Abstract
Though both malaria and leptospirosis are frequent in the tropics, co-infections are under-recognized due to overlapping of clinical features. Here, we reviewed clinical manifestations of published co-infection along with our three cases. Out of a total of 18 patients, nine patients (50%) required ICU admission. Almost all patients had prodromal symptoms in the form of fever, headache and myalgia. Seven patients (37%) had altered sensorium, three patients (17%) had hypotension at admission, and 11 patients (61%) had acute kidney injury (AKI). Pulmonary manifestations in the form of pulmonary bleeding were present in four cases (22%). Three (17%) patients had acute lung injury/ acute respiratory distress syndrome. Almost 55% patients had DIC in the form of altered prothrombin time, activated partial thromboplastin time and low fibrinogen level. Four patients (22%) had subconjuctival suffusion, two of them had haematuria, while one presented with nasal bleeding. All patients had altered liver function tests. Of all the 18 patients, 17 (94%) survived, while one died.
Introduction
In patients with fever, renal failure and jaundice differential diagnoses include severe malaria, leptospirosis, rickettsial diseases, enteric fever, viral hepatitis and Hantaan virus infection. Co-infection of malaria with a wide variety of infectious diseases, such as dengue, hantavirus and filariasis, has been reported. Also, a few case reports of co-infection of malaria with leptospirosis have been recently published. 1–4 Both malaria and leptospirosis are infectious diseases worldwide and are endemic, especially in the tropics. We report three cases of co-infection of malaria with leptospirosis during the rainy season, which required admission to the ICU. The clinical features make it difficult to separate single from dual infections because of the marked variation in presentation which may complicate the clinical features and, in the presence of an undiagnosed co-infection, the clinical course may be worsened by the lack of an appropriate therapy. 1–5 Apart from malaria, viral hepatitis and enteric fever, assays for diagnosing other infections are not readily available.
Case 1
A 55-year-old woman, with a known case of diabetes mellitus and hypertension for six years was admitted to the intensive care unit (ICU) with a history of high grade fever for the previous 15 days, vomiting for the past three days, a decreased urine output for the past three days, altered sensorium associated with seizures for one day along with a nasal bleed for the past one day. On examination her Glasgow Coma Score (GCS) was E2V2M5, heart rate 120/m, blood pressure 90/50 mmHg, respiratory rates 30/m with bilateral crepts and extremities cool with the presence of bilateral lower limb oedema. There was conjunctival suffusion and nasal bleeding present. Her initial investigations revealed Hb 6.2 g/dL, platelets 38,000/mm3, activated partial thromboplastin time (aPTT) 69 s (against 27.5 s), serum creatinine (SCr) 3.7mg/dL, serum fibrinogen 63 mg/dL, serum bilirubin 3.1 mg/dL and SGOT/SGPT 222/62 U/L. A chest X-ray revealed diffuse bilateral infiltrates and arterial partial pressure of oxygen (PaO2)/fractional inspiratory oxygen (FiO2) ratios were suggestive of acute lung injury. Empiric antibiotics were started. Her peripheral blood smear microscopy was positive for malarial parasites and an anti-malarial was started. As a result of a worsening of the sensorium and tachypnoea, endotracheal intubation was done and the patient was kept on mechanical ventilation. Fluid resuscitation was performed for shock and she was started on vasopressors. She had an endotracheal bleed for that platelet and fresh frozen plasma and cryoprecipitate transfusions were given. In view of worsening of the clinical course and multi-organ failure, a workup for other infection was done as the leptospiral IgM was positive. Tablets for doxycycline were also added.
During her stay in ICU, haemodialysis was done in view of oliguria and raised creatinine. For persistently altered sensorium we performed a cerebrospinal fluid CSF analysis which revealed: five cells (all lymphocytes); proteins 15 mg/dL; and sugars 86 mg/dL. A magnetic resonance imaging study was normal. In due course, she developed ventilator associated pneumonia (causative agent Escherichia coli-extended spectrum beta lactamases [ESBL]) and started on the appropriate antibiotics. Gradually, her sensorium improved and she was weaned off the ventilator. For the renal failure, she was continued on alternate day haemodialysis (her urine output improved to 1000 mL/day) and she was transferred to the nephrology unit after 25 days in the ICU.
Case 2
A 50-year-old woman, a known sufferer of diabetes mellitus and hypertension, was admitted to our ICU with chief complaints of: a high grade fever associated with chills and rigor of 2–3 days duration 10 days earlier; vomiting of 1–2 days duration seven days earlier; a yellowish discolouration of the eyes for the past five days; respiratory distress for the past three days; and low urine output for one day. At the time of admission she was conscious but drowsy with respiratory rates of 35/m with bilateral diffuse crepitations, heart rate 110/m and blood pressure 110/80 mmHg. She was initiated on a non-invasive ventilation but, as there was no improvement, invasive ventilation started. Her peripheral blood smear was positive for plasmodium falciparum.
Other investigations revealed: haemoglobin 9.0 g/dL; 82,000/mm3 platelets; aPTT 47.1 s (compared to 27.5 s); SCr 2.6 mg/dL; fibrinogen 122; serum bilirubin 9 mg/dL; and SGOT/PT-200/90 U/L. Dengue and Leptospira serology were taken. She was continued on artessunate and third generation cephalosporin, doxycycline was added empirically and leptospira IgM became positive. During her stay, as the endotracheal aspirate cultures grew Aspergillus spp., voriconazole was also started. Gradually her sensorium improved and she was weaned off the ventilator, extubated and discharged after 15 days in the ICU.
Case 3
A 35-year-old man who did not drink alcohol and was a non-smoker was admitted with a history of recurrent fever associated with chills and rigors for the past 15 days, pain in the abdomen along with abdominal distension, vomiting, loose stools for the past 10 days and low urine output for the past five days. He had also been suffering from respiratory distress for five days for which he was intubated and was thereafter transferred to our hospital. At the time of his admission to our ICU, he was conscious, oriented, on a ventilator and haemodynamically stable with a 100/m heart rate and his blood pressure was 130/80 mmHg. His initial PaO2/FiO2 ratios were suggestive of acute respiratory distress syndrome (ARDS; <100) and he was initiated on broad spectrum antibiotics. His urine cultures and endotracheal aspirate grew yeast-like cells for which he was started on an antifungal. The initial investigations revealed: Hb 8.2 g/dL; platelets 90000/mm3; bilirubin 2.8 mg/dL; and serum creatinine 2.6 mg/dL. He remained febrile with a temperature reaching as high as 40.5°C which was associated with haemodynamic instability for which he was given fluid resuscitation and vasopressors were started. Malaria, leptospira and dengue serologies were sent. He was positive for both Plasmodium vivax and falciparum gametocytes on microscopy and antigen card test was also positive both for P. vivax and falciparum and the leptospira IgM was also positive. He responded well to artessunate, quinine and doxycycline. Gradually, he was weaned off vasopressors. His kidney function also began to improve and he was weaned off the ventilator and extubated. He was discharged after 25 days in the ICU.
Discussion
There are about 500 million cases of malaria and 1.1 million deaths worldwide. 6 Leptospirosis is a common infection in the tropics. Large epidemics are reported after heavy rainfall. China, South East Asia, Africa, South and Central America have areas where the disease is endemic. In India, leptospirosis is endemic in Kerala, Tamil Nadu and Andamans. 7 As malaria and leptospirosis are both frequently seen in the tropics and co-infections are common. In a recent study by Singhsilarak et al. sera from adult patients with falciparum malaria were found to be positive for co-infections with leptospirosis in 7.7% (out of 194 samples). 8
However, clinical manifestations of only 15 cases (eight from India and seven from Thailand) of co-infection of malaria and leptospirosis have been reported in the literature. They are under recognized due to an overlapping of the clinical features and the unavailability of leptospiral assay kits. Microscopic agglutination test (MAT) is the gold standard diagnostic test for leptospirosis but it is complicated and less sensitive compared to newer tests such as IgM ELISA and the slide agglutination test (SAT). Thus, both ELISA and SAT have been included with an appropriate score in Faine's criteria for defining leptospirosis. 7
The difficulties in utilizing MAT are because (a) paired sera are required to demonstrate a fourfold rise of titre and the antibody titres rise and peak only in the second or third week and (b) the test is complicated, requiring dark-field microscopy and cultures of various serovars which may not be available in smaller laboratories. While the ELISA IgM and SAT are simple, sensitive tests which measure IgM antibodies, they are also used to diagnose current leptospirosis at a very early stage and a single sample is adequate. The IgM ELISA test is particularly useful in making an early diagnosis, as it can show a positive as early as two days into an illness – a time when the clinical manifestation may be non-specific. In one study it was found to be 100% sensitive and 93% specific. 9
Of 18 patients with co-infection of malaria and leptospirosis (15 reported earlier and our three cases), nine patients (50%) required ICU admission (Table 1). Of seven cases from Thailand, only two required hospitalization. Most of the patients were young with a median age of 33 years (24–60 years) and the majority were male (14 cases). The APACHE II score is commonly used in ICU to assess the severity of an illness. Of 18 patients, the APACHE II score was available only for eight who had a median score of 16.
Clinical and laboratory manifestation and course of illness in patients with co-infection of malaria and leptospirosis
* The first three cases are reported from our institute
APTT, activated partial thromboplastin time; ARDS, acute respiratory distress syndrome; IgM, immunoglobulin G; DCI, disseminated intravascular coagulation; AKI, acute kidney injury; LFT, liver function test; MAT, microscopic agglutination test; APACHE II score, acute physiological and chronic health evaluation (APACHE) II score; ICU, intensive care unit; PD, peritoneal dialysis; M/E, microscopic examination; S/N, serial number
Almost all patients had prodromal symptoms in the form of fever, headache and myalgia. Seven had altered sensorium (37%) including one who also had a seizure. Three patients (17%) had hypotension on admission which required vasopressor support. Pulmonary manifestations in the form of a pulmonary bleed was present in four cases (22%); three (17%) patients had acute lung injury/acute respiratory distress syndrome. Eleven patients (61%) had acute kidney injury (AKI) and, of these, two required haemodialysis and one required peritoneal dialysis. Almost 55% patients had dissseminated intravascular coagulation (DIC) in the form of an altered prothrombin time, activated partial thromboplastin time and a low fibrinogen level. Four patients (22%) had subconjuctival suffusion – two of them had haematuria and one presented as a nasal bleed. All patients had altered liver function in the form of raised bilirubin and raised SGOT/SGPT at least three times the normal value. Of the 18 patients, 17 (94%) survived and one died.
Artessunate is the drug of choice for the treatment of severe malaria cases. Ceftriaxone is effective against enteric fever and doxycycline is effective against atypical organisms such as rickettsia and leptospira. As malaria is easily recognized by microscopy and antigen tests, most of these patients are started on artessunate only. However, we propose that, in critically ill patients with severe malaria, third generation cephalosporin and doxycycline could be added to the management if the clinical condition does not respond to anti-malarials while the results of diagnostic workup for other co-infections are still pending.
Conclusion
Co-infections are rarely reported but we should have a high index of clinical suspicion as diagnosing them late will lead to an increase in morbidity and mortality. Thus, for patients with severe malaria presenting with fever, thrombocytopenia, altered liver function test and altered renal function test, one should consider starting empirical treatment with third generation cephalosporin and doxycycline along with anti-malarial drugs as it covers most of the causative agents such as malarial parasite, leptospira, rickettsia and salmonella in cases of co-infection seen in the tropics.