Survival Against the Odds—Hemophagocytic Lymphohistiocytosis Amidst the Shadows of Disseminated Histoplasmosis: A Case Report and Literature Review

Abstract

Hemophagocytic lymphohistiocytosis (HLH) secondary to Histoplasma capsulatum is rare, impacting <1% globally, with a mortality rate of up to 31%. Herein, we present a rare case of HLH secondary to H capsulatum, affecting a 57-year-old female with rheumatoid arthritis. Extensive investigations were unrevealing and despite broad-spectrum antibiotics, her condition worsened, leading to respiratory failure requiring extracorporeal membrane oxygenation (ECMO) support, shock requiring multiple vasopressors, and acute kidney injury (AKI) requiring hemodialysis. Diagnosis confirmed disseminated histoplasmosis (DHP), prompting Amphotericin B and methylprednisolone treatment, resulting in significant improvement and discharge with posaconazole therapy. Secondary HLH, primarily arising from severe infections like DHP, is discussed. Limited research exists on this condition in human immunodeficiency virus (HIV)-seronegative individuals. Diagnosis involves HLH-2004 and HScore criteria. Managing histoplasmosis-associated HLH remains challenging due to multiorgan failure risks and treatment complexities and needs further research.

Introduction

Hemophagocytic lymphohistiocytosis (HLH) secondary to Histoplasma capsulatum infection is an exceedingly rare disorder with mortality rates reaching as high as 31%.^1-3 Although cases in patients with human immunodeficiency virus (HIV) infection have been well-documented, there is limited research on this condition in HIV-seronegative individuals. ⁴ The available literature reports approximately 26 cases of secondary HLH in the context of disseminated histoplasmosis (DHP), predominantly affecting immunocompromised individuals. ⁵

Disseminated histoplasmosis can be triggered by various factors, including tumor necrosis factor (TNF)-α inhibitors, albeit at a relatively low incidence of around 1 to 2 cases per 10 000 in patients on these medications. ⁶ Untreated DHP, per se, carries a 100% mortality rate, whereas even with treatment, it is estimated to result in a mortality rate of 30% to 50%. Despite the availability of effective therapeutic options, the mortality rate for histoplasmosis can still exceed 20%.^6,7

This case emphasizes the development of DHP complicated by HLH in a patient receiving TNF-α inhibitors. It features the importance of considering histoplasmosis as a potential complication in individuals with a history of exposure to regions where this fungal infection is prevalent, especially when they present with unexplained fever.

Case Presentation

This complex clinical case involves a 57-year-old female patient with a history of rheumatoid arthritis who had been treated with methotrexate and tofacitinib therapy. Subsequently, she was prescribed golimumab, a TNF-α inhibitor, which coincided with the onset of her medical issues. The patient tested negative for tuberculosis and viral hepatitis before initiating golimumab.

The patient was admitted due to unresolved fever, reaching 39.4°C, and fatigue. Her vital signs were initially stable, apart from heart rate (HR) 110 bpm. She also had pallor and splenomegaly on examination.

Initial tests showed a white blood cell (WBC) 2.5 × 10⁹/L, hemoglobin (HbG) 8.6 g/dL, platelet count 131 × 10⁹/L, aspartate aminotransferase (AST) 505 U/L, alanine aminotransferase (ALT) 333 U/L, alkaline phosphatase (ALP) 439 U/L, total bilirubin 9.5 mg/dL, ferritin 2411 mg/dL (normal level: 10-120 ng/mL), and triglycerides 398 mg/dL. Initial computed tomography of the chest (Figure 1) and abdomen revealed diffuse ground-glass opacities, newly identified pulmonary nodules, fatty liver, and splenomegaly measuring 14.6 cm.

Figure 1.

Axial CT of the chest showing bilateral ground-glass opacities, more on the left side.

The patient’s condition deteriorated significantly, with a development of severe bilateral consolidation (Figure 2), and her clinical course was complicated by acute hypoxemic respiratory failure, necessitating intubation and the subsequent development of acute respiratory distress syndrome (ARDS). In addition, she developed circulatory shock requiring 3 pressors. Furthermore, her condition was complicated by acute kidney injury (AKI), which necessitated renal replacement therapy. Hepatic impairment worsened with AST jumping up to 6732 u/L and ALT to 1160 u/L. Although WBC remained relatively stable at 2.5 × 10⁹/L, the hemoglobin levels decreased to 6.6 g/dL and platelets to 29 × 10⁹/L. During this time, the antibiotics spectrum was broadened to include vancomycin and piperacillin-tazobactam.

Figure 2.

Axial CT of the chest showing bilateral upper lobe consolidation.

The combination of multiorgan failure not responding to antibiotics, pancytopenia, and markedly elevated ferritin levels led to a narrowed differential diagnosis, including septic shock of non-bacterial origin and HLH. Subsequent evaluation revealed Triglycerides 398 mg/dL (normal level: less than 150 mg/dL) and fibrinogen 58 mg/dL (normal level: 200-400 mg/dL). The patient was diagnosed with HLH based on the HLH-2004 criteria (fever, splenomegaly confirmed on CT, anemia, thrombocytopenia, hypertriglyceridemia, hypofibrinogenemia, and markedly elevated ferritin levels) and an HScore of 267 points, indicating a probability of HLH of over 99%.

To determine the triggering cause of HLH, we conducted tests for hepatitis B surface (HBs) antigen, anti-hepatitis C virus (HCV) antibodies, and anti-HIV antibodies, all of which returned negative results. Screening for SARS-CoV-2 and tuberculosis also yielded negative findings. Investigations for other viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), and parvovirus B19 also came back negative. Cerebrospinal fluid studies were not performed due to the patient’s normal neurological status. In addition, the autoimmune workup was negative.

Surprisingly, urinary Histoplasma antigen was detected at a level of 15 ng/mL (normal <0.5 ng/mL). Based on these clinical and laboratory findings, the diagnosis of HLH secondary to DHP was the most likely.

Therapy with Amphotericin B at a dose of 5 mg/kg was initiated in addition to the introduction of methylprednisolone therapy to manage HLH. The respiratory condition continued to worsen, and she eventually required extracorporeal membrane oxygenation (ECMO) support. Of note, fungal blood cultures came back positive for H Capsulatum after 4 weeks which supported the diagnosis of DHP.

Following a 30-day course of Amphotericin B therapy, the patient’s treatment transitioned to itraconazole. However, therapeutic levels (1.0-2.0 mcg/mL) could not be achieved, which led to the initiation of posaconazole therapy, planned for a 12-month duration. Ultimately, she was discharged safely.

As her treatment progressed, her symptoms resolved completely, the urine Histoplasma antigen test showed negligible results and all laboratory abnormalities normalized. Subsequently, she continued posaconazole treatment and remained off biological agents.

Discussion

Hemophagocytic lymphohistiocytosis is a rare, severe hyperinflammatory syndrome characterized by an overactive yet ineffective immune response, leading to systemic inflammation, multiorgan failure, and high mortality rate. ⁸ Although more frequently diagnosed in infants, HLH can also affect adults, with a higher incidence in elderly males. ⁵ It is often characterized into primary or secondary form. Primary HLH arises from inherited genetic mutations and is typical in early infancy, whereas secondary HLH is often triggered by infections, autoimmune diseases, immune deficiencies, immunosuppression, or cancers. However, classifying HLH into primary and secondary forms may limit recognition, as it is influenced by a combination of genetic and environmental factors. ⁸

Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis

Histoplasmosis-associated hemophagocytic lymphohistiocytosis (HA-HLH) cases were primarily linked to disseminated histoplasmosis. ¹ Disseminated histoplasmosis is a severe condition but is typically treatable with antifungal medication. However, patients with both DHP and HLH face a graver prognosis. In a retrospective study of 11 such cases, 45% died within 30 days, and 63% within 90 days, ⁹ emphasizing the urgency for accurate and timely diagnosis for effective intervention.

Histoplasmosis-associated hemophagocytic lymphohistiocytosis is historically reported in patients with HIV, hematologic malignancies, and transplant recipients undergoing immunosuppressive therapy. Growing numbers of non-HIV patients, such as organ transplant recipients, chemotherapy patients, and those receiving immunosuppressive treatments, have contributed to the rising incidence of HLH. A subset of patients had no clearly identified underlying immunodeficiency. In HIV-seronegative patients, a literature review revealed that 15.6% of cases had rheumatic diseases, and 33.6% received immunosuppressive therapies, including TNF inhibitors, steroids, and chemotherapy.^1,4

There are growing concerns for progressive disseminated disease in individuals treated with biologics, particularly TNF-α inhibitors.^6,10 To our knowledge, there is only 1 reported case of HA-HLH associated with Golimumab, a TNF-α inhibitor. ⁴ Herein, we report another case of HA-HLH secondary to golimumab. A previous review of patients diagnosed with histoplasmosis while on TNF-α inhibitors revealed that most of them were receiving additional immunosuppressive agents, and 89% had disseminated illness. ¹¹

Diagnosis of Hemophagocytic lymphohistiocytosis

Diagnosing HLH is complicated due to clinical overlap with other conditions. Diagnostic steps involve blood and fungal cultures, imaging, cerebrospinal fluid analysis, and bone marrow assessment, with particular emphasis on urine antigen testing for histoplasmosis. The diagnostic criteria for HLH used in the HLH-2004 are shown in Table 1. The ferritin levels can be viewed with concern for HLH at >500 ng/mL, with levels ≥3000 ng/mL as concerning, and levels ≥10 000 as highly suspicious in pediatric patients. ¹²

Table 1.

HLH-2004 Diagnostic Criteria.

The diagnosis of HLH can be confirmed if criterion 1 or 2 is fulfilled
1	A molecular diagnosis consistent with HLH with the identification of specific pathologic mutations in particular genes
2	Diagnostic criteria for HLH fulfilled (5 of the 8 below)
	a	Fever ≥38.5°C
	b	Splenomegaly
	c	Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood), hemoglobin <9 g/dL, platelets <100 000/cm3, neutrophils <1000/cm3
	d	Hypertriglyceridemia and/or hypofibrinogenemia; fasting triglycerides ≥265 mg/dL, fibrinogen ≤150 mg/dL
	e	Hemophagocytosis in bone marrow or spleen or lymph nodes; no evidence of malignancy
	f	Low or no NK cell activity
	g	Ferritin ≥500 ng/mL
	h	sCD25 (soluble IL-2 receptor) ≥2400 U/mL

Abbreviations: HLH, hemophagocytic lymphohistiocytosis; NK cells, natural killer cells; sCD25, soluble CD25; IL, interleukins.

Although the HLH-2004 criteria are useful for initial clinical suspicion and disease monitoring, they might lack sensitivity for secondary HLH and other inflammatory disorders. ¹² An HScore for adults, using clinical, biochemical, and cytological factors, offers a strong sensitivity (90%) and specificity (79%) in identifying secondary HLH.^1,8 In a validation study, a threshold HScore of 169 was found to offer a high diagnostic sensitivity of 93% and a substantial diagnostic specificity of 86% for acquired HLH in adults. ³ Our patient has an HScore of 267 points, indicating a probability of HLH of over 99%.

It is essential to perform blood cultures to identify any potential infectious causes, and imaging studies can be useful when an underlying malignancy is suspected. Cerebrospinal fluid analysis is abnormal in approximately 50% of cases, characterized by pleocytosis, elevated protein levels, or the presence of hemophagocytic cells. ¹² Quantitative flow cytometric findings in HLH often reveal altered cell populations, particularly in EBV-related cases. Hemophagocytosis, a characteristic feature of HLH, involves macrophages engulfing various blood cell types. Hemophagocytosis is not specific or necessary for an HLH diagnosis if other criteria are met. Bone marrow assessment is vital for ruling out other conditions, and special stains can aid in identifying microorganisms in suspected infections. ¹²

Disseminated Histoplasmosis

To identify DHP as the cause of HA-HLH, the isolation of H capsulatum through culture or histopathology is necessary. Diagnostic methods include antigen detection, serological testing, and molecular testing. In patients receiving anti-TNF-α therapy, the sensitivity of this diagnostic approach has been reported to be as high as 100%. Antibodies are most useful for subacute or chronic cases, appearing 4 to 8 weeks after infection, with varying sensitivity based on the patient’s immunosuppressive state. Molecular testing can be valuable, thanks to its high sensitivity and specificity, although its precise role is still evolving.^2,13 The frequent co-occurrence of histoplasmosis with other opportunistic infections, especially tuberculosis, highlights the importance of ruling out tuberculosis even when a diagnosis of histoplasmosis is made. ¹⁴

Treatment of Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis

Histoplasmosis-associated hemophagocytic lymphohistiocytosis lacks established treatment guidelines. A case series indicated a slightly lower-case fatality rate with a lipid formulation of Amphotericin B. The efficacy of adding etoposide and steroids remains uncertain, but a regimen with these medications showed a survival rate of 4 out of 5 patients. ¹ An HIV patient’s favorable outcome resulted from treating underlying infections without immunochemotherapy. ¹² Mortality rates varied across treatments: 25.0% with Amphotericin B, 20% with steroids and etoposide, 62% with intravenous immunoglobulin (IVIG), and 31% with steroids. ¹

Mild cases of histoplasmosis often respond to itraconazole alone. Severe disseminated histoplasmosis requires initial therapy with liposomal Amphotericin B for 1 to 2 weeks, followed by itraconazole for 12 months.^6,10,13 Choice of antifungal depends on various factors, such as patient tolerance and central nervous system involvement. ⁶

In a case series of HA-HLH, patients who received Amphotericin B had a slightly lower-case fatality rate. The impact of adding etoposide and steroids remains uncertain, but a regimen with these medications showed a survival rate of 4 out of 5 patients. It is advisable to promptly start a lipid formulation of Amphotericin B per Infectious Diseases Society of America (IDSA) guidelines for moderate to severe disseminated histoplasmosis. Nevertheless, there is still insufficient data to establish an optimal treatment protocol and the role of immunosuppressive therapy and IVIG in HA-HLH. ¹ A case report of HLH in an HIV patient with disseminated histoplasmosis, Mycobacterium avium complex, and Escherichia coli bacteremia had a favorable outcome through the treatment of underlying infections, without immunochemotherapy. ¹² The mortality rate was 25.0% in patients who received Amphotericin B, 20% in patients who received steroids and etoposide with or without cyclosporine (all received Amphotericin B), 62% in patients who received IVIG, and 31% in patients who received steroids. One patient received Anakinra and IVIG and survived. ¹

Prophylaxis

When initiating immunosuppressive therapy, antifungal prophylaxis is recommended for individuals with a recent history of active histoplasmosis. In such cases, the IDSA guidelines recommend prophylaxis with itraconazole before initiating therapy with a new immunosuppressive agent, like a TNF-α inhibitor. Hage et al suggest using itraconazole for 3 months before starting a TNF-α blocker, with continuation for at least 1 year after therapy initiation. In a group of 1500 patients who received immunosuppressive therapy for solid organ or bone marrow transplantation, histoplasmosis did not occur during a 16-month follow-up period. Additional precautions when initiating TNF-α inhibitor therapy depend on histoplasmosis history. In recent cases, these precautions include a chest radiograph, 3-month itraconazole prophylaxis, and considering therapy discontinuation if active histoplasmosis is detected. For remote cases, regular monitoring of urinary histoplasma antigen levels, symptom observation, and, if needed, additional diagnostics or empiric antifungal treatment for high antigen levels are recommended. ¹¹

Resuming Biologic Treatment After Histoplasmosis

The safety of resuming biologic agents after histoplasmosis treatment remains unclear, and caution is advised due to the risk of relapse in immunosuppressed patients. A case series suggested low relapse rates when TNF-α inhibitors were resumed after histoplasmosis treatment, primarily with continued itraconazole therapy. ¹⁵ Studies suggest a low overall survival, particularly for malignancy-associated HLH, with some cases of remission in secondary HLH after treating the underlying disease. ¹² The inpatient case fatality rate varies, with 31% overall and higher rates among HIV patients. ¹ Out of 21 patients with available death data, 10 patients died within 2 weeks of admission, and 4 patients passed away between hospital days 16 and 44. ¹

Conclusion

Histoplasmosis-associated hemophagocytic lymphohistiocytosis in adults is rare but life-threatening condition characterized by excessive, yet ineffective immune activation. Considering disseminated histoplasmosis with secondary HLH in TNF-α inhibitor patients with unexplained fever, particularly if they recently traveled to endemic regions, is crucial. The best HLH treatment regimen remains uncertain. Multicenter studies are needed to establish the best use of immunosuppressive therapy in this setting, refine treatment outcomes, enhance survival rates, and validate current diagnostic criteria.