Coinfections are commonly seen in subtropical and tropical areas of the world with higher incidence in the developing nations as India. Tropical coinfections represent the condition with the simultaneous occurrence of two or more diseases that are vector borne and seen in a single host. Coinfections have a synonym to poly infections, concurrent infections, and mixed infections. Coinfections have more harmful effects on the health of the hist compared to the single infection. Coinfections are rising as a major phenomenon seen in subjects with AUFI (acute undifferentiated febrile illness). Various studies have depicted that a widespread geographical distribution in India is mainly seen for four coinfections as leptospirosis, dengue fever, malaria, and scrub typhus. Coinfections widely affect Indian subjects.1

Coinfections that occur in Indian subjects can be explained by two different mechanisms. It can either be seen from contracting various infections concurrently within a particular time of resulting from increased coincident pathogenicity and subclinical infection from altered immune response. Coinfections are usually seen while two organisms coexist and increase penetration of virulence for each other leading to mortality and more severe outcomes as mortality. These diseases usually show non-specific and overlapping symptoms as gastrointestinal issues, body aches, headache, and fever. These overlapping symptoms makes it challenging and difficult to accurately diagnose these conditions making confusion in diagnosis and delay adequate management. Lack in distinct features in early coinfections/ AUFI usually result in therapeutic and clinical dilemmas for clinicians, particularly in atypical presentation. Serological cross-reactivity in various pathogens can further complicate the diagnosis and delayed management.2

Coinfections need strong suspicion and substantial data as mistreatment and underdiagnosis can have various adverse events. As various clinical features of AUFI have overlapping, Indian Society of Critical Care Medicine group reported a syndromic approach for diagnosis and treatment which can be helpful in simplification of treatment and narrowing the possibilities. However, coinfection might not always have the syndromic approach as clinical presentation might blur. Considering the treatment, coinfections can warrant integrated management approach, decreased efficacy, risk infection, and complicate the drug regimens.3

It is vital to have a better understanding for coinfections and its etiology which can help in assessment of true disease burden and in developing the preventive strategies, development of integrated surveillance systems, resource allocation, and guiding public health interventions. It helps in shift from disease-specific vertical programs to integrated and horizontal healthcare system to allow better treatment for complex health conditions. The present study was aimed to comparatively assess the prevalence, clinical profile, outcomes, and laboratory data in subjects with coinfection that presented with AUFI (acute undifferentiated febrile illness) at an Indian healthcare centre.

The present prospective observational study was aimed to comparatively assess the prevalence, clinical profile, outcomes, and laboratory data in subjects with coinfection that presented with AUFI (acute undifferentiated febrile illness) at an Indian healthcare centre. Verbal and written informed consent were taken from all the subjects before study participation.

The present study assessed 158 subjects that were confirmed for coinfection from all the subjects that presented with AUFI at the Institute within the defined study period. The inclusion criteria for the study were subjects aged >18 years and hospitalized with AUFI as fever of ≤14 days, no evidence of localized infection, and had the diagnosis of tropical coinfections. AUFI was considered as fever of <2weeks with no organ specific symptoms at onset. Coinfection was considered as infection in a host by two or more pathogens. The exclusion criteria for the study were subjects that had fever with localized infection evidence, prior hospitalization, prior use of antibiotics, fever of >14 days’ duration, malignancy, and autoimmune diseases.

After final inclusion, all the subjects were assessed comprehensively and assessed with complete hemogram, renal function test, liver function test, urine examination, C-reactive protein, erythrocyte sedimentation rates, and complete hemogram. This was done along with various tests as brucella serology, CHIK, leptospirosis, scrub typhus, malaria, and dengue fever. Other viral serology was also done as hepatitis E and A following clinical suspicion and considering possibility of diagnosis.

Diagnosis of malaria was made following raid diagnostic tests for detection of antigen and for malaria parasite including mixed, plasmodium vivax, and plasmodium falciparum trophozoites. Detection of dengue NS1 antigen test or IgM antibody confirmed the dengue diagnosis. IgM ELISA for Leptospira organisms was considered to diagnose chikungunya, brucellosis, scrub typhus, and leptospirosis. Salmonella typhi was diagnosed with Widal test/typhi dot IgM/blood cultures.

Specific imaging tests were done as and when needed. Subjects that had more than one infection in them simultaneously were taken as coinfection cases. To assess and document the complications, the definitions used in the study included acute respiratory distress syndrome (ARDS) that followed the Berlin’s criteria.5 Acute kidney injury (AKI) was taken into consideration depending upon KDIGO AKI staging6 and Acute liver injury (ALI) was defined according to EASL guidelines as an elevation of liver enzymes 2–3 times the upper normal limit.7

The data gathered were analyzed statistically with chi-square test, Fisher’s exact test, Mann Whitney U test, and SPSS (Statistical Package for the Social Sciences) software version 24.0 (IBM Corp., Armonk. NY, USA) using ANOVA, chi-square test, and student's t-test. The significance level was considered at a p-value of <0.05.

The present prospective observational study was aimed to comparatively assess the prevalence, clinical profile, outcomes, and laboratory data in subjects with coinfection that presented with AUFI (acute undifferentiated febrile illness) at an Indian healthcare centre. The present study assessed 158 subjects that were confirmed for coinfection from all the subjects that presented with AUFI at the Institute within the defined study period. The mean age of the study subjects was 39.2±17.1 years. Investigations were done to assess diagnosis for AUFI. In subjects with dengue+ leptospirosis, AST/ALT (aminotransferase/alanine transaminase) was minimally increased. In tropical fever cases, mild to moderate anemia was seen. In subjects with scrub typhus and leptospirosis, leukocytosis was seen. Mild to moderate thrombocytopenia was seen in all the subjects. Significant results were not seen in any other parameter in any group (Table 1).

It was seen that for complications and organ involvement, 86% subjects had minimum one complication among encephalopathy, myocarditis, pneumonia, ARDS, acute kidney injury, and acute liver injury. Acute liver injury was mainly seen in dengue and scrub typhus group. Multiorgan dysfunction was significantly higher in subjects from scrub typhus group. On the contrary, polyserositis was seen in majority of the subjects that had dengue fever as coinfection. Other complications including mucosal bleed, encephalopathy, hemodynamic shock, and myocarditis were seen in only few subjects. However, pneumonia was seen in 86% subjects that had dengue fever (Table 2).

The study results showed that for various syndromic distribution in four types of coinfections, fever with encephalopathy was seen in 28 subjects with 9% (n=2), 25% (n=6), 30% (n=12), and 19% (n=8) subjects from Scrub typhus with leptospirosis, Dengue with chikungunya, Dengue with scrub typhus, and Dengue with leptospirosis group respectively depicting a non-significant difference with p=0.184. Similar non-significant difference was seen for fever with respiratory disease, fever with renal failure, fever with hepatitis, and fever with thrombocytopenia in four groups with p-value of 0.583, 0.619, 0.325, and 0.737 respectively (Table 3).

On assessing the various predictors of mortality in study subjects with coinfection, reported deaths in study subjects were 16.25% (n=26) cases which was highest in subjects with dengue fever and leptospirosis and dengue fever with scrub typhus leading to a total of 77% deaths. On distributing the mortality in different groups, it was seen that myocarditis, GI bleed, polyserositis, shock, ARDS, hepatitis, and AKI were found to be independent predictors of the mortality (Table 4).

Table 1: Laboratory parameters in 4 coinfection study groups

Table 2: Comparison for multiorgan dysfunction in major coinfection groups

Table 3: Distribution of symptoms in study subjects with coinfection

Table 4: Assessment of various predictors of mortality in study subjects with coinfection

The present study assessed 158 subjects that were confirmed for coinfection from all the subjects that presented with AUFI at the Institute within the defined study period. The mean age of the study subjects was 39.2±17.1 years. Investigations were done to assess diagnosis for AUFI. In subjects with dengue+ leptospirosis, AST/ALT (aminotransferase/alanine transaminase) was minimally increased. In tropical fever cases, mild to moderate anemia was seen. In subjects with scrub typhus and leptospirosis, leukocytosis was seen. Mild to moderate thrombocytopenia was seen in all the subjects. Significant results were not seen in any other parameter in any group. These data were comparable to the previous studies of Chan KR et al8 in 2022 and Raina S et al9 in 2019 where authors assessed subjects with data comparable to the present study in their studies.

The study results showed that for complications and organ involvement, 86% subjects had minimum one complication among encephalopathy, myocarditis, pneumonia, ARDS, acute kidney injury, and acute liver injury. Acute liver injury was mainly seen in dengue and scrub typhus group. Multiorgan dysfunction was significantly higher in subjects from scrub typhus group. On the contrary, polyserositis was seen in majority of the subjects that had dengue fever as coinfection. Other complications including mucosal bleed, encephalopathy, hemodynamic shock, and myocarditis were seen in only few subjects. However, pneumonia was seen in 86% subjects that had dengue fever. These findings correlated with the results of Karnad DR et al10 in 2021 an Subramanyam VN et al11 in 2020 where complications and organ involvement data reported by the authors in their subjects with coinfections were comparable to the present study results.

It was seen that for various syndromic distribution in four types of coinfections, fever with encephalopathy was seen in 28 subjects with 9% (n=2), 25% (n=6), 30% (n=12), and 19% (n=8) subjects from Scrub typhus with leptospirosis, Dengue with chikungunya, Dengue with scrub typhus, and Dengue with leptospirosis group respectively depicting a non-significant difference with p=0.184. Similar non-significant difference was seen for fever with respiratory disease, fever with renal failure, fever with hepatitis, and fever with thrombocytopenia in four groups with p-value of 0.583, 0.619, 0.325, and 0.737 respectively. These results were consistent with the findings of Kulshrestha M et al12 in 2024 and Mewada et al13 in 2020 where results similar to the present study for various syndromic distribution in coinfections were comparable to the results of the present study.

Concerning the various predictors of mortality in study subjects with coinfection, reported deaths in study subjects were 16.25% (n=26) cases which was highest in subjects with dengue fever and leptospirosis and dengue fever with scrub typhus leading to a total of 77% deaths. On distributing the mortality in different groups, it was seen that myocarditis, GI bleed, polyserositis, shock, ARDS, hepatitis, and AKI were found to be independent predictors of the mortality These findings were in line with the results of Md-Lasim A et al14 in 2021 and Thein TL et al15 in 2017 where results comparable to the present study for various predictors of mortality were also reported by the authors.,

Considering its limitations, the present study concludes that most commonly seen coinfections in Indian subjects being scrub typhus with leptospirosis, dengue with chikungunya, dengue with scrub typhus, and dengue with leptospirosis. Despite significant involvement of organs in these combinations, clinical differentiation from monomicrobial infections is difficult and accurate management for possible coinfection can be started early and empirically.

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