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. [1] Acute 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.

EPIDEMIOLOGY

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 [1].

LITERATURE

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 [2].

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 observed [3].

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 [4].

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 [5].        

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 [6].

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 has been increasing incidence of scrub typhus in our state for over   last decade, though the entity initially remained undiagnosed, awareness of this treatable illness 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. [7]

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.

1. Chrispal, A. Forn et al. "Acute Undifferentiated Febrile Illness in Adult Hospitalized Patients: The Disease Spectrum and Diagnostic Predictors - An Experience from a Tertiary Care Hospital in South India." Tropical Doctor, vol. 40, no. 4, 2010, pp. 230–234.

2. Ray, P. Forn et al. "Chikungunya Infection in India: Results of a Prospective Hospital-Based Multi-Centric Study." PLoS One, vol. 7, no. 2, 2012, e30025.

3. Phuong, H.L. Forn et al. "Dengue as a Cause of Acute Undifferentiated Fever in Vietnam." BMC Infectious Diseases, vol. 6, 2006, p. 123.

4. Laoprasopwattana, K. Forn et al. "Differential Diagnosis of Chikungunya, Dengue Viral Infection and Other Acute Febrile Illnesses in Children." Pediatric Infectious Disease Journal, vol. 31, no. 5, 2012, pp. 459–463.

5. Reller, M.E. Forn et al. "Unsuspected Dengue and Acute Febrile Illness in Rural and Semi-Urban Southern Sri Lanka." Emerging Infectious Diseases, vol. 18, no. 2, 2012, pp. 256–263.

6. Abhilash, K.P. Forn et al. "Acute Undifferentiated Febrile Illness in Patients Presenting to a Tertiary Care Hospital in South India: Clinical Spectrum and Outcome." Journal of Global Infectious Diseases, vol. 8, no. 4, 2016, pp. 147–154. https://doi.org/10.4103/0974-777X.192966.

7. Raina, S. Forn et al. "Coinfections as an Aetiology of Acute Undifferentiated Febrile Illness among Adult Patients in the Sub-Himalayan Region of North India." Journal of Vector Borne Diseases, vol. 55, no. 2, 2018, pp. 130–136.

8. Dhingra, B., and D. Mishra. "Early Diagnosis of Febrile Illness: The Need of the Hour." Indian Pediatrics, vol. 48, no. 11, 2011, pp. 845–849.