Fulminant Neisseria septicemia with secondary hemophagocytic lymphohistiocytosis

INTRODUCTION

Neisseria meningitidis is a Gram-negative encapsulated diplococcus responsible for invasive meningococcal disease, which manifests as meningitis or septicemia. Globally, it accounts for approximately 1.2 million cases annually, with a mortality rate of up to 15% despite treatment.^[1] Fulminant meningococcal septicemia is a severe form characterized by disseminated intravascular coagulation, multi-organ dysfunction syndrome, and purpuric rash.^[2] Secondary hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome triggered by infections, with N. meningitidis rarely implicated. HLH is marked by excessive activation of immune cells leading to cytokine storm, hemophagocytosis, and multi-organ failure. Early recognition and treatment are critical, as mortality exceeds 50% if left untreated.^[3] This report discusses a unique case of fulminant N. meningitidis septicemia complicated by HLH in a young soldier, emphasizing diagnostic challenges and therapeutic strategies.

CASE REPORT

Clinical history

A 26-year-old male soldier stationed in a remote hilly region presented with:

• Day 1–2: High-grade fever

• Day 3–4: Migratory inflammatory arthritis involving large joints

• Day 5: Non-blanchable petechial lesions over the lower limbs.

He subsequently developed worsening fatigue and dyspnea on exertion. On arrival at the tertiary center, he reported progressive respiratory distress. His significant examination findings at the time of presentation included:

1. Respiratory System: Increased work of breathing, bilateral fine crackles in the infrascapular areas

2. Cardiovascular System: Grade 3 pansystolic murmur in the mitral area

3. Dermatologic Findings: Non-blanchable petechial rash on the lower limbs [Figure 1] that generalized over time with Janeway lesions on the palms [Figure 2].

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Figure 1:

Non-blanchable petechial rash on the lower limbs.

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Figure 2:

Janeway lesions on the palms.

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Laboratory parameters showed anemia, polymorphic leukocytosis, thrombocytopenia, elevated alanine aminotransferase and aspartate transaminase (>3× upper limit of normal), hyperferritinemia (2,100 ng/mL), and high prolactin and hypertriglyceridemia (345 mg/dL). A bacterial septicemia diagnosis was made and was started on broad-spectrum antibiotics (ceftriaxone, vancomycin, doxycycline) along with oxygen support. Blood and urine cultures were collected before initiating antibiotics; however, the patient reported taking amoxicillin-clavulanate for 2 days before arrival, which may have influenced culture results. In view of elevated ferritin levels and triglyceride levels, splenomegaly and with a normal coagulation profile, HLH was suspected. Bone marrow aspiration histology showed evidence of hemophagocytes, confirming the diagnosis of HLH [Figure 3] as per HLH-2004 criteria. Transthoracic echocardiography (TTE) revealed moderate mitral regurgitation, however, had no vegetation in any of the valves; however, the absence of vegetation does not rule out the diagnosis of IE. Chest imaging indicated bilateral pulmonary edema secondary to acute mitral regurgitation (MR). Although blood and urine cultures were sterile, bone marrow culture confirmed the presence of N. meningitidis [Figure 4]. Intravenous immunoglobulin (IVIG) at dosing 2 grams/kilogram body weight divided into 5 days was started along with dexamethasone and was continued on culture-sensitive antibiotics. Oxygen requirements reduced drastically within 48 hours, pulmonary edema secondary to acute left ventricle failure due to MR resolved, and the patient became afebrile by day 3 of IVIG therapy. Rash regressed, and organ function normalized. The patient was discharged in a stable condition after 10 days, with complete resolution of symptoms, and steroids were slowly tapered on subsequent follow-up.

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Figure 3:

Bone marrow aspiration histology showed evidence of hemophagocytes (red arrow).

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Figure 4:

Bone marrow culture showed growth of Neisseria meningitidis on chocolate agar medium.

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DISCUSSION

While fulminant N. meningitidis septicemia is a recognized clinical entity, its progression to secondary HLH is very rare. Most cases of HLH are triggered by viral infections, with bacterial causes accounting for <10% of cases.^[4] Invasive N. meningitidis infections typically present as meningitis or septicemia, with skin manifestations such as petechial or purpuric rash in 50–75% of cases.^[5] The addition of HLH and vasculitic lesions, as observed here, represents an unusual and severe presentation. This case highlights the challenges in early identification of sepsis and its progression to secondary HLH. Bone marrow biopsy played a crucial role in confirming HLH. Moreover, sterile blood cultures due to prior antibiotic therapy necessitated reliance on bone marrow culture for identifying N. meningitidis.^[6] Secondary HLH results from excessive immune activation triggered by infections. The hallmark is hemophagocytosis, driven by the release of cytokines such as tumor necrosis factor-alpha and interleukin-6, which perpetuate the hyperinflammatory state.^[7] In this case, the endotoxin-mediated systemic inflammation of N. meningitidis likely initiated the HLH cascade. The global incidence of invasive meningococcal disease is estimated at 1.2 million cases annually, with a mortality rate of 10–15% despite treatment. Vaccination has reduced the disease burden, but vaccine escape strains remain a concern.^[8] The prognosis of meningococcal septicemia improved significantly with early administration of antibiotics and early immunomodulatory therapy in HLH reduces mortality by 50%.^[9] In this patient, rickettsial illness was suspected initially with a history of fever, cytopenias, and a history of living in hilly terrain areas, in view of the same doxycycline was started as part of broad-spectrum empirical antibiotic therapy. Acute left ventricular failure was secondary to MR, MR in this case could be secondary to septicemia leading to myocardial dysfunction and subsequently valvular dysfunction^[10] or due to infective endocarditis (IE) which was not visible on TTE. IE was suspected in view of the new development of cardiac murmur along with Janeway lesions which is a characteristic of septic emboli; however, demonstration of vegetation on valves is key for diagnosing the same along with positive blood culture. The absence of vegetation on TTE cannot totally rule out the diagnosis of IE, transesophageal echocardiography (TEE) is required in highly suspicious cases.^[11] Due to the unavailability of TEE, despite sterile serial blood cultures and no vegetation on TTE in view of high clinical suspicion of IE (septic emboli and MR) empirical antibiotics (Ceftriaxone and Vancomycin) were started in this patient. HLH was diagnosed as per HLH 2004 protocol guidelines. IVIg being the standard care of treatment, steroids were also started in this case in view of rapid progression to multiorgan involvement.^[12] The combination therapy along with early identification of HLH led to a remarkable recovery in this case.

CONCLUSION

This case underscores the critical importance of recognizing atypical complications of common infections. Fulminant N. meningitidis septicemia with HLH represents a life-threatening but treatable condition when diagnosed promptly. Clinicians should maintain a high index of suspicion for HLH in cases of severe sepsis with unexplained hyperinflammation, and bone marrow evaluation should be considered in ambiguous cases.