Case Report: An Imported Case of Severe Leptospirosis with Septic Cardiomyopathy Requiring Venoarterial Extracorporeal Membrane Oxygenation in Japan

ABSTRACT.

A 29-year-old Japanese man presenting with fever, joint pain, and diarrhea was admitted to the intensive care unit for cardiogenic and distributive shock. We suspected leptospirosis based on conjunctival hyperemia, skin rash, elevated bilirubin, and renal involvement; a travel history to Laos was also suggestive. We confirmed the diagnosis with blood and urine polymerase chain reaction and microscopic agglutination tests using paired serum samples. His hemodynamics were unstable, and his echocardiogram showed diffuse and severe left ventricular systolic dysfunction on day 2. He initially required venoarterial extracorporeal membrane oxygenation (V-A ECMO) support but responded and recovered on antimicrobial therapy. His cardiac function and hemodynamics improved on day 5. Severe leptospirosis may cause jaundice, renal failure, pulmonary hemorrhage, acute respiratory distress syndrome, and central nervous system involvement; however, few studies have reported severe cardiac manifestations. Herein, we report the first case of septic cardiomyopathy secondary to leptospirosis that was successfully managed with V-A ECMO. Leptospirosis should be included in the differential diagnosis when a patient returning from an endemic area presents with cardiogenic shock. Furthermore, intensive care management with prompt initiation of V-A ECMO should be considered to reverse septic cardiomyopathy.

INTRODUCTION

Leptospirosis is an infection endemic to several countries, especially those in tropical regions such as South and Southeast Asia, Oceania, the Caribbean, parts of sub-Saharan Africa, and parts of Latin America. In Japan, only 16–48 annual cases have been reported since 2007.¹

Human infection usually results from exposure to environmental sources such as animal urine, contaminated water, and soil. The portal of entry includes mucous membranes, conjunctivae, and abrasions on the skin. Affected individuals generally present with fever, chills, headache, muscular pain, conjunctival hyperemia, anorexia, nausea, and vomiting. Severe leptospirosis can cause complications such as jaundice, renal failure, and pulmonary hemorrhage.

Including leptospirosis in differential diagnoses in nonendemic areas is challenging because of diverse and nonspecific symptoms. However, adequate diagnosis and management are necessary because mortality rates of severe leptospirosis range from 5% to 20%.²

Herein, we report an imported case of severe leptospirosis associated with cardiogenic shock, possibly secondary to septic cardiomyopathy, in Japan.

CASE REPORT

A previously healthy 29-year-old Japanese man presented with fever, joint pain, and diarrhea that lasted 4 days. He was in Laos for 7 days followed by Thailand for 7 days, and he returned to Japan 4 days before admission. He reported that his symptoms started the day after returning from the trip. He was transferred to the emergency room (ER) because of worsening symptoms. He was unable to move because the joint pain and malaise due to dehydration were progressive on day 5 after onset.

On admission, his temperature was 39.7°C, blood pressure was 98/53 mm Hg, heart rate was 125 beats/minute, respiratory rate was 29/minute, and peripheral saturation was 99% on room air. Physical examination findings included prominent conjunctival injections (Figure 1). Blood tests revealed a white blood cell count of 14 × 10³/μL (neutrophils 98%), C-reactive protein level of 24.5 mg/dL, thrombocyte count of 7.3 × 10⁴/L, and hemoglobin level of 14.8 mmol/L. The results of the coagulation panel were normal. Liver function tests revealed an aspartate aminotransferase level of 24 IU/L, an alanine transaminase level of 13 IU/L, and a total bilirubin level of 2.94 mg/dL. Kidney function tests and electrolytes revealed a creatinine level of 1.71 mg/dL, blood urea nitrogen level of 40.1 mg/dL, potassium level of 3.5 mEq/L, and sodium level of 128 mEq/L. The lactic acid concentration was 16.8 mg/dL. Chest computed tomography showed only a slight nonspecific bilateral bronchiolitis.

Figure 1.

Conjunctival injection.

The initial and presumptive diagnoses were infectious colitis and dehydration, and the patient was admitted from the ER. However, his blood pressure decreased after the administration of 3 L of intravenous Ringer acetate, meropenem, and vancomycin. Vasopressors were also administered, but his hemodynamics did not improve substantially, and the patient was intubated in the intensive care unit within hours of admission. The next day, his systolic blood pressure decreased to less than 50 mm Hg with maximal vasopressor and positive inotrope doses; an echocardiogram showed diffuse and severe left ventricular systolic dysfunction of 20–30% ejection fraction (EF). The contractility was clearly decreased compared with the initial evaluation completed on admission. An electrocardiogram (ECG) showed a slight ST-segment elevation in leads V1 and V2. There was a mild increase in troponin-I level (1.930 ng/mL). The patient was started on emergent venoarterial extracorporeal membrane oxygenation (V-A ECMO) and intraaortic balloon pumping (IABP) because we expected his cardiac function to be restored in the event of septic cardiomyopathy.

Leptospirosis was considered based on his travel history to Laos and physical examination findings of conjunctival infection, jaundice, and abdominal petechiae (Figures 1 and 2) upon consultation with an infectious disease physician. Furthermore, minocycline and atovaquone-proguanil were added for potential rickettsiosis and malaria, respectively.

Figure 2.

Tiny petechiae of the abdomen.

The patient’s hemodynamics improved, and a follow-up echocardiogram revealed a myocardial contractile function recovery on day 5. On day 6, V-A ECMO and IABP were discontinued, and the patient was extubated. Blood, sputum, and urine cultures on admission were all negative. Rapid tests for influenza, malaria, and dengue fever, as well as Giemsa staining (thrice), were all negative. However, leptospiral polymerase chain reaction for the Leptospira flaB gene³ from blood and urine was positive, and flaB sequencing revealed that the infecting species was Leptospira interrogans (DNA Data Bank of Japan accession numbers LC738778 and LC738779). Moreover, seroconversion was detected by a microscopic agglutination test on days 1 and 10 of hospitalization, and the highest antibody titer was against serogroup Grippotyphosa (Table 1). Therefore, the patient was diagnosed with severe leptospirosis.

Table 1.

Results of the microscopic agglutination test

Test organisms	Antibody titer, day 1	Antibody titer, day 10
Leptospira borgpetersenii serovar Castellonis	< 50	100
L. borgpetersenii serovar Javanica	< 50	< 50
L. borgpetersenii serovar Poi	< 50	400
Leptospira interrogans serovar Australis	< 50	< 50
L. interrogans serovar Autumnalis	< 50	< 50
L. interrogans serovar Bataviae	< 50	< 50
L. interrogans serovar Canicola	< 50	< 50
L. interrogans serovar Copenhageni	< 50	< 50
L. interrogans serovar Hebdomadis	< 50	50
L. interrogans serovar Icterohaemorrhagiae	< 50	< 50
L. interrogans serovar Kremastos	< 50	50
L. interrogans serovar Pomona	< 50	< 50
L. interrogans serovar Pyrogenes	< 50	< 50
L. interrogans serovar Rachmati	< 50	< 50
Leptospira kirschneri serovar Grippotyphosa	< 50	800

After extubation, the patient reported entering a waterfall and lagoon in Laos after falling off a motorcycle and injuring his leg. Antibiotics were switched to penicillin G, which was administered for a total of 10 days. A follow-up echocardiogram revealed that the left ventricular systolic function recovered to normal on day 17. The patient was discharged on day 21. His total bilirubin level rose to a maximum of 14.5 mg/dL before returning to normal on day 40.

DISCUSSION

It is challenging to maintain a high level of clinical suspicion for leptospirosis in cases of sepsis or shock in nonendemic countries, including Japan, because it has a wide range of nonspecific symptoms. In fact, in this case, leptospirosis was not included in the differential diagnosis in the ER.

The following approaches are required to address the fever of returning travelers: First, the travel location, latency, and exposure history are checked. Second, severe, treatable, and frequently encountered diseases are excluded.

In this case, the travel location was Laos, the latency was 8–14 days, and there was a history of exposure to river water. A wide range of infectious diseases has been described in Laos, including malaria, typhoid fever, scrub typhus, murine typhus, sennetsu ehrlichiosis, dengue fever, leptospirosis, Japanese encephalitis, and influenza.⁴

Falciparum malaria can rapidly progress to severe forms and is potentially lethal.⁵ Leptospirosis is an important, treatable cause of fever in rural Laos and should be considered in any acutely febrile patient with a negative malarial test.

The test for leptospirosis is not commercially available in Japan and is only available in a few facilities. Hence, we cannot make a diagnosis without actively suspecting leptospirosis and sending appropriate specimens to a special facility. In febrile patients with a travel history to a leptospirosis-endemic area, especially those involved in outdoor activities with freshwater exposure, an extensive medical history should be taken to clue physicians in to leptospirosis.

The patient described here presented with severe leptospirosis, which caused shock. With regard to evaluation of the etiology of the shock, we considered both septic and cardiogenic etiologies, as well as the contribution of potential Jarisch-Herxheimer reaction (JHR).

Although ECG abnormalities indicating atrioventricular block and acute pericarditis have been reported, they are nonspecific, and few studies have reported cardiac abnormalities caused by leptospirosis.⁶ In a case series of five patients with severe leptospirosis, the reported cardiac manifestations included nonspecific ECG changes, arrhythmias, myocarditis, pericarditis, endocarditis, and cardiogenic shock. The pathophysiological mechanisms of these manifestations are unclear. A study of 20 autopsies of patients who died of leptospirosis also reported myocardial invasion, acute coronary arteritis, and aortitis, suggesting that myocarditis and cardiomyopathy may not be rare in severe leptospirosis.²

In this case, the etiologies considered most likely as the etiology of cardiogenic shock were septic cardiomyopathy or myocarditis.

Septic cardiomyopathy is characterized by left ventricular dilatation, decreased EF, and reversible myocardial damage. Cardiac contraction usually improves in 7–10 days.^7,8 Myocarditis is characterized by highly variable clinical manifestations, including fatigue, chest pain, heart failure, arrhythmias, and cardiogenic shock.⁹ Similar to septic cardiomyopathy, it presents with new-onset or worsening heart failure, which can be life-threatening. Acute myocarditis resolves in approximately 50% of cases within the first 2–4 weeks, approximately 25% develop persistent cardiac dysfunction, and 12–25% may acutely deteriorate and die or have end-stage dilated cardiomyopathy necessitating heart transplantation.¹⁰

The most characteristic feature of the present case was a rapid cardiac function improvement in only 5 days. Hence, we diagnosed septic cardiomyopathy.

Severe cardiogenic shock due to septic cardiomyopathy may improve with VA-ECMO use.^7,11–13 Therefore, prompt VA-ECMO initiation should be considered for patients who have visited or lived in the tropics and present with signs of idiopathic cardiogenic shock.

Furthermore, in this case, JHR could have contributed to the shock in addition to cardiogenic factors; patient hemodynamics suddenly destabilized after antibiotic initiation. JHR is a febrile inflammatory reaction characterized by chills, shaking, hypotension, or increasing body temperature after the initiation of antimicrobials in spirochetal diseases such as leptospirosis.¹⁴ Hence, in addition to cardiac problems, V-A ECMO may be an effective way to support circulation while allowing time for the JHR to resolve.

In summary, we report an imported case of severe leptospirosis requiring V-A ECMO who returned to Japan from Laos. This is the first case of successful V-A ECMO treatment of severe leptospirosis complicated by septic cardiomyopathy. In patients with fever and cardiogenic shock in endemic areas, prompt antimicrobial therapy should be initiated for possible leptospirosis, as well as V-A ECMO for circulatory support.