Background

Dengue is one of the fastest-growing mosquito-borne viral diseases and poses a significant public health threat. It is an arthropod-borne disease transmitted through the bite of infected mosquitoes and is highly prevalent in tropical and subtropical regions. According to the World Health Organization (WHO), approximately half of the worlds population is now at risk of dengue infection, with an estimated 100–400 million infections occurring annually [1]. While dengue incidence was historically limited to the monsoon season, recent epidemics in Bangladesh indicate a shift, with longer transmission periods resulting in increased human infections. Climate change, with its associated rise in global temperatures, is likely to expand the geographic range and incidence of dengue by promoting viral reproduction and survival [2, 3].

Leptospirosis is a zoonotic disease with a higher incidence in tropical and subtropical regions. Human infection occurs through accidental exposure to the urine of infected animals or contaminated soil and water. According to the Centers for Disease Control and Prevention (CDC), an estimated 1 million cases occur globally each year, resulting in nearly 60,000 deaths [4]. The incidence of leptospirosis has increased in recent decades, largely due to climate change [3, 5] and natural disasters [6]. While most infections are subclinical, a minority result in severe disease involving multiple organs such as the kidneys, liver, lungs, and brain.

Given the overlapping geographic distribution of dengue and leptospirosis, coinfection is a likely occurrence and poses a significant public health concern. The reported prevalence of coinfection ranges from 0.9% to 5.9% [7,8,9,10]. The overlapping symptoms and signs in the early phase can create a diagnostic challenge, potentially leading to fatal consequences, particularly during dengue epidemics [11].

In the year 2023, Bangladesh, a densely populated nation, confronted its most significant dengue outbreak in history, recording 316,411 confirmed cases of infection and 1650 fatalities [12]. Conversely, Bangladesh has a high annual occurrence of leptospirosis [13].

In this report, we delineate the concurrent occurrence of dengue and Leptospira infections in two patients initially admitted to our dengue ward with suspected dengue fever.

Case presentation

Case 1

A 25-year-old Bangladeshi male, residing in a rural village and employed as an agricultural worker, presented to our health center with a 3-day history of high-grade fever. Additionally, the patient complained of myalgia, severe bodily pain, and episodes of vomiting. Over the past day, he had experienced abdominal pain and loose, watery stools. Notably, the patient observed yellow discoloration of both his urine and eyes for the past day.

During the physical examination, the patient appeared conscious and oriented, without any signs of meningeal irritation. He presented with a temperature of 103 °F, dehydration, jaundice, and leg edema. His pulse was recorded at 90 beats per minute (bpm), and his blood pressure measured 130/80 mmHg. Skin examination revealed petechial rash on the chest and extremities, as well as subconjunctival hemorrhage in both eyes. The tourniquet test yielded a positive result. Considering the ongoing outbreak, dengue serology was performed, confirming positivity. Further investigations revealed elevated serum bilirubin levels and thrombocytopenia.

We started management for dengue fever with guideline (DGHS, 2018)-directed cautious fluid resuscitation and frequent clinical and biochemical monitoring. The patient was doing well for the next 2 days; however, on the fourth day since admission, the temperature spiked again, accompanied by an increase in liver biochemistry and serum creatinine levels (Table 1). Considering the differential diagnoses, we subsequently conducted testing for leptospirosis, which yielded a positive result. Treatment was augmented to incorporate intravenous administration of Ceftriaxone at a dosage of 2 g per day. Subsequent monitoring revealed gradual improvement in both clinical and biochemical parameters over time. The patient was discharged in a stable condition.

Table 1 Time trends of investigations of the first patient
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On the tenth day, a follow-up serological test for leptospirosis was conducted, revealing an elevated titer of 3600, suggestive of recent infection with leptospirosis.

Case 2

A 35-year-old previously healthy Bangladeshi male was transferred to our facility from a distant district, presenting with a 3-day history of high-grade fever and altered consciousness. The patient’s attendant reported fresh rectal bleeding occurring over the past day. The patient had no documented systemic illnesses. The physical examination revealed impairment in higher cognitive function, as indicated by a Glasgow Coma Scale score of 9 (E2V4M3). The patient exhibited a pulse rate of 100 beats per minute, blood pressure of 90/60 mmHg, and normal jugular venous pressure. Additionally, the patient presented with a temperature of 100 °F and jaundice. Pupillary examination demonstrated bilaterally equal and reactive pupils. The neurological assessment revealed a stiff neck and bilateral extensor plantar response. Abdominal examination detected the presence of ascites, as indicated by shifting dullness and a palpable liver. Additionally, bilateral subconjunctival hemorrhage was observed. The patient was transferred to the dengue ward on the same day of admission after receiving a positive result for dengue infection. A tentative diagnosis of expanded dengue syndrome was made and supportive management was started accordingly. The patient was then shifted to intensive care unit for better monitoring and relevant laboratory investigations were sent. Chest X-ray showed normal radiological appearance of lung with no cardiomegaly (cardiothoracic ratio 0.45). Initial investigations unveiled leukocytosis, thrombocytopenia, elevated alanine transaminase (ALT), and increased serum creatinine levels. Additionally, cerebrospinal fluid (CSF) analysis revealed pleocytosis, with normal protein and glucose concentrations which prompted us to do test for Leptospira and it came as positive on day 3. A reevaluation of leptospirosis serology on the ninth day revealed an increasing titer of 1:3200, signifying a recent infection with leptospirosis.

Injection ceftriaxone 2 g/daily was then added to ongoing treatment. All parameters gradually started to return to normal and he was stable without additional fluid support. On day 7, the patient suddenly developed palpitation, respiratory distress, and orthopnea. Physical examination revealed tachycardia, tachypnea, hypotension, and elevated jugular venous pressure, accompanied by crackles over both lung fields. A repeat chest X-ray showed an enlarged cardiac silhouette, prominent vascular markings, and opacities in the lower regions of both lungs, indicative of pulmonary edema. The electrocardiogram (ECG) revealed sinus tachycardia, reduced R-wave amplitude, depressed ST segments, and T-wave inversion in chest leads, alongside an elevated serum troponin I level (refer to Table 2). Subsequent 2D-echocardiography demonstrated features suggestive of global hypokinesia, with an ejection fraction of 40%. Based on the ESC 2013 criteria proposed by Caforio et al., a diagnosis of probable myocarditis was established. Management involved oxygen inhalation and diuretic therapy. The patient’s condition showed gradual improvement over the subsequent days, eventually resulting in discharge in a stable hemodynamic state on day 14.

Table 2 Time trends of investigations of the second patient
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To facilitate a better understanding and a clear comparison of the clinical features and outcomes of these cases, we have created a table that summarizes key aspects of each case (Table 3).

Table 3 Comparison of two cases
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Follow-up

The patient presented for a follow-up appointment 2 months postdischarge. The patient exhibited stable hemodynamic status and normal physical functioning. Follow-up echocardiography demonstrated the absence of regional wall motion abnormalities.

Discussion

Acute febrile illness (AFI) represents a frequent cause of hospitalization, especially prevalent in tropical and subtropical regions. The diagnostic process poses challenges for clinicians, especially in low-income countries such as Bangladesh, where appropriate diagnostic tools may be limited. Clinicians often adopt a syndrome-based approach to address this diagnostic dilemma. Among the spectrum of AFI etiologies, including malaria, scrub typhus, enteric fever, and Rickettsia diseases, dengue and leptospirosis hold considerable significance in India, an adjacent nation to Bangladesh [14, 15]. Correspondingly, outpatient studies conducted in Bangladesh have reported similar findings [16].

Dengue virus infection ranks as the most prevalent arthropod-borne illness globally, with widespread distribution. While typically sporadic in developing nations, cases often arise from travel to endemic regions. However, rising global temperatures are fostering the ecological persistence of the virus, leading to shifts in epidemiology. Bangladesh is currently facing the largest dengue outbreak with an unprecedented rise in infection rate and case fatality rate (CFR) of 0.47%. Notably, Dengue virus serotype 2 (DENV2) has reemerged as the predominant circulating serotype in 2023, following its prevalence in 2018 [17].

The clinical presentation typically features a marked increase in body temperature, severe myalgia, often termed as “break-bone fever,” and retro-orbital pain. Key characteristics of this infection include capillary leakage and hemorrhagic manifestations, which are pivotal in the development of severe complications such as shock syndrome and subsequent multiorgan failure.The typical biochemical alterations are dynamic, characterized by leukopenia, significant thrombocytopenia, and an elevation in hematocrit levels during the critical phase. These parameters gradually normalize during the recovery phase.

Conversely, leptospirosis, a zoonotic infection caused by Leptospira spp., poses a substantial risk of mortality [18]. It is known to precipitate recurrent outbreaks, particularly in tropical regions, attributable to favorable epidemiological shifts [19, 20]. In addition to fever, characteristic symptoms at presentation include abdominal pain, jaundice, and oliguria. Unlike dengue infection, leukocytosis is commonly observed in leptospirosis. Organ dysfunction features, such as elevated bilirubin and ALT levels, along with increased serum creatinine levels, are prominent in leptospiral infection.

While dengue is traditionally not recognized as a neurotropic virus, recent findings indicate its neurotropic potential. Neurological complications have been documented in 0.5–6.2% of cases [21, 22]. A surveillance study conducted in India identified dengue as the causative agent in 5% of acute encephalitis syndrome cases [23]. In our second case, the presentation likely stemmed from dengue encephalopathy.

The occurrence of probable myocarditis in the second case is likely due to leptospiral infection. Myocarditis associated with leptospirosis has been documented in both clinical cases [24, 25] and postmortem biopsies [26]. Alternatively, the myocarditis may also be attributable to dengue infection. A recent systematic review and meta-analysis reported a pooled prevalence of myocarditis in dengue fever of 12.4% [27].

As both diseases peak during the monsoon season, coinfection is expected to occur frequently. Without a strong clinical suspicion, the diagnosis of coinfection may be delayed, resulting in fatal outcomes. Dengue management primarily revolves around timely and adequate fluid resuscitation, while leptospirosis requires antibiotic therapy along with appropriate organ support if warranted.

Several studies have endeavored to investigate clinical and biochemical indicators that could aid clinicians in promptly diagnosing coinfection with dengue and leptospirosis [28, 29]. It was observed that abdominal discomfort and fatigue were more prevalent in the dengue–Leptospira coinfection group, while symptoms such as headache, arthralgia, epigastric pain, retro-orbital pain, acute kidney injury, and gum bleeding were more commonly reported in cases of dengue infection alone. Additionally, in the coinfection group, the typical progression from febrile to critical and convalescent phases of dengue was less clearly delineated [9].

The documented cases discussed here had certain noteworthy characteristics that led us to consider possibilities other than dengue: jaundice, disruption of the classical phase of dengue, leukocytosis, and a marked deterioration in liver and renal function. Both cases respond dramatically after addition of antibiotic.

Limitations

Owing to the unavailability of resources at our facility, we were unable to conduct polymerase chain reaction (PCR) testing on cerebrospinal fluid (CSF) for Japanese encephalitis and herpes simplex virus. Furthermore, cardiac magnetic resonance imaging (MRI) was not feasible to provide enhanced confirmation of myocarditis.

Conclusions

The convergence of clinical syndromes during the initial undifferentiated phase of leptospirosis and dengue fever may result in its under-recognition, particularly amid dengue fever epidemics, potentially leading to a poorer prognosis.

Guidelines

The case report presentation followed CARE guidelines [30].

Learning points for clinicians

Considering the strikingly similar clinical presentations of dengue and Leptospira infections, clinicians practicing in endemic areas should exercise heightened vigilance and include these conditions in the differential diagnosis of acute febrile illnesses (AFI). Even in cases suspected or confirmed as dengue, leptospirosis should be actively excluded, given its specific antibiotic treatment, which can substantially enhance overall patient survival.