients.
• Chikungunya : 6% of patients.

10. Non-malarial AUFI
Viral
Arboviral*
Dengue,
Chikungunya
Other viruses:
Influenza
Bacterial
Blood stream
infections
Enteric
Fever
Bacterial
zoonoses
Spirochetal
infections. E.g.
Leptospirosis
Rickettsial
infections e.g.
Scrub typhus
Parasitic
Hepatic amebiasis

11. A mnemonic to sum up AUFIs: MA-ESR
Disease group Examples Diagnosis
M alaria P.V. P.F., P.K Demonstration of
organism
A rboviral Dengue, Chik, Zika NS1 antigen, IgM
E nteric Fever Typhoid, paratyphoid Culture , Serology
S pirochetal Leptospirosis , Borreliosis Serology
R ickettsial Scrub typhus, Murine
typhus,
Spotted fever
Serology

12. Principles of a rational approach to AUFIs
Epidemiologic , clinical information and laboratory tests are similar to
diagnostic tests conducted serially .
Although individual elements may be non-specific, the combination
may be highly suggestive.
Early initiation of empiric therapy is required to reducing morbidity
and mortality in non-AUFIs, especially rickettsial and spirochetal
infections.

13. Step 5: Monitor therapeutic response, follow up test results
Step 4: Integrate information from 1,2,3 to formulate a confirmed or probable diagnosis. Initiate therapy.
Step 3: Perform first-line and wherever possible confirmatory tests
Step 2: Evaluate clinical features
Step 1: Collect epidemiological information

14. Consider how this works:
AUFI of 3 days / AUFI with above features in rainy season in a region
endemic for dengue
AUFI of 3 days with rash
AUFI of 3 days with rash and leukopenia
AUFI of 3 days with rash and leukopenia and thrombocytopenia

15. A patient has 3 days of AUFI . On examination he has skin rash(LR+ 2.8). His
CBC shows leukopenia(LR+ 3.3)and thrombocytopenia(LR+ 2.0) – Bottieau E.
Medicine 2007.
Pretest probability = 0.1 or 10% Pre-test odds are P/1-P= 0.1/(1-0.1)= 0.11
• Post-test odds of dengue with fever and skin rash = 0.11 x 2.8= 0.308.
• Post-test odds with leukopenia = 0.308 x 3.3 = 1.0164
• Post-test odds with thrombocytopenia: 1.0164x 2.0= 2.0328
Post-test probability = Odds/Odds +1 =2.0328/2.0328+1 = 0.67 or 67%
If during a dengue outbreak our pre-test probability would be higher(0.2)
and the post-test probability would be 82%

16. Step 1 : Epidemiological information
A.Agent of disease: Local disease prevalence, seasonality : Most
diseases in post-monsoon season.
B.Environment and exposures : Vectors, contaminated food, water,
animals and their excretions.
C. Host and Risk factors: Age, Comorbidities, immunosuppression,
pregnancy

17. “Scrub typhus is probably the single most prevalent, under-
recognized, neglected and severe but easily treatable disease
in the world.”-
Paris D.H. etal. Am.J.Trop.Med.Hyg 2013; 89(2): 301-307

18. Scrub Area
Areas Around Houses
Dry Habitats Wet Habitats
Rice FieldThe term scrub of scrub typhus
came from the type of
vegetations (terrain between
woods & clearings) that harbor
the vectors.
Moist Areas: Swamp & Bog
Leptotrombidium Chigger’s Habitats
Edges of Dense Forest

20. Rickettsial infections: A broad classification
Typhus Group
Epidemic Typhus R. prowazekii Human body Lice
Murine ( Endemic ) Typhus R. Typhi Rat flea
Spotted fever group
Rocky mountain spotted
fever
R. Rickettsii Tick
Orientia group
Scrub typhus O.tsutsugamushi, O.chuto Larvae of Trombiculid mite

21. Tilak R, Kunte R, MJAFI 2019; 75:8-17

22. Adult Trombiculid Mite Larva of Trombiculid mite:
Leptotrombidium deliense
Courtesy: Dr. Rina Tilak, AFMC, Pune

25. Tilak R, Kunte R, MJAFI 2019; 75:8-17

27. ? The importance of comorbidities:
Pneumonia +/-septicemia +/- abscesses in a patient with
diabetes/renal failure
Manson’s Tropical Diseases. 23rd
edition

28. Some other viral zoonotic diseases can begin with AUFI
Viral hemorrhagic fever group :
•Crimean –Congo Hemorrhagic fever: Tick borne infections, Gujarat,
Rajasthan.
•Kyasanur Forest Disease: Karnataka, Goa, and other states.
Nipah virus : Fruit bats, encephalitis
COVID-19

29. Step 2: Evaluate clinical features
A.Assess severity of illness
B.Rule out localised infections
C. Assess key clinical features
Onset, duration, progression
Rule in and rule out features
Characteristic pattern of organ involvement.

30. Red flag features: comprehensive evaluation, inpatient care,
empiric parenteral therapy
1. Altered mental status (Glasgow coma scale <13), convulsions/positive meningeal
signs.
2. Breathless/RR> 22/minute /cyanosis /arterial oxygen saturation < 92 on room air,
3. BP < 100 mm Hg systolic /cold clammy extremities/capillary refill > 3 secs.
4. Hyperpyrexia (temperature > 41.50
c) or hypothermia (temperature < 360
C) or
rigors.
5. Prostration: Unable to stand or sit or walk without support.
6. Severe pallor.
7. Jaundice on examination of sclera (except mild jaundice which can occur in
uncomplicated malaria)
8. Abdominal pain severe/persistent vomiting.
9. Petechial or purpuric rash.
10. Significant bleeding from nose, gums or venepuncture sites/hematemesis/melena.
WHO : Guidelines for treatment of Malaria. 2015, Seymour CW etal. JAMA. 2016. WHO : Dengue . 2009.

31. Rule out localised infections
Clinical pearl 1:
Some localised infections may present like AUFI early in the course
e.g. Influenza
Clinical pearl 2:
Some AUFIs may present later in the course with s/o localised infections
Malaria – encephalopathy
Scrub typhus – Pneumonia, ARDS
Leptospirosis – Jaundice : Hepatobiliary infections

33. Onset ,progression and duration of illness
Onset and progression:
•Malaria, dengue, scrub, lepto: abrupt onset with often rapid
progression to complications in 1 week.
•Enteric fever: less abrupt onset with complications in 2nd
/3rd
week
Duration :
Dengue 7-12 days
Influenza : 3-8 days.

34. Potential diagnostic clues: Rule in and rule out
features
Rule in features: signs which alone or in combination indicate
moderate or high likelihood of disease ~ Good predictors
Rule out features: signs which alone or in combination indicate low to
very low likelihood of a disease ~ Good excluders

35. Rule-in features
• Malaria: Fever > 400
C , splenomegaly, ↓ platelets, ↑bilirubin
• Arboviral infections: Rash +/- arthritis.
• Enteric Fever: None
• Leptospirosis: Suffusion + jaundice + conjunctival hemorrhage + muscle
tenderness
• Scrub typhus: Eschar
Bhargava A, Ralph R, Chatterjee B etal BMJ 2018

36. Eschar: A pathognomonic sign of scrub
typhus
•Painless, non-pruritic ulcer at site of bite with black scab and
erythematous halo.
•> Frequent in primary infections
•Best specimen for PCR.
•Frequency 10-45% in Indian case series. 17% in our case series.

41. Rule out features which suggest alternative diagnoses
•Malaria: Rash , lymphadenopathy.
•Dengue : Fever > 12 days, Normal tourniquet test and leukocyte
count suggest alternative diagnosis.
•Enteric Fever: Rash, lymphadenopathy, complications in first week.
•High fever with jaundice: Viral hepatitis is less likely

42. Clinical examination
General appearance and vitals
• Acutely ill patient: Severe forms of MAESR.
• Relative bradycardia: Enteric fever, dengue fever, scrub typhus
• Hypotension in the first week: Dengue, scrub typhus, Malaria, Lepto Enteric fever
less likely
Eyes
• Jaundice : Malaria, lepto, scrub typhus, enteric fever
• Conjunctival suffusion: lepto, scrub typhus
• Non-purulent conjunctivitis: Zika, chikungunya
• Conjunctival hemorrhage: Lepto.
• Roth spots
Neck
Lymphadenopathy: Dengue, Scrub typhus.

43. Skin :
Abscesses subcutaneous ,or in parotids : Melioidosis
Maculopapular rash: Dengue, scrub typhus, rickettsial infections
Eschar: scrub typhus, anthrax, tularemia
Petechial, purpuric: Dengue, rickettsial infections
Rose spots: Enteric fever

44. Respiratory
• Hemoptysis: Leptospirosis
• Few signs despite severe
pneumonia: Scrub typhus
• Pleural effusion: Dengue with
plasma leakage
Abdominal examination
Hepatomegaly: Tender
hepatomegaly with intercostal
tenderness in hepatic
amebiasis.Enlarged in malaria,
enteric fever, scrub typhus, lepto
Splenomegaly
Malaria, enteric fever, scrub
typhus ( +/-) unusual in lepto
Ascites: Dengue fever with plasma
leakage

45. Musculoskeletal examination
•Oligoarthritis or Polyarthritis: Chikungunya
•Muscle tenderness: Leptospirosis

46. The General Physical examination holds the key
•M uscle tenderness
•A denopathy, arthritis
•E schar
•S uffusion ( conjunctival)
•R ash
•J aundice

48. Characteristic pattern of systemic involvement:
Lung, kidney, brain, CVS, bleeding
•Dengue: Jaundice, renal involvement less common. Bleeding
common.
•Enteric fever: acute renal failure and lung involvement less common.
•Malaria: thrombocytopenia + but bleeding rare. Transaminases n.

49. Clinical syndrome N=284(percen
t)
Community acquired
pneumonia
115 (40%)
Without ARDS 69
With ARDS 45
Undifferentiated fever 28%
Fever with shock 11%
Acute confusional state 10%
Fever with GI/Hepatic
symptoms
5%
Others 6%
Bhargava A etal . IJMR 2016

51. MA-ESR as a mnemonic for complications of
AUFI
•M ultiorgan failure
•A RDS
•E ncephalopathy
•S hock
•R enal failure

52. Step 3 : Perform basic and confirmatory
tests
•Perform microscopy or RDT for malaria, CBC, Urinalysis : in all
•Biochemical ( localised symptoms, complications)
•Imaging ( localised symptoms, complications)
•Demonstration of organism by culture, DNA:
•Demonstration of antibody: by serology

53. Diagnostic value Prognostic value
Leukocytosis Leptospirosis, scrub typhus, amebiasis In enteric fever, leptospirosis
Leukopenia Early leukopenia + thrombocytopenia
: Dengue
Falling TLC +
thrombocytopenia + Rising
hematocrit: Severe dengue
Thrombocytopenia No discriminant value In association with bleeding
Urine Hematuria, proteinuria in lepto Hemoglobinuria in malaria
Bilirubin Malaria Vs. dengue In all AUFIs except malaria.
Liver enzymes Poor discriminant value. May be
modest elevation despite large
increases in bilirubin in Lepto
Dengue
Renal function and
electrolytes
AKI + hypokalemia in leptospirosis Prognostic value in all severe
forms of AUFI

54. Imaging in AUFI
X ray chest :
• Scrub typhus, Leptospirosis, occ. Malaria: Bilateral pneumonia/ARDS
Pneumonia occasionally in Enteric fever. Pleural effusion in Dengue
Nodular shadows, cavities: Melioidosis
Ultrasound abdomen:
Ascites, pleural effusion, gall bladder wall edema: Dengue fever
Mesenteric adenopathy: Enteric Fever
Acalculous cholecystitis : Dengue, other AUFIs
Hepatic amebiasis: abscess
Multiple hepatic and splenic abscess : Melioidosis.

55. Testing: Parallel or sequential
Diagnostic algorithms with appropriate sequential testing predicted correct identification
of aetiology in 74% and 89% of patients in India and Cambodia respectively compared to
46% and 49% with simultaneous testing. Pokharel S etal Clin Inf Dis 2019

56. Confirmatory tests
Microscopy: Malaria
Culture : Enteric Fever, Leptospirosis.
Nucleic acid amplification: Dengue, Leptospirosis, Scrub typhus
Serology
Immunochromatographic tests : Rapid Diagnosic Tests (RDTs)
ELISA based : IgM
Widal test: Not useful. Weil-Felix test: Low sensitivity
Available only in reference labs: Immunofluorescence based: IFA IgM
for Scrub typhus, Microscopic agglutination test for Leptospirosis

57. Comments on confirmatory tests
Malaria : Caveats with RDTs
• Low sensitivity to low level parasitemia
• Variable performance, deterioration at high temp. humidity
• Populations of P.falciparum with deletion in PfHRP2 genes
Serological confirmation:
IgM seroconversion or More than 4 fold rise in IgG titer alone diagnostic
Dengue, Scrub typhus, Leptospirosis: IgM based tests:
• Rapid but not early
• Persistence after infection.
• Cross reactivity: dengue, leptospirosis.
Best combination would be : PCR(+ in early disease) + Serology (+ later)

58. IgM positive for 2 pathogens
OR Smear positive for malaria + positive serology
Coinfections possible : malaria , dengue/chikungunya
scrub typhus, leptospirosis
Background positivity : Scrub typhus, leptospirosis.
Cross-infections: chikungunya, dengue.

59. Step 4 : Probable diagnosis
Initiate therapy based on setting and severity of illness.
Ceftriaxone 2 g OD + Doxycycline 100 mg BD- severe bacterial AUFI
Enteric fever Leptospirosis Scrub typhus
(10-14d) (7 days) (7 days)
Singhi S etal. Indian journal of critical care medicine 2014;18(2):62-9
Thompson CN etal. The American journal of tropical medicine and hygiene.
2015;92(4):875-8.

60. Ceftriaxone + doxycycline
•Could serve in patients with AUFI complicated by Acute lung injury,
renal failure and encephalopathy.
•No dosage modification required in renal failure.
•Patients with severe falciparum often complicated by blood stream
infections.

61. Uncomplicated AUFIs
•Enteric Fever: Azithromycin, Cephalosporins (No Cefixime). NO
Fluoroquinolone.
•Scrub typhus: Doxycycline, Azithromycin.
•Leptospirosis : Ampicillin, Doxycycline, Azithromycin.
•Azithromycin in Enteric Fever: 1 g OD x 5 days or 1 g on day 1 ---500
mg OD x 6 days
•Azithromycin in Scrub typhus or Leptospirosis: 500 mg OD x 3-5 days

62. Step 5 : Monitor response, review results
•Monitor responses
•Follow up test results
•Consider alternative diagnosis: Amebiasis, endocarditis, TB,
brucellosis.

63. Summary
• 5 major disease groups cause AUFIs in India : MA-ESR. This is also a mnemonic for
key clinical findings and complications
• A step-wise epidemiological and clinical approach can be useful in reaching a
probable diagnosis, initiating therapy and saving lives. Rule in and rule out features
should be seen in all patients, and look, look and you may find an eschar.
• Basic tests can provide information of diagnostic and prognostic value.
• A positive confirmation of diagnosis is easiest with malaria and dengue. Serology in
the other AUFIs should be cautiously interpreted.
• Ceftriaxone and Doxycycline is recommended as presumptive antibacterial therapy in
patients with severe possible bacterial AUFIs. Azithromycin may offer choice of
appropriate Rx for probable bacterial AUFIs which are uncomplicated.

64. Acknowledgements
•Emmanuel Bottieau
•Ravikar Ralph
•Biswaroop Chatterjee

65. Yakshagana: Musical Theater , Karnataka
anuragb17 @gmail.com