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Disseminated infection to immune activation.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by a febrile illness associated with multiorgan involvement. (1) HLH is generally associated with a genetic mutation, immunodeficiency syndromes, or immunodeficiency triggers including malignancy, rheumatologic disorders, or infections. (1,2) A rare but serious trigger of HLH is disseminated histoplasmosis, which can be as difficult to diagnose as HLH itself. (3) We present a case of a woman with a history of long-term immunosuppression who developed HLH secondary to disseminated histoplasmosis.


A 61-year-old woman with rheumatoid arthritis on infliximab presented with fever and cough, for which a course of levofloxacin was completed. Symptoms persisted 1 month later, and the patient developed painless jaundice, prompting return to the hospital. On admission, she was febrile with a temperature of 39[degrees]C and tachycardic with a heart rate of 111 beats per minute. On physical examination, scleral icterus was present, her skin was jaundiced, and enlargement of the liver was noted. Computed tomography of the abdomen revealed hepatosplenomegaly, and computed tomography of the thorax demonstrated bilateral perihilar ground-glass opacities. Hepatitis A, B, and C serology was negative. A respiratory panel was positive for metapneumovirus. Broad-spectrum antibiotics were started with vancomycin and piperacillin/tazobactam, but all cultures remained negative for the first week of hospitalization. The patient developed worsening cytopenias throughout her hospitalization, with a low fibrinogen level of 82 mg/dL and elevated triglyceride level of 453 mg/dL. Ferritin was initially elevated and serial levels showed an upward trend to >20,000 ng/mL.

The hematology service was consulted on day 7 of hospitalization. A bone marrow biopsy demonstrated a hypercellular bone marrow with reactive changes and increased histiocytes with hemophagocytosis. The patient met diagnostic criteria for HLH, including fever, splenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis in bone marrow, and elevated ferritin. She was started on high-dose steroids and etoposide. Two days later, results from the fungal blood cultures were reported positive for histoplasmosis. She was started on liposomal amphotericin B treatment in addition to immunosuppressants. After 2 days of concurrent therapy, it was decided to discontinue etoposide and aggressively treat the histoplasmosis with antifungal therapy only. Over the course of the next 2 weeks, the patient clinically improved and was discharged from the hospital. She is doing well and remains on antifungal treatment with itraconazole for a planned duration of 1 year.


HLH is a rare clinical syndrome characterized by activation of the mononuclear phagocytic system. (1) The course of HLH is characterized by uncontrolled macrophage activity leading to increased secretion of cytokines causing a cytokine storm, resulting in tissue damage and organ failure. (1,4) According to the HLH-2004 diagnostic and therapeutic guidelines for HLH, the diagnosis is made by the presence of five of the following eight criteria: fever, splenomegaly, cytopenia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis, low natural killer cell activity, elevated ferritin, and elevated soluble interleukin-2 levels. (2)

Hemophagocytosis is identified as a diagnostic criterion for HLH, but it is not essential for diagnosis or specific to HLH. It is seen in many illnesses, including infectious processes and bone marrow disorders. (1) It should also be noted that hemophagocytosis develops in a more advanced stage of the process and thus may not be present on bone marrow pathology early in the disease. (5) Ultimately, however, a bone marrow biopsy should be performed to search for an underlying malignancy, (5) because these patients typically have higher associated mortality. (1)

The estimated median survival in patients with HLH is <2 months if left untreated. (1) Certain prognostic factors can predict a patient's morbidity and mortality risk. Those patients with malignancy-associated HLH typically have worse survival outcomes. (1,4) Other adverse prognostic factors include age >30, thrombocytopenia, male sex, low albumin, and lack of etoposide therapy. (4)

The most common etiology of HLH is infection, comprising about 40% of cases, with other etiologies including malignancies, autoimmune disorders, primary immunodeficiency, and solid organ transplantation. (1) There are reported cases of HLH in patients taking infliximab (6) as well as other tumor necrosis factor inhibitors. (7,8) However, it is unclear whether these cases are related to the agent or to infection caused by the agent's immunosuppressive effects. (6) There are reported cases of success in treating patients with refractory HLH with infliximab, (9) so it is likely that both scenarios are plausible.

Our patient had a history of rheumatoid arthritis that had been treated with infliximab for over a year and was thus immunocompromised. The possible etiology of HLH in this patient included opportunistic infections given the patient's immunocompromised state, infliximab use itself, or the patient's underlying rheumatologic condition. When fungal blood cultures grew histoplasmosis, it was determined that the patient likely acquired HLH due to disseminated histoplasmosis, which was secondary to her immunocompromised state in the setting of long-term infliximab use.

The diagnosis of histoplasmosis can often be delayed, because it is typically slow growing on fungal cultures. In our case, histoplasmosis was not reported on fungal blood cultures until day 9 of hospitalization. In addition, clinical suspicion for histoplasmosis can be delayed, because many symptoms of disseminated fungal infection and HLH overlap, including fever, hepatosplenomegaly, pancytopenia, and coagulopathy. (3)

Our patient was initially treated according to HLH-2004 guidelines with etoposide and high-dose steroids. However, once disseminated histoplasmosis was identified, these immunosuppressive and chemotherapeutic agents were discontinued and the patient was started on antifungal treatment, to which she responded well.

It is important for clinicians to identify the constellation of symptoms of HLH to avoid a delay in diagnosis and to look for the likely underlying cause in order to successfully treat patients with HLH. The syndrome is likely underdiagnosed and, due to the variety of treatment options, treatment of HLH, especially in immunocompromised patients, is complicated. Further data are needed to determine the role of these immunosuppressive agents in the treatment of immunocompromised patients with Histoplasma-induced HLH. (10)


Jill Yeager (iD)

(1.) Otrock ZK, Eby C. Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 2015; 90:220-224. doi:10.1002/ajh.23911. PMID:25469675.

(2.) Henter JI, Horne AC, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007; 48:124-131. doi:10.1002/pbc.21039. PMID:16937360.

(3.) Ferguson-Paul K, Mangum S, Porter A, Leventaki V, Campbell P, Wolf J. Hemophagocytic lymphohistiocytosis and progressive disseminated histoplasmosis. Emerg Infect Dis. 2016; 22:1119-1121. doi:10.3201/eid2206.151682. PMID:27191972.

(4.) Hayden A, Park S, Giustini D, Lee AYY, Chen LYC. Hemophagocytic syndromes including hemophagocytic lymphohistiocytosis (HLH) in adults: a systematic scoping review. Blood Rev. 2016; 30:411-420. doi:10.1016/j.blre.2016.05.001. PMID:27238576.

(5.) Machowicz R, Janka G, Wiktor-Jedrzejczak W. Your critical care patient may have HLH (hemophagocytic lymphohistiocytosis). Crit Care. 2016; 20:215-216. doi:10.1186/s13054-016-1369-3. PMID:27389585.

(6.) Oda Y, Urushidani Y, Ooi S, et al. Hemophagocytic lymphohistiocy tosis in a rheumatoid arthritis patient treated with infliximab. Intern Med. 2012; 51:655-657. doi:10.2169/internalmedicine.51.5687. PMID:22449679.

(7.) Ramanan AV, Schneider R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2003; 30:401^03. PMID:12563702.

(8.) Stern A, Riley R, Buckley L. Worsening of macrophage activation syndrome in a patient with adult onset Still's disease after initiation of etanercept therapy. J Clin Rheumatol. 2001; 7:252-256. doi:10.1097/00124743-200108000-00013. PMID:17039144.

(9.) Henzan T, Nagafuji K, Tsukamoto H, et al. Success with infliximab in treating refractory hemophagocytic lymphohistiocytosis. Am J Hematol. 2006; 81:59-61. doi:10.1002/ajh.20462. PMID:16369976.

(10.) Townsend JL, Shanbhag S, Hancock J, Bowman K, Nijhawan A. Histoplasmosis-induced hemophagocytic syndrome: a case series and review of the literature. Open Forum Infect Dis. 2015; 2:ofv055. doi:10.1093.ofid/ofv055. PMID:26380347.

Jill Yeager, DO, and Barbara Krenzer, MD

Department of Internal Medicine, State University of New York Upstate Medical University, Syracuse, New York

Corresponding author: Jill Yeager, DO, 4 Morningside Drive, Cortland, NY 13045 (e-mail:

Received March 11, 2018; Revised April 9, 2018; Accepted April 12, 2018.
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Author:Yeager, Jill; Krenzer, Barbara
Publication:Baylor University Medical Center Proceedings
Article Type:Clinical report
Date:Jul 1, 2018
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