Case Report: Relapsing Leptospirosis in an Immunocompromised Host

ABSTRACT.

Leptospirosis is typically a self-limited febrile illness; when it occurs, meningitis usually develops early in the course. Here, we describe a patient who had engaged in freshwater activities in Kauai that was immunocompromised due to a history of mantle cell lymphoma, autologous hematopoietic cell transplant, and hypogammaglobulinemia. He developed leptospiral meningoencephalitis 11 weeks after illness onset and persistently detectable Leptospira DNA in blood and cerebrospinal fluid along with ongoing clinical illness, despite appropriate treatment.

CASE REPORT

Leptospirosis is an important zoonotic bacterial disease caused by Leptospira species. The course is usually an acute self-limited febrile illness occasionally complicated by jaundice and renal failure. Clinically apparent leptospiral meningitis may occur in up to a quarter of patients who contract leptospirosis.^1–3

A 66-year-old man presented with a history of mantle cell lymphoma (in remission) and previous autologous hematopoietic cell transplant in 2019; he had also been treated with rituximab, with the last dose given in November 2021. In December 2021, he visited Kauai, where he went rafting in a freshwater river and swam in freshwater ponds while staying in a remote jungle home.

In January 2022, 2 weeks after returning home to Northern California, he developed fever, nausea, vomiting, and abdominal pain. After 8 days of these symptoms, he presented to the emergency department and was found to be in septic shock with acute kidney injury and mild liver enzyme elevations. Piperacillin-tazobactam and doxycycline were begun. Urine Leptospira polymerase chain reaction (PCR) was positive, and blood Leptospira PCR was negative (Table 1). Other infectious work-up such as blood cultures were negative, and his septic picture was attributed to leptospirosis. His symptoms improved, and he was discharged home after a 9-day hospitalization. He completed a week of intravenous beta-lactam antibiotic therapy and 10 days of doxycycline.

Table 1.

Leptospira values of admissions (1/2022, 2/2022a, 2/2022b, 3/2022, 4/2022b) and emergency department visit (4/2022a)

Encounter	Leptospira DNA, urine	Leptospira DNA, blood	Leptospira DNA, CSF	Leptospira serum IgM
1/2022	Detected	Not detected
2/2022a	Not detected
2/2022b				Not detected
3/2022	Not detected	Detected	Detected	Not detected
4/2022a		Not detected
4/2022b	Detected	Detected	Detected

CSF = cerebrospinal fluid.

Leptospira DNA real time PCR in urine, blood and CSF was performed by Quest Diagnostics.¹⁷ Leptospira serum IgM qualitative immunoblot was performed by ARUP laboratories.¹⁸

In early February 2022, he re-presented with 2 days of generalized weakness, nausea, and fevers. He was admitted for septic shock and mild to moderate liver enzyme elevations. He briefly received intravenous piperacillin-tazobactam and later levofloxacin and metronidazole. Urine Leptospira PCR was negative (Table 1). He improved and was discharged to complete a 14-day course of levofloxacin and metronidazole. He was readmitted at the end of February 2022 for fever, rigors, and altered mental status. His mental status improved within a day of treatment with vancomycin, cefepime, ampicillin, acyclovir, azithromycin, and intravenous fluids. Given his rapid improvement, a lumbar puncture was not performed. Antibiotics were stopped after 3 days; blood cultures, positron emission tomography–computed tomography, and transthoracic echocardiogram did not reveal a focus of infection. Of note, serum Leptospira IgM antibody was negative at this time (Table 1). He was discharged in early March 2022 and was clinically well.

In mid-March 2022, he presented with 1 week of fever, headache, neck stiffness, confusion, and myalgia. On admission, he had reduced range of motion in his neck. His peripheral white blood cell count was normal, but his absolute lymphocyte count and IgG levels were low (Tables 2 and 3). A lumbar puncture was performed before the administration of antibiotics, which revealed a mild lymphocytic pleocytosis and high protein (Table 3). Leptospira PCR was positive from both blood and cerebrospinal fluid (CSF) (Table 1).

Table 2.

Laboratory values of admissions (1/2022, 2/2022a, 2/2022b, 3/2022, 4/2022b) and emergency department visit (4/2022a)

Encounter	WBC (cells/μL)	ALC (cells/μL)	Creatinine (mg/dL)	Total bilirubin (mg/dL)	AST (units/L)	ALT (units/L)	ALP (units/L)
1/2022	5.90	0.20	5.00	3.70	204	78	176
2/2022a	3.20	0.70	1.30	3.20	106	215	144
2/2022b	1.90	0.08	1.09	1.10	55	71	67
3/2022	5.30	0.68	1.17	0.60	35	63	63
4/2022a	2.40	0.20	1.10	0.70	47	53	57
4/2022b	3.10	0.20	2.30	1.10	101	55	64

ALC = absolute lymphocyte count; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; WBC = white blood cell count.

Table 3.

Laboratory values of admissions (1/2022, 2/2022a, 2/2022b, 3/2022, 4/2022b) and emergency department visit (4/2022a)

Encounter	Total IgM (mg/dL)	Total IgG (mg/dL)	CSF
			WBC (/µL)	Glucose (mg/dL)	Protein (mg/dL)
1/2022
2/2022a
2/2022b
3/2022	< 20	380	166	69	109
4/2022a
4/2022b			32		125

CSF = cerebrospinal fluid; WBC = white blood cell count.

At this time, 16S rRNA gene PCR amplicon sequencing was performed and identified the infecting species to be L. interrogans, using methods similar to that reported in West et al.⁴ Serum Leptospira IgM was negative during this admission, as was urine Leptospira PCR (Table 1). Serum Leptospira IgG was not tested at this time (nor at any point in his course). He was diagnosed with leptospiral meningoencephalitis and completed a 2-week course of high-dose intravenous ceftriaxone. On follow-up 1 week after completion of antibiotics, he reported resolution of most symptoms, apart from mild intermittent headache.

In late April 2022, he was admitted for acute hypoxic respiratory failure, altered mental status, and septic shock. He required vasopressor support and bilevel positive airway pressure. Chest imaging showed diffuse ground-glass opacities. Leptospira PCR was positive on his CSF, blood, and urine (Table 1). He was treated with intravenous ceftriaxone and doxycycline. He was also given high-dose methylprednisolone with eventual taper to oral prednisone, and he was also given intravenous immunoglobulin. His hypoxia resolved, and he was discharged on oral doxycycline, with plans for him to remain on this long term. At 12-month follow-up, he was doing well on this regimen, with no signs or symptoms of recurrence and no adverse effects from the doxycycline.

DISCUSSION

Patients with leptospirosis can present with a wide spectrum of clinical manifestations, most often as self-limited disease, to occasionally life-threatening illness. Our patient was unusual in that he developed severe, relapsing-remitting symptoms resulting in five admissions over the course of 5 months, despite having completed multiple appropriate courses of antimicrobial therapy. Although there is no direct laboratory evidence of leptospiral involvement for the two February admissions, we strongly suspect that these episodes represented leptospirosis given his overall clinical presentations. Leptospira DNA was still detectable by PCR in blood and CSF 4 months after initial illness. His recurrent symptoms and clinical presentations suggest that the DNA detected reflected live bacteria causing active infection rather than just residual DNA from previously killed organisms.

In humans, neither blood nor CSF is known to serve as a chronic reservoir for Leptospira bacteria. Detection of Leptospira by blood cultures and quantitative PCR is more likely during the first 1 to 2 weeks of illness, before the formation of antibodies; however, in some untreated cases, Leptospira DNA has been detected after day 15 of illness.^3,5–7 Data are limited regarding the window of detection of Leptospira in CSF by culture or PCR, but reports suggest that culture of CSF is only likely to yield organisms within the first 2 weeks of illness.^2,3,8 We are only aware of two other reports of late-onset leptospiral meningitis, although we recognize that this entity could be underdiagnosed due to the challenges of diagnosis by routinely available microbiologic tests. One of these patients was a 14-year-old boy with severe combined immunodeficiency who presented three times over the course of 4 months with fever and headache with eventual diagnosis of leptospiral meningitis by next-generation sequencing. After appropriate antibiotic therapy, this patient’s symptoms resolved.⁹ The other patient was a 35-year-old farm laborer who initially presented with fevers and jaundice. He presented again 4 months later with meningitis. Although no organisms were directly identified in his CSF, leptospirosis was reproduced by xenodiagnosis. This patient’s symptoms resolved despite not being treated with antibiotics.¹⁰ Unlike our patient, neither of these patients had received antibiotic therapy for leptospirosis before they developed meningitis.

In contrast to blood and CSF, detection of Leptospira by PCR in urine has been observed for weeks to years after treatment of patients with acute leptospirosis.¹¹ It is thought that leptospires persist in the tubular lumen and interstitium of kidneys, which can result in chronic tubulointerstitial nephritis and interstitial fibrosis.¹² Chronic or recurrent ocular manifestations of leptospirosis such as uveitis have also been described.^3,13

Leptospires are extracellular pathogens and humoral immunity is important for host defense against this infection. The majority of antibodies are developed against the lipopolysaccharide of leptospires. These antibodies play a role in opsonization and activation of the complement pathway.¹⁴ We hypothesize that our patient may have had persistent live spirochetes in his CSF, blood, and urine because of his immunocompromised state. He had previously received rituximab, which is an anti-CD20 monoclonal antibody that depletes B lymphocytes for many months after each dose. Our patient had lymphocytopenia and hypogammaglobulinemia, which are well-described effects of rituximab and may have increased his risk of persistent infection, as evidenced in part by his lack of Leptospira IgM formation.¹⁵ An alternative explanation could be that leptospiral DNA detection reflected dead leptospires and that the meningitis was primarily immune-mediated; however, we feel this is less likely.

In conclusion, we report a relapsing form of leptospirosis with central nervous system and respiratory involvement and recurrent septic shock in an immunocompromised patient. Given our experience and other case reports, hypogammaglobulinemic patients may be at increased risk of persistent or more severe leptospirosis despite treatment with appropriate antibiotics, although further research is required to investigate the importance of humoral immunity in host defense against leptospirosis. Clinicians caring for patients with leptospirosis who are immunocompromised should bear this in mind when formulating a treatment plan and assessing response; in addition, longer term antibiotics may need to be considered for selected patients. In this case, longer term doxycycline was chosen. Long-term doxycycline use is generally well tolerated but could be associated with adverse effects such as photosensitivity or the development of resistant bacteria.¹⁶ Further research is needed to determine the best approach in managing leptospirosis in this patient population.