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Go Back       Himalayan Journal of Community Medicine and Public Health | Volume:3 Issue:1 | Jan. 10, 2022
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DOI : 10.47310/Hjcmph.2022.v03i01.010       Download PDF       HTML       XML

Understanding the Differential Diagnosis of Acute Undifferentiated Febrile Illness in a Health Care Setting: A Critical Review

Jishtu V1 and Kumar A*2

1Dr Vinay Jishtu, Department of Medicine, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India

2Dr Arjun Kumar, Department of Medicine, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India

*Corresponding Author

Dr Arjun Kumar

Article History: | Received: 20.12.2021 | Accepted: 31.12.2021 | Published: 10.01.2022|

Abstract: Acute onset of fever, chills, myalgia, and fatigue are common features of many infections that are endemic in India. In many areas of developing countries, where diagnostic facilities are limited, etiologies of acute undifferentiated febrile illness (AUFI) remain largely unknown. Physicians often diagnose patients presumptively based on clinical features and assumptions regarding circulating pathogens. These AUFI that includes scrub typhus, dengue fever, malaria, enteric fever, and leptospirosis among others cause significant mortality and morbidity. Through this article we wish to focus on the differential diagnosis of Acute Undifferentiated Febrile Illness.

Keywords: Acute Undifferentiated Febrile Illness, Differential Diagnosis, Etiology.

Copyright @ 2022: This is an open-access article distributed under the terms of the Creative Commons Attribution license which permits unrestricted use, distribution, and reproduction in any medium for non commercial use (NonCommercial, or CC-BY-NC) provided the original author and source are credited.


Acute febrile illness (AFI) is defined as a patient with fever of 38°C or higher at presentation or history of fever that persisted for 2–7 days with no localizing source.iAcute febrile illness is a common cause of patients seeking health care settings posing a diagnostic and therapeutic challenge to the health care workers. Field studies on fever aetiology in India are few, and surveillance is limited by lack of accessibility to health facilities. These infections may be indistinguishable clinically, and the choice of empiric antibiotics depends on the etiologic profile which is variable and is region specific. Dengue fever and malaria are arthropod-borne diseases and are endemic in many parts of India during the monsoon season. Leptospirosis and scrub typhus are zoonotic infections and are widely prevalent in areas with heavy monsoon and agrarian way of life. It becomes imperative to maintain a sound epidemiological database of AFIs so that evidence-based diagnostic criteria and treatment guidelines can be developed.


Local prevalence of individual diseases influence the prioritization of the differential diagnoses of a clinical syndrome of acute undifferentiated febrile illness (AFI). A 1-year prospective, observational study was conducted among participants aged more than 16 years who presented with an undifferentiated febrile illness of duration 5-21 days and required hospitalization. Blood cultures, malarial parasites and febrile serology (acute and convalescent), in addition to clinical evaluations and basic investigations were performed. Comparisons were made between each disease and the other AFIs. A total of 398 AFI patients were diagnosed with: scrub typhus (47.5%); malaria (17.1%); enteric fever (8.0%); dengue (7.0%); leptospirosis (3.0%); spotted fever rickettsiosis (1.8%); Hantavirus (0.3%); alternate diagnosis (7.3%); and unclear diagnoses (8.0%). Leucocytosis, acute respiratory distress syndrome, aseptic meningitis, mild serum transaminase elevation and hypoalbuminaemia were independently associated with scrub typhus. Normal leukocyte counts, moderate to severe thrombocytopenia, renal failure, splenomegaly and hyperbilirubinaemia with mildly elevated serum transaminases were associated with malaria. Rash, overt bleeding manifestations, normal to low leukocyte counts, moderate to severe thrombocytopenia and significantly elevated hepatic transaminases were associated with dengue. Enteric fever was associated with loose stools, normal to low leukocyte counts and normal platelet counts.ii

Some fever syndromes have a more clear localization to skin and soft tissue (abscess or cellulitis), meninges or neural tissue (headache, neck-stiffness, altered sensorium with or without focal neurological signs), respiratory tract (cough, breathlessness), or urinary tract (dysuria, hematuria). These syndromes have better developed guidelines for their management. On the other hand, AUF-syndromes (such as fever-rash, fever-myalgia, fever arthralgia, fever-hemorrhage, and fever-jaundice) have overlapping aetiologies, which makes their diagnosis and management even more challenging.iii

The term Acute Undifferentiated Fever (AUF) is used to denote fevers that typically do not extend beyond a fortnight, and lack localizable or organ-specific clinical features. AUF poses a diagnostic and therapeutic challenge to the health workers, particularly in limited resource settings. A number of viruses, bacteria, protozoa and rickettsia can cause FUO. The non-specificity of symptoms and signs and lack of availability of accurate diagnostics not only test the clinical mettle of even astute physicians but often leads to irrational use of antibiotics and antimalarials.iv


In a recent registry of 1564 AUF patients from various secondary hospitals of north-east and south India (during April 2011 to November2012), Gopalakrishan S et al, reported that Malaria was diagnosed in 17% (268/1564) and among these 54% had P. falciparum. Dengue was diagnosed in 16% (244/1564). Bacteraemia was found in 8% (124/1564), and among these Salmonella typhi or S. paratyphi constituted 35%. Scrub typhus was diagnosed in 10%, leptospirosis in 7% and chikungunya in 6%. Fulfilling more than one case definition was common, most frequent in chikungunya where 26% (25/98) also had positive dengue test.v

In another study comprising of 10670 samples, revealed a heavy burden with four major tropical infections viz. dengue, chikungunya, enteric fever and malaria for the years 2013 and 2014. Overall seropositivity of 34.17% for Dengue virus infection, 18.6% for Chikungunya infection, 10.9% for Enteric fever and 4.7% for Malaria parasite was

A prospective observational study was conducted in a tertiary hospital in South India. All adult patients presenting with AUFI of 3–14 days duration were evaluated for etiology, and the differences in presentation and outcome were analyzed. The study cohort included 1258 patients. A microbiological cause was identified in 82.5% of our patients. Scrub typhus was the most common cause of AUFI (35.9%) followed by dengue (30.6%), malaria (10.4%), enteric fever (3.7%), and leptospirosis (0.6%). Both scrub typhus and dengue fever peaked during the monsoon season and the cooler months, whereas no seasonality was observed with enteric fever and malaria. The mean time to presentation was longer in enteric fever (9.9 [4.7] days) and scrub typhus (8.2 [3.2] days). Bleeding manifestations were seen in 7.7% of patients, mostly associated with dengue (14%), scrub typhus (4.2%), and malaria (4.6%). The requirement of supplemental oxygen, invasive ventilation, and inotropes was higher in scrub typhus, leptospirosis, and malaria. The overall mortality rate was 3.3% and was highest with scrub typhus (4.6%) followed by dengue fever (2.3%). Significant clinical predictors of scrub typhus were breathlessness (odds ratio [OR]: 4.96; 95% confidence interval [CI]: 3.38–7.3), total whole blood cell count >10,000 cells/mm3 (OR: 2.31; 95% CI: 1.64–3.24), serum albumin <3.5 g % (OR: 2.32; 95% CI: 1.68–3.2). Overt bleeding manifestations (OR: 2.98; 95% CI: 1.84–4.84), and a platelet count of <150,000 cells/mm3 (OR: 2.09; 95% CI: 1.47–2.98) were independent predictors of dengue fever.vii

In 2018, a hospital based open cohort study was conducted over a period of two months (September and October) in 2016. All the patients above the age of 18 yr admitted in medical wards and fulfilling the definition of AUF were included. The patients diagnosed with dual infections were the subjects of the study. Standard guidelines were used for case definitions of scrub typhus, dengue, chikungunya, malaria and leptospirosis. Dual infections were noted in 16 patients admitted with AUF. The most common coinfection was scrub typhus and dengue, reported in 10 patients. Scrub typhus and leptospirosis coinfection was observed in three patients. Dengue and chikungunya was observed in one patient. Scrub typhus, dengue and vivax malaria was detected in one patient. Scrub typhus and vivax malaria was detected in one patient. Out of the 10 cases positive for both scrub and dengue, four had no history of travel outside Himachal Pradesh. All three cases positive for both scrub and leptospirosis were indigenous without any history of travel outside Kangra, Himachal Pradesh. The outcome of all the patients was with full recovery. The study established the presence of coinfections (mainly dengue fever and leptospirosis) as a cause of AUF .viii

A better understanding of ‘AUF causes’ helps in better management of such cases with attendant reduction in morbidity and mortality. Differentiating bacterial from viral infections will help reduce inappropriate antibiotic use, which can contribute to the development of antibiotic-resistant bacteria. Biomarkers such as C-reactive protein (CRP) and procalcitonin have some utility in delineating between bacterial and viral infections and guiding healthcare workers on the appropriate use of antibiotics in patients with respiratory tract infections in high income settings.ix

Although acute febrile illnesses the leading causes of morbidity and death in India yet till date, only a few studies from India are available on the pattern and outcome of acute undifferentiated fevers. There have been increasing incidence of scrub typhus in our state for over last decade, though the entity initially remained undiagnosed , awareness of this treatable illnesses is increasing at the hospital level–as reflected by the high proportion of cases correctly managed by local physician but this is not the case at the community level where doxycycline is seldom used. It is notable the rarely mixed infection or co-infection can occur and must me managed accordingly.


A high overlap between case definitions probably reflects high prevalence of prior infections, cross reactivity and subclinical infections, rather than high prevalence of coinfections. Low accuracy of routine diagnostic tests should be taken into consideration when approaching the patient with acute undifferentiated fever in India.


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ii Chrispal A, Boorugu H, Gopinath KG, Chandy S, Prakash JA, Thomas EM, Abraham AM, Abraham OC, Thomas K. Acute undifferentiated febrile illness in adult hospitalized patients: the disease spectrum and diagnostic predictors - an experience from a tertiary care hospital in South India. Trop Doct. 2010 Oct;40(4):230-4.

iii Ray P, Ratagiri VH, Kabra SK, Lodha R, Sharma S, Sharma BS, Kalaivani M, Wig N. Chikungunya infection in India: results of a prospective hospital based multi-centric study. PloS one. 2012 Feb 17;7(2):e30025.

iv Phuong HL, de Vries PJ, Nga TT, Giao PT, Hung LQ, Binh TQ, Nam NV, Nagelkerke N, Kager PA. Dengue as a cause of acute undifferentiated fever in Vietnam. BMC infectious diseases. 2006 Dec;6(1):1-9.

v Laoprasopwattana K, Kaewjungwad L, Jarumanokul R, Geater A. Differential diagnosis of chikungunya, dengue viral infection and other acute febrile illnesses in children. The Pediatric infectious disease journal. 2012 May 1;31(5):459-63.

vi Reller ME, Bodinayake C, Nagahawatte A, Devasiri V, Kodikara-Arachichi W, Strouse JJ, Broadwater A, Østbye T, de Silva A, Woods CW. Unsuspected dengue and acute febrile illness in rural and semi-urban southern Sri Lanka. Emerging infectious diseases. 2012 Feb;18(2):256.

vii Abhilash KP, Jeevan JA, Mitra S, Paul N, Murugan TP, Rangaraj A, David S, Hansdak SG, Prakash JA, Abraham AM, Ramasami P. Acute undifferentiated febrile illness in patients presenting to a tertiary care hospital in South India: clinical spectrum and outcome. Journal of global infectious diseases. 2016 Oct;8(4):147.. doi:10.4103/0974-777X.192966

viii Raina S, Raina RK, Agarwala N, Raina SK, Sharma R. Coinfections as an aetiology of acute undifferentiated febrile illness among adult patients in the sub-Himalayan region of north India. J Vector Borne Dis. 2018 Apr-Jun;55(2):130-136.

ix Dhingra B, Mishra D. Early diagnosis of febrile illness: the need of the hour. Indian pediatrics. 2011 Nov 1;48(11):845-9.

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