|Year : 2018 | Volume
| Issue : 2 | Page : 130-136
Coinfections as an aetiology of acute undifferentiated febrile illness among adult patients in the sub-Himalayan region of north India
Sujeet Raina1, Rashmi Kaul Raina2, Niraj Agarwala1, Sunil Kumar Raina3, Rajesh Sharma1
1 Department of Medicine, Dr Rajendra Prasad Government Medical College, Kangra, Himachal Pradesh, India
2 Department of Pathology, Dr Rajendra Prasad Government Medical College, Kangra, Himachal Pradesh, India
3 Department of Community Medicine, Dr Rajendra Prasad Government Medical College, Kangra, Himachal Pradesh, India
|Date of Submission||05-Jan-2018|
|Date of Acceptance||03-Mar-2018|
|Date of Web Publication||1-Oct-2018|
Assistant Professor, C-15, Type-V Quarters, Dr Rajendra Prasad Government Medical College Campus, Tanda, Kangra-176 001, Himachal Pradesh
Source of Support: None, Conflict of Interest: None
Background & objectives: In India, certain geographic regions witness simultaneous outbreaks of two or more diseases like scrub typhus, dengue fever, malaria, leptospirosis and chikungunya during monsoon and post-monsoon period, sharing common indication of acute febrile illness. The objective of the present study was to assess the prevalence of coinfections among patients with acute undifferentiated fevers (AUF) admitted in a tertiary care hospital in the northern hilly state of Himachal Pradesh, India.
Methods: This was a hospital based open cohort study 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.
Results: 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.
Interpretation & conclusion: The study established the presence of coinfections (mainly dengue fever and leptospirosis) as a cause of AUF in the study area, which is a nonendemic region. The role of easily available and widely performed serological tests in the aetiological diagnosis of AUF is significant. Studies are required to determine the normal titres in the local population before using the imported commercially available serological tests in the diagnosis of AUF.
Keywords: Coinfections; cross reactivity; Himachal Pradesh; seasonal fever; tropical fever
|How to cite this article:|
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;55:130-6
|How to cite this URL:|
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 [serial online] 2018 [cited 2020 Jan 27];55:130-6. Available from: http://www.jvbd.org/text.asp?2018/55/2/130/242560
| Introduction|| |
The people residing in tropical countries like India, frequently suffer from acute undifferentiated fevers (AUF) during monsoons and in post-monsoon period. The causes include dengue fever, chikungunya, rickettsial infections/scrub typhus, malaria, enteric fever, leptospirosis and seasonal influenza. Most of these febrile illnesses are arthropod vector borne. The dynamics which govern transmission of these predominant vector borne disease during monsoon and post-monsoon period are changing and becoming more conducive. The factors like high prevalence of infective vectors, increased human vector contact, temperature, humidity, prolonged rains, stagnant water, floods, abundant growth of vegetation, sleeping habits of human, density and biting patterns of vectors turn the milieu favourable for disease transmission. Acute undifferentiated fevers are defined as fever of two weeks or shorter in duration with lack of localizable or organ-specific clinical features in patients.
The clinical features of these diseases are non-specific and so overlapping that it is almost impossible to achieve differential diagnosis. Knowledge of local prevalence of infections is critical in target-oriented investigations and treatment protocols. In resource limited settings, serology-based investigations play a vital role in establishing diagnosis. Seasonal trend analysis of fever cases seeking health care services have revealed increasing trend of AUF illness during and after monsoon period in the sub-Himalayan state of Himachal Pradesh. Scrub typhus is the leading cause of AUF in this region. Dengue fever remains unsuspected in febrile cases among indigenous population in this nonendemic region. A rising trend has been observed in the imported dengue fever cases from the state in the last few years and the trend runs parallel to the prevalence of cases from endemic areas,. Indigenous cases of dengue without history of travel to an endemic area have not been reported from the region so far. Leptospirosis also seems to be an important cause of AUF in this state,. Prevalence of malaria is very low and only sporadic cases in a decreasing trend have been reported from this sub-Himalayan state. The presence of monoinfections has been frequently reported from the state. In endemic regions, occurrence of dual infections among AUF patients should be common in view of the dynamics of infectious diseases transmission existing during monsoon and post-monsoon time. However, a single case report of a coinfection has been published from the state. Dual infections have been reported from the neighbouring northern state of Uttarakhand, India during epidemics of acute febrile illnesses.
The aim of the present study was to assess the prevalence of coinfections among patients diagnosed with acute undifferentiated fevers admitted in a tertiary care centre in the sub-Himalayan state of Himachal Pradesh.
| Material & Methods|| |
The study was conducted in a tertiary care referral hospital of Kangra district in Himachal Pradesh, India. The hospital caters to the medical needs of the population residing in the physiogeographic region of Shivalik and lesser Himalayas and includes lower hills of Kangra, Hamirpur, Una, Bilaspur, lower parts of Mandi and Chamba districts. The region experiences sub-tropical monsoon, mild and dry winter and hot summer. Within this zone, altitude varies from 350 to 1500 m. Besides the seasonal variations, the climate of Himachal Pradesh varies across the state with the altitude. The average rainfall is 152 cm (60 inches). The highest rainfall occurs in Kangra district followed by Shimla district. During the rainy season, areas at lower altitudes have an average temperature of 20–35°C, which is conducive to the spread of arthropod vectors.
All the patients above the age of 18 yr fulfilling the definition of AUF, and positive for coinfections were included in the study. The study was conducted in two phases. In phase 1, all patients fulfilling the inclusion criteria (patients of AUF) were recruited. This formed the sampling frame for identifying study participants for this study. Recruitment of cases was done using an open cohort design conducted from September through October 2016 for a period of two months when the patients presented to Department of Medicine. Throughout the recruitment period, regular note reviews were undertaken in an attempt to ensure complete ascertainment of presenting cases.
This was followed by phase 2 of the study, where in all patients of AUF found positive for coinfections on follow up were included for further evaluation. Those without a clinical and microbiological diagnosis were categorised as unknown infections and excluded. Flow chart showing methodology adopted is shown in [Figure 1]. Individual written consent was sought from all living cohort members contacted for follow up for linkage to the clinical, laboratory and sociodemographic data described below at the time of interview.
Patients data namely, demographic, clinical, biochemical, microbiological and radiology were entered as per the structured proforma. As per the guidelines of the Government of Himachal Pradesh, the investigations for scrub typhus, dengue, chikungunya and malaria were performed free of cost in Department of Microbiology, Dr. Rajendra Prasad Government Medical College Kangra. Serology for leptospirosis was done from SRL diagnostics laboratory attached to the medical college. All the serological tests were performed as per the manufacturer’s guidelines. ELISA assay was used to measure scrub typhus and chikungunya specific IgM levels (InBios International Inc, USA). Dengue fever was diagnosed by ELISA based NS1 detection and IgM Capture (RecombiLISA, USA). IgM based immunoassay was used for the diagnosis of leptospirosis (SD Bioline, Republic of Korea). Microscopic examination of both thick and thin smear was done in Department of Pathology for confirmation of malaria. Blood culture for bacterial growth by BACTEC (BD, Ireland) was performed in the microbiology department.
Acute undifferentiated fever: It was defined as fever of two weeks or shorter in duration, with lack of localizable or organ-specific clinical features in the patients.
Scrub typhus: A probable case is with consistent clinical features as defined in the Department of Health Research-Indian Council of Medical Research, India guidelines for diagnosis and management of rickettsial diseases, along with a positive IgM ELISA for scrub typhus.
Dengue: Clinical description compatible with dengue fever as defined by the National Vector Borne Disease Control Programme, India with positive demonstration of NS1 antigen and IgM antibody in serum by ELISA.
Leptospirosis: A probable case is with clinical features as defined in national guidelines of programme for prevention and control of leptospirosis along with positive result in IgM based immunoassay.
Chikungunya: Clinical criteria as defined by the national guidelines for clinical management of chikungunya along with presence of virus specific IgM antibodies in single serum sample during fever.
Malaria: History of fever with parasitological diagnosis on light microscopy or rapid diagnostic tests (RDT).
Coinfection: Observation of more than one infective aetiology among outlined infections.
Data were analysed in Microsoft excel 2010. Qualitative data was calculated in the form of frequency and percentage. Quantitative data was presented as mean ± standard deviation (SD).
The study was approved by institutional ethics committee (Approval number: HFW-H-DRPGMC/ETH-ICS/115/2016, dated December 29, 2016).
| Results|| |
As per the records obtained from the medical records section and integrated disease surveillance programme (IDSP) of the hospital, a total of 1164 patients attended hospital with AUF during the study period and were investigated for various aetiologies. Scrub typhus was diagnosed in 262 (22.5%) patients, dengue fever in 91(7.8%) patients, leptospirosis in 8(0.6%) patients, chikungunya was diagnosed in 7(0.6%) and vivax malaria in 2 (0.1%) patients. In the rest of 778 (66.8%) patient’s no infection was diagnosed. Mixed infections were noted in 16 (1.3%) patients. The sex distribution was 15 males and one female. The distribution of different coinfections is shown in [Figure 2]. The results of clinical features are shown in [Figure 3] and [Figure 4]. The laboratory details are shown in [Table 1]. Out of 10 patients with a coinfection of scrub typhus and dengue fever, eight had thrombocytopenia; and one patient with dengue and chikungunya also had thrombocytopenia. Seven patients were natives of Himachal without any history of travel out of the state. Nine patients had visited other parts of the country outside Himachal Pradesh. All the three cases positive for both scrub and leptospirosis were indigenous without any history of travel outside Kangra, Himachal Pradesh. Of the 10 cases positive for both scrub typhus and dengue, four had no travel history outside Himachal Pradesh. Both the patients with malaria coinfections had a history of recent visit to malaria endemic regions of the country. All the patients improved clinically at the time of discharge.
|Figure 2: Distribution of different coinfections among the patients; S— Scrub typhus; D—Dengue; L—Leptospirosis; C—Chikunguny; M—Malaria.|
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|Figure 3: Frequency of different symptoms among the patients in the study area; S—Scrub typhus; D—Dengue; L—Leptospirosis; C—Chikungunya; M—Malaria.|
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|Figure 4: Frequency of different signs among the patients in the study area; S—Scrub typhus; D—Dengue; L—Leptospirosis; C— Chikungunya; M—Malaria.|
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|Table 1: Demographic, haematological and biochemical parameters of coinfections groups|
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| Discussion|| |
In India, different regions are hit by various tropical fevers depending on the geography, climate, season and distribution of vectors. The infectious diseases like pneumonia, diarrhoea, HIV/AIDS, malaria, tuberculosis (TB) and neonatal infections occur throughout the year. But diseases like dengue fever, rickettsial infections/scrub typhus, malaria, enteric fever, leptospirosis and common viral infections like influenza occur mostly during the season of monsoon and post-monsoon periods. Dengue outbreaks coincide with outbreaks of chikungunya fever, malaria, scrub typhus and leptospirosis. Himachal Pradesh is well known for the endemicity of scrub typhus and its life threatening complications,,,,. Vector species Leptotrombidium deliense and Gahrliepia (Schoengastilla) spp have been recorded in an entomologic study in Himachal Pradesh· In patients without eschar, it is almost impossible for clinicians to differentiate scrub typhus from other aetiologies of AUF.
Dual infection with more than one aetiological agent concurrently results in illness with overlapping symptoms. It further makes the diagnosis and management of such patients challenging. Due to growing population, frequent travels, better laboratory services and more awareness, coinfections are emerging as a major concern in tropical countries.
The prevalence of dual infections observed in this study was 1.3%. Scrub typhus and dengue coinfection was the commonest and was found in 10 patients. Coinfection of scrub typhus and leptospirosis was observed in three patients; dengue fever and chikungunya were observed in one patient. One patient had a triple infection with scrub typhus, dengue fever and vivax malaria. Coinfection of scrub typhus and vivax malaria was detected in one patient. Coinfection has been reported in 1.88% patients of AUF illness, in a study conducted in a tertiary care hospital of Uttarakhand. Most common mixed infections were dengue with scrub typhus (15 cases), malaria with scrub typhus (11 cases) and malaria with dengue (8 cases). Scrub typhus and dengue fever coinfection has also been reported from a tertiary care hospital in southern coast of India. Malaria is a common coinfection in dengue and is an emerging problem across Asian countries. However, in the current study P. vivax malaria coinfection was diagnosed in patients with scrub typhus. In addition, in one of the patients with dual infection of scrub typhus plus malaria, dengue serology was also positive. Very few reports are available in literature on the scrub typhus and malaria coinfections from the study region,. A case of triple infection with scrub typhus, malaria and dengue has been reported from Uttarkhand. There are reports of coinfection of dengue and chikungunya from different states of India,. This is not very unusual as both dengue and chikungunya are arboviral diseases, transmitted by the same Aedes mosquitoes.
The clinical features across the spectrum of different coinfection categories were nonspecific. Fever with chills and myalgia were common symptoms. Jaundice and hepatomegaly was present in all the patients of scrub typhus with leptospirosis group. Transaminasemia was observed across all the categories. SGOT levels were higher than SGPT in patients with coinfections of scrub typhus with dengue; with leptospirosis; and dengue with chikungunya. Bilirubin levels were prominently raised in scrub typhus with leptospirosis group. Recent observational studies have presented the clinical significance of dual infections in the literature. In a study from Uttarakhand, India the coinfection group was found to be associated with milder clinical manifestations, non-progressive organ dysfunction, and lesser need for intensive care, mechanical ventilation and dialysis as compared to monoinfections.
In another study from Mumbai City, India while studying concurrent dengue and malaria with their monoinfections, it was observed that epigastric pain, transaminitis, bleeding manifestations and renal dysfunction were more common in patients with coinfection as compared to monoinfections. Similarly, in a study on dengue and chikungunya coinfections, it was observed that bone pain, myalgia and thrombocytopenia were frequent in patients with dengue monoinfection than dengue and chikungunya coinfections. These might be true mixed infections and not due to serological cross reactivity. The aetiologic agents responsible for these infectious diseases are members of different families. Scrub typhus is caused by Orientia tsutsugamushi, a gram-negative bacillus. Leptospirosis is caused by Leptospira species, a spirochete and dengue fever is due to single stranded RNA virus belonging to Flavivirus group. Thus, the antigens are not common and are highly diverse. Data on cross reactivity of various serological tests among these infections are not available in literature. Non-structural protein (NS1) antigen ELISA is a good investigative/diagnostic test for early detection of dengue infection. It is also specific for dengue virus and hence, overcomes the disadvantage offered by cross reactivity among various Flaviviruses. IgM capture ELISA test further enhances the case detection rate of current dengue infection. All the eleven patients diagnosed as dengue fever were NS1 antigen positive.
Himachal Pradesh is a nonendemic region for dengue fever. Increased number of imported cases have been reported from the state in past. All the patients reported had acquired infection outside the state. Travel of the population from the state into the dengue-endemic neighbouring states is responsible for these imported cases,. In the present study, natives had contracted the disease indigenously as there was no history of travel in these cases. There is an indication of autochthonous transmission as no record of travel history was observed in the patients. Himalayan region above the height of 500 m has been found completely free, of the main dengue vector, Aedes aegypti. However, presence of Aedes albopictus has been reported in other Himalayan areas. Expansion of dengue cases to a new geographic area is a challenge in eradication of disease from the region. The possible reasons for this geographical shift are the modifying effects to the ecosystem associated with change in temperature (particularly night time minimum temperature), precipitation and peak relative humidity.
The prevalence of leptospirosis and scrub typhus is not known in the state of Himachal Pradesh. Extensive PubMed search using keywords and mesh words “Prevalence”, “Leptospirosis”, “scrub typhus”, “Himachal Pradesh” did not reveal any results. Though, sporadic cases of leptospirosis have been reported from the state,. The rural population in this physiographic zone of Shivalik and lesser Himalayas is predominantly agrarian society involved in rice cultivation and linked with animal husbandry. The area also witnesses heavy rainfall. These conditions are favourable for maintenance and transmission of leptospirosis.
The result of this study arises some questions. What do mixed infections, diagnosed on the basis of widely available serology-based tests, mean to a treating clinician? They over rely for diagnosis on imported commercially available serological tests, which use cutoffs derived from low endemicity areas. What is the local seroprevalence data on the cutoffs based on these single-time point tests? Does simultaneous coinfection constitute a definite separate identity among various aetiologies for AUF, which requires separate relevant action plans? There is a need to report more often on the prevalence of concurrent infections for future research. It is also necessary to develop a robust local population based seroprevalence data based on the serological tests.
The observations from this study would be helpful in alerting the treating physicians of this region to consider dengue fever, leptospirosis and chikungunya fever in addition to scrub typhus in the list of differentials of AUF during monsoon and post-monsoon period. Further, studies are required for better analyses and differentiation of the signs and symptoms between patients with coinfections and patients having individual infections. The study design should include molecular studies to rule out serological cross reactivity.
Duration of study was short. Scrub typhus diagnosis was IgM ELISA based.
| Conclusion|| |
This study established the presence of coinfections as a cause of AUF in the state of Himachal Pradesh, India. The role of easily available and widely performed serological tests in the aetiological diagnosis of AUF is significant. It is necessary to establish normal titres of the frequently prescribed serological tests in the local population. The impact of coinfections on the natural history of individual disease requires further studies.
Conflict of interest: None.
| Acknowledgements|| |
The technical assistance of Mr. Sushant Sharma, Lecturer Statistics, Department of Community Medicine, Dr Rajendra Prasad Government Medical College, Kangra (Tanda), HP, India, is gratefully acknowledged.
| References|| |
Susilawati TN, McBride WJ. Acute undifferentiated fever in Asia: A review of the literature. Southeast Asian J Trop Med Public Health
Joshi R, Colford JM Jr, Reingold AL, Kalantri S. Nonmalarial acute undifferentiated fever in a rural hospital in central India: Diagnostic uncertainty and overtreatment with antimalarial agents. Am J Trop Med Hyg
Varghese GM, Janardhan J, Mahajan SK, Tariang D, Trowbridge P, Prakash JAJ, et al
. Molecular epidemiology and genetic diversity of Orientia tsutsugamushi
from patients with scrub typhus in three regions of India. Emerg Infect Dis
Verma S, Kanga A, Singh D, Verma GK, Mokta K, Ganju SA, et al
. Emergence of travel: Associated dengue fever in a nonendemic, hilly state. Adv Biomed Res
Jaryal SC, Chauhan S, Thakur K, Sood A, Kashyap N. Never ending challenge of dengue Current scenario in the hilly state of north India. National J Lab Med
2016; 5(3): MO11–4.
Chauhan V, Mahesh DM, Panda P, Mokta J, Thakur S. Profile of patients of leptospirosis in sub-Himalayan region of North India. J Assoc Physicians India
Chauhan V, Thakur S. Leptospirosis in sub-Himalayan region: A neglected entity. Indian J Med Microbiol
2016; 34(3): 390–409.
|8.|Annual Report 2014–15
. Delhi: National Vector Borne Disease Control Programme, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. Available from: http://nvbdcp.gov.in/Doc/Annual-report-NVBDCP-2014-15.pdf]
(Accessed on January 31, 2017).
Ahmed S, Dhar M, Mittal G, Bhat NK, Shirazi N, Kalra V, et al
. A comparative hospital based observational study of mono and coinfections of malaria, dengue virus and scrub typhus causing acute undifferentiated fever. Eur J Clin Microbiol Infect Dis
2016; 35(4): 705–11.
Rahi M, Gupte MD, Bhargava A, Varghese GM, Arora R. DHR-ICMR guidelines for diagnosis and management of rickettsial diseases in India. Indian J Med Res
|12.|National treatment guidelines for antimicrobial use in infectious diseases
. Delhi: National Centre for Disease Control. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. Available from: http://www. ncdc.gov.in/writereaddata/mainlinkfile/File558.pdf
(Accessed on January 31, 2017).
Sharma A, Mahajan S, Gupta ML, Kanga A, Sharma V. Investigation of an outbreak of scrub typhus in the Himalayan region of India. Jpn J Infect Dis
2005; 58(4): 208–10.
Mahajan SK, Rolain JM, Kashyap R, Bakshi D, Sharma V, Prashar BS, et al
. Scrub typhus in Himalayas. Emerg Infect Dis
2006; 12(10): 1590–2.
Mahajan SK, Raina R, Singh B, Singh D, Kanga A, Sharma A, et al
. Pattern of clinical presentation, laboratory findings and mortality risk among patients of scrub typhus in western Himalayas. J Assoc Physicians India
2016; 64(3): 26–30.
Kumar R, Thakur S, Bhawani R, Kanga A, Ranjan A. Clinical profile and complications of scrub typhus: Hospital based study in sub-Himalayan region. J Assoc Physicians India
2016; 64(12): 30–4.
Kumar K, Saxena VK, Thomas TG, Lal S. Outbreak investigation of scrub typhus in Himachal Pradesh (India). J Commun Dis
Mittal G, Ahmad S, Agarwal RK, Dhar M, Mittal M, Sharma S. Aetiologies of acute undifferentiated febrile illness in adult patients an experience from a tertiary care hospital Northern India. J Clin Diagn Res
2015; 9(12): DC22–4.
Basheer A, Iqbal N, Mookkappan S, Anitha P, Nair S, Kanungo R, et al
. Clinical and laboratory characteristics of dengue- Orientia tsutsugamushi
coinfection from a tertiary care center in South India. Mediterr J Hematol Infect Dis
2016; 8(1): e2016028.
Selvaretnam A, Sahu PS, Sahu M, Ambu S. A review of concurrent infections of malaria and dengue in Asia. Asian Pac J Trop Biomed
2016; 6(7): 633–8.
Sharma A, Raina R, Dhiman P, Bellad A, Madhabhavi I, Panda P. Rare coinfection of scrub typhus and malaria in immunocompetent person. Online J Health Allied Sci
Mahajan SK, Kaushik M, Raina R, Thakur P. Scrub typhus and malaria coinfection causing severe sepsis. Tropical doctor
2014; 44(1): 43–5.
Ahmed S, Dhar M, Bhat NK, Shirazi N, Mittal G. Rare coinfection of malaria, scrub typhus and dengue virus in an immunocompetent patient. Int J Curr Microbiol App Sci
2015; 4(5): 295–7.
Chahar HS, Bharaj P, Dar L, Guleria R, Kabra SK, Broorl S. Coinfections with chikungunya virus and dengue virus in Delhi, India. Emerg Infect Dis
2009; 15(7): 1077–9.
Londhey V, Agrawal S, Vaidya N, Kini S, Shastri JS, Sunil S. Dengue and chikungunya coinfections: The inside story. J Assoc Physicians India
Barua A, Gill N. A comparative study of concurrent dengue and malaria infection with their monoinfection in a teaching hospital in Mumbai. J Assoc Physicians India
2016; 64(8): 49–52.
Kalra NL, Kaul SM, Rastogi RM. Prevalence of Aedes aegypti
and Aedes albopictus
—Vectors of dengue and dengue haemorrhaghic fever in north, northeast and central India. Dengue Bull
[Figure 1], [Figure 2], [Figure 3], [Figure 4]