Distinguishing Jarisch-Herxheimer Reaction From Septic Shock in Leptospirosis Patients: A Case Study

Introduction

Leptospirosis is a zoonotic spirochetal infection that is most prevalent in tropical environments. Humans acquire leptospirosis through direct contact with the urine of infected mammals, particularly rats, or through exposure to freshwater environments contaminated with rat urine [1].

Leptospirosis presents with various clinical manifestations, and diagnosing it in resource-limited settings is challenging, particularly because other infections can present with overlapping syndromes. Patients with rickettsial diseases, for example, may exhibit similar signs and symptoms, including fever, malaise, thrombocytopenia, and liver dysfunction [2].

Initiation of antibiotic therapy in spirochetal infections can trigger a febrile inflammatory reaction, known as the Jarisch-Herxheimer reaction (JHR). JHR is an acute inflammatory response triggered by antibiotic treatment for spirochetal infections, such as syphilis, leptospirosis, Lyme disease, and relapsing fever. It is primarily mediated by innate immune activation through Toll-like receptor 2 (TLR2) recognition of spirochetal lipoproteins, resulting in a rapid release of proinflammatory cytokines, including TNF, IL-6, and IL-8. Additional mechanisms – such as phagocytosis, complement activation, histamine and kinin release, and disseminated intravascular coagulation (DIC) – also contribute to its pathogenesis. The reaction typically peaks within hours of antibiotic administration [3]. However, JHR is not common. A review of 976 cases of leptospirosis treated with antibiotics revealed detection of JHR in 92 patients, with an incidence of only 9% [4].

Fever, chills, hypotension, rigors, nausea, vomiting, and skin lesions are known to occur within hours of administering β-lactam antimicrobial agents in patients with spirochetal infections. Although JHR can lead to hypotension, only 2 reported cases required vasopressors, and one of them necessitated endotracheal intubation, underscoring the rarity of such severe outcomes [5,6].

This report describes the case of a 51-year-old woman who worked clearing land, with confirmed leptospirosis, who developed transient fever and hypotension following treatment with ceftriaxone (Jarisch-Herxheimer reaction).

Case Report

A 51-year-old Japanese woman presented with fever and chills that had begun 3 days before admission. On the day of presentation, she was transported to the hospital by ambulance owing to difficulty moving. On admission, her vital signs were: blood pressure 109/70 mmHg, heart rate 114 beats per minute, respiratory rate 15 breaths per minute, SpO2 100% (room air), and temperature 40°C. She reported feeling joint pain in her limbs and back pain, yet physical examination revealed no signs of arthritis, and there was no tenderness over the spine. Conjunctival injection was evident, and insect bites were absent. The white blood cell count was 12 800/μL, aspartate aminotransferase was 129 U/L, alanine aminotransferase was 127 U/L, creatinine was 1.21 mg/dL, and C-reactive protein was 12.16 mg/dL. Table 1 presents additional laboratory test results. A detailed history revealed that 2 months prior, she had started clearing land in the mountains and drinking river water. Laboratory tests indicated elevated white blood cell count, C-reactive protein, thrombocytopenia, liver dysfunction, and acute kidney injury.

Based on her medical history, leptospirosis and rickettsial infections were suspected, and she was treated with ceftriaxone 2 g every 24 hours on day 2. Three hours after receiving the antibiotic, she developed chills, a fever of 42°C, and a systolic blood pressure of 70 mmHg. Her response to vasopressors was inadequate, leading to her transfer to the ICU and intubation for mechanical ventilation. Echocardiography revealed no causes of shock. Although septic shock was suspected, the antibiotics were not escalated, as the clinical course suggested JHR. Toxic shock syndrome was considered, and the antibiotic regimen was modified by adding clindamycin to ceftriaxone.

After 15 hours of antibiotic therapy, her blood pressure improved, and on the third day of hospitalization, vasopressors were discontinued, and extubation was performed. Blood and urine cultures obtained on admission were negative. Clindamycin was discontinued on the third day, and ceftriaxone was continued for a total of 7 days. She was discharged on the ninth day of hospitalization. Three days after discharge, polymerase chain reaction (PCR) testing for Leptospira in both serum and urine returned positive results, leading to a definitive diagnosis of leptospirosis.

Discussion

DIFFERENTIAL DIAGNOSIS:

In this case, it was essential to exclude other conditions with overlapping clinical features. Several differential diagnoses were considered. Viral hemorrhagic fevers (VHFs), which are prevalent in tropical regions, share features with leptospirosis, such as fever, hepatic dysfunction, and hypotension. However, the absence of recent travel outside Japan, lack of mosquito exposure, and the patient’s clinical history and laboratory results made VHF unlikely. Toxic shock syndrome was also considered. However, the onset of shock – occurring after antibiotic administration on the day following admission – reduced the likelihood of this diagnosis, although it could not be entirely ruled out. Given the potential severity, clindamycin was initiated, and the patient was closely monitored. As PCR testing for Leptospira in both serum and urine returned positive, the shock was retrospectively attributed to a JHR.

Conclusions

Even when patients present with nonspecific symptoms, such as fever, detailed history-taking, including potential exposure to environmental factors such as land clearance, is essential. Patients started on antibiotic therapy for leptospirosis should be closely monitored, particularly during the first 24 hours, when JHR most commonly occurs. Regular assessment of vital signs, oxygenation, and hemodynamic status is essential for early detection. If JHR is suspected, antibiotic treatment should be continued, and supportive care – including fluid resuscitation and vasopressors – should be provided as needed. Escalation of antibiotic therapy should be avoided unless there is clear evidence of true septic shock or a new infection. Clinicians should maintain vigilance and intervene only when clinically justified to prevent unnecessary modifications to the antimicrobial regimen. This report has shown the importance of taking a detailed clinical history for patients at risk from exposure to spirochete infections, and highlights the association between antibiotic treatment and the occurrence of transient symptoms that can mimic episodes of parasitemia or sepsis.