Prevalence, Clinical, and Demographic Characteristics of Concomitant Dengue Fever and Leptospirosis among Acute Dengue Fever Patients in The Western Province of Sri Lanka

Abstract

Dengue and leptospirosis are hyperendemic diseases in Sri Lanka. We aimed to determine the prevalence and clinical manifestations of concomitant infections of leptospirosis and acute dengue infection (ADI) in clinically suspected dengue patients. A descriptive cross-sectional study was carried out in five hospitals in the Western Province, from December 2018 to April 2019. Venous blood and sociodemographic and clinical details were collected from clinically suspected adult dengue patients. Acute dengue was confirmed by DENV NS1 antigen ELISA, IgM ELISA, IgG ELISA, and IgG quantification assay. Leptospirosis was confirmed by the microscopic agglutination test and real-time polymerase chain reaction. There were 386 adult patients. The median age was 29 years, with male predominance. Among them, 297 (76.9%) were laboratory confirmed as ADI. Concomitant leptospirosis was present in 23 (7.74%) patients. In the concomitant group, the majority (65.2%) were female, in contrast to ADI (46.7%). Myalgia was significantly more common in patients with acute dengue fever. All other symptoms were similar in both groups. In conclusion, the 7.74% of patients of ADI had concomitant leptospirosis, and it was more common in females.

Introduction

Dengue fever and leptospirosis are endemic diseases in Sri Lanka. In 2019, 104,660 dengue fever cases with 150 deaths and 5966 leptospirosis cases were notified.[¹]

The diagnosis of these diseases is challenging to clinicians in the tropics due to the similarity of clinical manifestations; thus, co-infections may remain undetected. Our aim was to determine the prevalence and clinical manifestations of concomitant infections of leptospirosis among patients with acute dengue infection (ADI).

Materials and Methods

Ethics approval was obtained from the Ethics Review Committee, Medical Research Institute, Sri Lanka (No. 23/2018).

This study was conducted as a hospital-based descriptive cross-sectional study, from December 2018 to April 2019, in five hospitals in the Western Province, where both infections have high prevalence. Adult patients in internal medicine wards diagnosed clinically by the treating physician and managed as suspected acute dengue were enrolled. Informed written consent was obtained. An interviewer-based questionnaire was administered to identify sociodemographic and clinical features, while clinical and laboratory investigational findings were obtained from medical records.

All samples were tested by microscopic agglutination test (MAT) for leptospirosis. Leptospira polymerase chain reaction (PCR) data were collected from clinical and laboratory records. Serum for dengue serology was stored at −70°C and tested in batches for dengue NS1 ELISA, IgM ELISA, IgG ELISA, and IgG quantification,[²] depending on each patient's duration of illness. The IgG ELISA-positive samples were tested with Dengue IgG ELISA for the IgG quantification to categorize as “acute secondary dengue infection (ASDI).”[²]

Statistical analysis was performed with SPSS software version 21 (SPSS Inc., Chicago, Illinois 60606-6307, U.S.A.). The Chi-square test and Fisher's exact tests were used for categorical variables. Analysis was made with a 95% confidence interval, and the level of significance was set at P < 0.05.

Results

Out of 386 blood samples from adult, clinically suspected acute dengue patients, the majority (53.6%, n = 207) were male. The median age was 29 years [Table 1].

Table 1: Comparison of the age distribution among acute dengue infection patients (n=274) by patients with concomitant infection (n=23)

ADI was confirmed in 297 patients; 267 (69.2%) were acute primary dengue infection and 30 (7.8%) were ASDI. Patients with recent dengue infection (n = 32, 6.3%) and past dengue infection (n = 12, 3.1%) were not included in ADI. Six (1.6%) patients were confirmed as having only leptospirosis with negative dengue serology, and 39 were negative for both and categorized as acute febrile illnesses.

Among patients with ADI, 23 patients also had laboratory-confirmed leptospirosis. The prevalence of concomitant infection of leptospirosis among ADI patients was 7.74% (n = 23/297).

In the concomitant group, ADI was confirmed in: 22 by dengue NS1 antigen and by dengue IgG (titer of >1:52,000 indicating secondary dengue infection). Leptospirosis in this group was confirmed by MAT with an optimal cutoff value of ≥1:320 (national cutoff) and 5 by Leptospira PCR; two had positivity for both Leptospira PCR and MAT.

In both groups, most patients belonged to the age range of 15 - 24 years years. In the concomitant group, the majority (82.6%) were <35 years [Table 1].

Females (n = 15, 65.2%) were approximately twice as common in concomitant infection than males (n = 8, 34.8%) in this study population, while ADI had equal gender distribution.

Regarding the occupation of the concomitant group, majority (82.6%) were indoor workers, such as nursing officers, teachers, and students. Home gardening, walking on muddy roads, and contact with abundant water sources were found to be their risk exposures.

In the concomitant group, 15 (65.2%) had risk exposures to leptospirosis, while 10 (43.5%) gave a history of risk exposure to dengue infection. None of them had antibiotic prophylaxis for leptospirosis or a history of leptospirosis. One patient had a history of dengue infection.

Fever was the most common symptom in both the ADI and concomitant groups. Myalgia was significantly more common in ADI than in the concomitant group (P < 0.05). All other symptoms were shared almost similarly.

The urine output and serum creatinine were normal during illness in all concomitantly infected patients. Ultrasound scan revealed free fluid (in pleural space, pelvis, hepatorenal pouch, and pericholecystic) in 6 (26.1%) patients in the concomitant group. Among ADI patients, 89 (32.5%) had free fluid.

Leptospirosis complications such as acute kidney injury, myocarditis, pulmonary hemorrhage, liver failure, pancreatitis, central nervous system features, and Guillain–Barre syndrome were not present in the patients with concomitant infection. All patients had a favorable outcome without complications.

Discussion

Both leptospirosis and dengue infection commonly occur during the rainy season and share common clinical features, and it is challenging to differentiate them or detect concomitant infection. Nevertheless, it is essential to specifically diagnose leptospirosis from dengue, for prompt antibiotic therapy that reduces the severity and duration of disease.[³] Although there is no specific treatment for dengue, early identification is essential for proper monitoring and vigilant management of fluids and reduces morbidity and mortality.[^4,5]

Similar previous studies in Colombo, Kandy, and Galle showed male predominance, and the leading age group was 15 - 35 years in patients with dengue fever.[⁶] These findings correspond with the current study. Regional analysis of the World Health Organization data from 1999 to 2005 on dengue patients in Sri Lanka also showed 61.8% of males.[⁷]

Dengue NS1Ag test could be as sensitive as molecular testing during the 1^st week of illness from day 1 to 7 of symptoms but not reliable thereafter.[⁸] We performed the NS1Ag test on patients who were symptomatic for less than 1 week.

There were 29 leptospirosis-confirmed patients in this study. In 6 (1.6%) patients, the diagnostic tests for dengue were negative. This finding reiterates the importance of awareness of shared clinical features, especially in a tropical country like ours, as both diseases are endemic and dependence on clinical diagnosis may miss concomitant infection. It also highlights the need for the use of laboratory investigations for patients with acute febrile illness, especially in an outbreak of dengue fever. Further, accurate early diagnosis may contribute to improved outcomes in patients.

The prevalence of concomitant leptospirosis among patients with ADI was 7.74% in the present study. Although there are no local studies to compare, there were two published case reports with a fatal outcome in one.[^4,9] However, all our patients with concomitant infection recovered completely without any significant complications.

Similar studies have been done in several countries in the region and had shown a lower prevalence of concomitant infection. Suppiah et al. (2017)[⁵] found a prevalence of 4.1% in Malaysia. In India, the prevalence was 0.9%, 1.3%, and 3.6% in Chandigarh, Kerala, and Andhra Pradesh, respectively.[^10,11,12] In Barbados (1997), there was 8% (2/25) concomitant infection, which was slightly higher than the current study, but their sample size was low. The high prevalence shown in our study is likely due to the high endemicity of both diseases in Sri Lanka in recent times.[¹³]

Interestingly, the majority (n = 15, 65.2%) of our patients with concomitant infection were female and in the age group of 15 - 24 years (52.2%) with a mean age of 26 years. According to the national data, leptospirosis is mostly a disease of men between 30 and 49 years of age.[¹⁴] This has been shown in local studies.[¹⁵] In contrast, a Malaysian study on concomitantly infected dengue and leptospirosis patients showed a male predominance of 90.9% (10/11) with a mean age of 32.3 years.[⁵]

The case-fatality rate of leptospirosis is high in Sri Lanka.[¹⁶] As it shares many clinical features with dengue, hantavirus, and typhus, it demands great watchfulness by the treating clinicians.

Majority (69.6%) of the leptospirosis patients were confirmed by MAT. In skilled hands, the MAT provides a very precise test result when it is carried out with live panels of common local pathogenic serogroups.[¹⁴] In addition, Leptospira real-time PCR is useful in the early diagnosis of the disease.[¹⁷]

Ten percent of the study population showed negative results in all the tests used for the diagnosis of dengue infection and leptospirosis. This finding illustrates the importance of considering common tropical diseases in the differential diagnoses and early use of appropriate laboratory testing without labeling patients by clinical syndromes.

We assessed the clinical features of dengue infection and leptospirosis. Fever was the most common symptom in both diseases. Majority of the concomitant and ADI groups had malaise and headache, while myalgia was significantly more common in acute dengue fever patients.

Majority of the clinical features among the two groups were similar without significant differences. Fever, chills and rigors, conjunctival suffusion, arthralgia, backache, nausea, vomiting, and discoloration of urine were found to be common (>50%) in both groups. Therefore, it is pivotal to keep both in the differential diagnosis, especially in dengue fever outbreaks.

In the Malaysian study, lethargy was present in 9.1% (n = 11) with no headache in concomitant infection. In the acute dengue fever group, 11 (4.3%) patients had headache and 7 (2.7%) had lethargy.[⁵]

Ultrasonography detects pleural effusions, ascites, and gallbladder edema in up to 95% of severe cases of dengue, while in leptospirosis, they are not reported.[¹⁸] In our study, 89 (32.5%) patients had free fluid (in pleural space, pelvis, hepatorenal pouch, and pericholecystic) in their ultrasound scans among ADI patients. In patients with concomitant infection, 6 (26.1%) had free fluid.

Shock was seen in one concomitant patient in the Malaysian study.[⁵] But severe complications were not observed in this study. There was no difference seen in the outcomes of the ADI group, the concomitant group, or in a patient with leptospirosis.

In this study, 15 (65.2%) patients in the concomitant group had risk exposure to leptospirosis. Karunanayake et al. reported 43.5% of patients with risk exposure to leptospirosis. Considerably high percentage in this study could be a result of the interviewer-administered questionnaire compared to retrospective laboratory data in the other local study.

The concomitantly infected group did not have farmers, agricultural sector workers, plantation workers, or personnel from armed forces who acquire leptospirosis more commonly in Sri Lanka.[^1,14] However, it was noted that the occupations of the patients with concomitant infection in the present study were mainly indoor workers. These factors show the clear shift of disease from rural areas to urban areas and occupational to environmental exposure. Our findings imply the importance of targeting current control strategies of leptospirosis, towards contaminated environment rather than occupation-based risk exposure as a prominent mode of transmission in an urban setting. In an outbreak of dengue, risk exposure to leptospirosis should be considered as both diseases emerge with rainfall. Epidemiologists should be aware of new information when designing their preventive and control strategies for urbanized and contaminated environments in both diseases.

In conclusion, the prevalence of concomitant leptospirosis among the patients with ADI was 7.74% in the Western Province, Sri Lanka. Concomitantly infected patients had a female predominance. Clinicians should be made aware of the high prevalence of concomitant infection among ADI patients. Appropriate and early use of laboratory facilities is important in a tropical setting like ours.

Financial support and sponsorship

This work was supported by the Medical Research Institute, Colombo 08, Sri Lanka (Project number: 23/2018).

Conflicts of interest

There are no conflicts of interest.

Acknowledgment

We acknowledge the contributions of P. S. M. Kalani J. Samarakoon and Randini Karunanayake for providing language help and proofreading.

We wish to state that there are no prior or duplicate publications or simultaneous submissions to journals elsewhere.