Serological evidence of leptospirosis and dengue coinfection in an endemic region in South India

Abstract

Background: Concurrent epidemics of both dengue fever and leptospirosis are known to occur in the tropics; however, it is unclear whether coinfection is associated with different clinical manifestations and outcomes. Materials and Methods: Medical records for patients with serological evidence of leptospirosis, dengue, and coinfection from January 2007 to December 2008 were abstracted using a standardized abstraction form. The patients’ demographic data, underlying diseases, clinical manifestations, laboratory data, and disease outcomes were retrospectively analyzed. Results: The frequency of leptospirosis was 15.8% (287/1814), while that of dengue was 14.8% (239/1610) and coinfection was seen in 1.3% (17/1309). Highest mortality of 29.6% (5/17) was seen in coinfected cases, followed by leptospirosis (14.6%) and dengue (3.7%). Conclusion: In the tropics, leptospirosis and dengue can coexist and increased awareness of coinfection, and an enhanced ability to diagnose it early in illness, will help guide the appropriate use antibiotics and supportive measures to reduce mortality.

Keywords: Coinfection, dengue, leptospirosis

How to cite this article:
Kumar A, Balachandran V, Dominic A, Dinesh KR, Karim S, Rao G. Serological evidence of leptospirosis and dengue coinfection in an endemic region in South India. Ann Trop Med Public Health 2012;5:286-90
How to cite this URL:
Kumar A, Balachandran V, Dominic A, Dinesh KR, Karim S, Rao G. Serological evidence of leptospirosis and dengue coinfection in an endemic region in South India. Ann Trop Med Public Health [serial online] 2012 [cited 2020 Aug 11];5:286-90. Available from: https://www.atmph.org/text.asp?2012/5/4/286/102012
Introduction

Leptospirosis is an anthropozoonotic infection of worldwide distribution caused by pathogenic Leptospira spp., [1] while dengue fever (DF) is an arthropod born viral disease caused by any one of the four serotypes of dengue virus. [2] Both these infections have emerged as an important public health problem in Kerala, which remained virtually a terra incognito for dengue infection till mid-1990s. [3] Recently, Kerala has been experiencing a string of widespread dengue epidemics annually which has now attained hyperendemicity with frequent reports of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). [4],[5] The incidence of both these diseases peaks during the monsoon season. [6] Early clinical signs of both the diseases are nonspecific and similar. Both the diseases have well-recognized severe forms which can be fatal. [7],[8] It is important to distinguish leptospirosis from dengue as early antibiotic therapy in leptospirosis leads to favorable outcome, while dengue as such has no specific treatment and is treated symptomatically. [9] Due to high prevalence of both the diseases in our region, incidence of coinfection is increasing and needs to be recognized early to initiate appropriate treatment and reduce mortality.

Materials and Methods

We conducted a retrospective, hospital-based, study between January 2007 and December 2008 to look for serological evidence of coinfection among patients of all age group reporting with acute febrile illness (AFI) in a 1200 bed tertiary care super-specialty teaching hospital, Amrita Institute of Medical Sciences, in the Southern Indian state of Kerala. Medical records for enrolled case-patients with serological evidence of leptospirosis, DF, and coinfection were abstracted using a standardized abstraction form. Acute plasma samples collected from AFI subjects were screened for antileptospira immunoglobulin M (IgM) using the PanBio IgM enzyme-linked immunosorbent assay (ELISA) and for antidengue IgM by the PanBio IgM antibody-capture (MAC) ELISA (PanBio Inc., Brisbane, Australia). All tests were done at the time of admission in the Clinical Microbiology Laboratory, Department of Microbiology, Amrita Institute of Medical Sciences. The hospital protocol is to test for both leptospirosis and dengue in all cases of acute undifferentiated fever. Persons who tested negative by ELISA were defined as dengue/leptospirosis negative cases, while subjects with equivocal values were excluded. A coinfection was defined as a patient who was positive for both dengue and leptospirosis by ELISA. Severe infections were managed with IV benzyl penicillin 5 MU to 8 MU per day for 5 days. In patients with penicillin allergy, erythromycin was used at 250 mg QID for 5 days. Doxycycline 100 mg BID orally for 10 days was added along with benzyl penicillin in a few cases. Both fatal and nonfatal cases were eligible for enrollment. Random leptospira IgM positive samples were sent for confirmation by microscopic agglutination test (MAT) at National Leptospirosis Reference Centre, Regional Medical Research Centre (World Health Organization collaborating centre for diagnosis in leptospirosis, ICMR) in Port Blair, Andaman and Nicobar Islands (data not shown). Due to the retrospective nature of our study, sequential sera of cases with dual infection could not be sent to the reference lab to record four-fold changes in the MAT titres. Of the 16 serum sample that were MAT positive, half of them (8/16) were icterohemorrhagiae, four were Pyrogenes, and one each of Canicola, Grippotyphosa, Hebdomadis, and Patoc.

Rainfall data from the Indian Meteorological Department for January 2007 through December 2008 were reviewed to investigate an association between rainfall and number of leptospirosis and dengue cases over the study period. Mean monthly precipitation data were analyzed and compared with month of illness onset in case-patients with leptospirosis, dengue, and coinfection.

Results

During the study period, 1814 and 1610 serum samples from patients presenting with AFI were tested for IgM leptosipra and IgM dengue, respectively. The frequency of leptospirosis was 15.8% (287/1814), while that of dengue was 14.8% (239/1610). Coinfection due to both leptospirosis and dengue was seen in 1.3% (17) of the 1309 cases who were investigated for both dengue and leptospirosis. Highest mortality of 29.6% (5/17) was seen in coinfected cases followed by leptospirosis (14.6%) and dengue (3.7%).

Among the 17 coinfected cases, 70% were male and the median age of involvement was 38 years. A summary of the coinfection cases is presented in [Table 1]. The average IgM antibody titers by ELISA were 26.1 and 16.7 PanBio units for dengue and leptospirosis, respectively. The clinical features at admission of the 17 coinfection cases are given in [Figure 1]. Of the 17 coinfected cases, 5 (29%) died due to multiorgan system failure and disseminated intravascular coagulation. The laboratory parameters are given in [Table 2]. Most of the patients presented with hepatorenal dysfunction and thrombocytopenia. Also, of note, only 35% hospitalized patients with coinfection had leukocytosis. Among the five patients who died due to coinfection, IgM titers for 80% (4/5) were higher for leptospira when compared to dengue while among the 12 survivors IgM titers of dengue for all of them were higher when compared to leptospira. All the patients received intravenous crystalline penicillin, and no serious short-term sequelae of leptospiral/dengue infection were noted among the patients who survived. The average duration of hospitalization was 8.6 days. Highest incidence of leptospirosis and dengue infection was seen during the monsoon season (May to October). Compared to 2007, 2008 showed a higher incidence of leptospirosis during the postmonsoon season (October to January) also [Figure 2] and [Figure 3].

Figure 1: Clinical features on admission to the hospital for 17 leptospirosis, dengue fever, and coinfection case-patients

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Figure 2: Month-wise distribution of serologically positive cases of dengue, leptospirosis, coinfection, and rainfall in Ernakulam for the year 2007

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Figure 3: Month-wise distribution of serologically positive cases of dengue, leptospirosis, coinfection, and rainfall in Ernakulam for the year 2008

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Table 1: Summary of leptospirosis and dengue coinfections (n = 17)

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Table 2: Laboratory values at admission to the hospital for 17 leptospirosis dengue fever coinfection case-patients

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Of the 42 patients who died due to leptospirosis 70% were male with the median age of 54 years and had a mean IgM antibody titer of 19.96. Of the 9 patients who died due to dengue 67% were male with median age of 49 years and had a mean IgM antibody titer of 20.33. The mean IgM antibody titer of dengue in patients dying of leptospirosis was 2.1 PanBio units, while that of leptospirosis in patients dying of dengue was 3.4 PanBio units, suggesting no cross reactivity between these two infections.

Discussion

Leptospirosis and dengue are increasingly being recognized as a cause of AFI throughout the tropical and subtropical regions of the world. Leptospirosis is an emerging zoonosis and early in the illness is often confused with dengue, malaria, scrub typhus, and typhoid in tropical settings. [1],[8],[10] The clinical manifestations of leptospirosis and dengue range from mild self-limited febrile illness to a severe and potentially fatal illness characterized by jaundice, renal failure and thrombocytopenia, and hemorrhage. Leptospirosis with 37% and dengue with 10% prevalence rate are increasingly being recognized as predominant cause of AFI throughout the state of Kerala. [11],[12] The emergence of coinfection has further complicated the situation. [13],[14],[15] Both typically occur during the rainy season and rapid laboratory confirmation of the infecting pathogen is generally not available. [6],[16],[17] Several studies have shown that leptospirosis is often confused with dengue and remains underdiagnosed in endemic regions. [18],[19],[20] An enhanced ability to distinguish leptospirosis from dengue and the ability to pick up coinfection in endemic population would guide clinicians and public health personnel to initiate appropriate antimicrobial therapy and reduce mortality. [19] Only one previous study by Brown et al. has reported dengue and leptospirosis coinfection. They found that 2.5% of the 314 dengue IgM positive samples were also positive for leptospira IgM. [20]

Kerala is home for more than 40 million people with a population density of 819/km 2 which is three times the national average, predominantly settled along the coastal region. Kerala is a state with notable feature of backwater areas adjoining the sea line of about 500 km 2 which is a crucified ecosystem of high fertility. Dead leaf, woody debris, animal remains, sewage, etc., constitute the main sources of organic matter in backwater environment providing a fertile breeding ground for mosquitoes and rodents. Rapid urbanization coupled with population density as high as 1500/km 2 in some districts has lead to stretching of natural resources and also imposing anthropogenic stress which has forced sylvatic mosquito like Ades albopictus to seek its new breeding habitat near human habitation and facilitating transmission of dengue virus in a virtually nonimmune population!. [4],[12] This region is humid and warm throughout the year with the relative humidity and temperature varying between 70 and 90% and 22-34.5°C, respectively, with an annual precipitation reaching up to 3000 mm, with the maximum number of rainy days (18-21 rainy days/month) being in May to August. Flooding of rodent nests during the monsoon season leads to contamination of surface water and fields. Leptospirosis is transmitted by cutaneous exposure of the legs while walking in stagnant water where leptospires are known to multiply. Twenty four percent of healthy human populations in Kerala were seropositive for antileptospira antibodies, suggesting leptospirosis is predominantly an environmental disease with an added component in the form of occupational activity. [11]

Dengue infection is amongst the most important emerging viral disease transmitted by mosquitoes to humans, in terms of both illness and death. It is estimated that 52% of global population residing in South East Asian Region, of which India is part of, are at risk of contacting DF or DHF. [21] The clinical features of dengue virus infection range from nonapparent infection through DF and the more severe DHF and the DSS. [2] Dengue-related deaths were reported from Kerala for the first time in 1997 with detection of DEN-1, 2, and 4 virus in human sera. [6] Dengue antibodies in human sera have been detected in various districts of Kerala as early as 1979 with two of the well-known vector species Ae. ageypti and Ae. albopictus thriving in these districts. [4] Kerala has now become hyperendemic (i.e., multiple virus circulation in nature) for dengue. [5]

The polluted backwaters of Kerala remain a perennial breeding ground for mosquitoes and rodents. Cases of dengue and leptospirosis were seen throughout the year with incidence peaking during the monsoon, when we end up having concurrent epidemics of both the diseases which is in agreement with studies done in Mayanmar. [22] Therefore, it is not unusual to find cases of AFI that are serologically positive for both these diseases. Leptospirosis is often underdiagnosed, especially in areas also endemic for dengue in those who do not present with the severe icteric form of disease. In a semiurban region of central Kerala, we found that leptospirosis accounted for 16%, while dengue for 15% of all AFI, and coinfection due to both was seen in 17 cases (1.4%). We used the PanBio IgM ELISA to screen for leptospirosis and dengue and it is unlikely that a large number of cases were missed, since the sensitivity of the PanBio IgM ELISA as used in this study has been reported as high as 76-90%. [23],[24] Random leptospira IgM positive samples were confirmed by MAT to rule out false positivity. There was a male predominance, cases peaked during times of flooding (i.e., late rainy season), and mortality was highest in coinfection cases (30%) followed by leptospirosis (15%) and dengue (4%). Leucocytosis often reported in leptospirosis was seen only in 35% of the coinfection cases. We found that coinfection was not that uncommon and had a very high mortality rate if not diagnosed early. Deranged hepatorenal function is very common in both dengue and leptospirosis. Thrombocytopenia which is the hallmark of dengue infection has also been reported in 87% cases of leptospirosis. [25] Therefore, in case of coinfection the progression to hepatorenal failure and disseminated intravascular coagulation is very rapid due to the compounding effect of the pathogenesis of both these infections. Due to the retrospective nature of our study we could not document the history of exposure. Ernakulam district in Kerala is known for its backwaters which are most often polluted. The district also has a significant rodent population and high mosquito (Ae. albopictus) density around these backwaters. During the monsoon season the area is prone to flooding from the overflowing backwaters and the mosquito density also increases which expose the susceptible population to leptospirosis and dengue. Leptospirosis, being a condition having definitive antibiotic therapy, should always be ruled out even if the patient is positive for dengue serology in regions endemic to both these diseases as early initiation of antibiotic therapy can reduce mortality significantly.

Limitations

Our study included only symptomatic patients presenting to a hospital for evaluation. Its conclusions cannot be extrapolated to the spectrum of disease that does not present to the hospital and may have different clinical and laboratory manifestations. Some potentially useful clinical variables also may not have emerged in our analysis due to the retrospective nature of the study.

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Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/1755-6783.102012

Figures

[Figure 1], [Figure 2][Figure 3]

Tables

[Table 1], [Table 2]

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