Canadian Journal of Infectious Diseases and Medical Microbiology

Canadian Journal of Infectious Diseases and Medical Microbiology / 2019 / Article

Review Article | Open Access

Volume 2019 |Article ID 7107326 |

Ra’ed Jabr, Wissam El Atrouni, Heather J. Male, Kassem A. Hammoud, "Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis: A Review of the Literature", Canadian Journal of Infectious Diseases and Medical Microbiology, vol. 2019, Article ID 7107326, 8 pages, 2019.

Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis: A Review of the Literature

Academic Editor: Sandra Gemma
Received20 Jun 2019
Accepted30 Aug 2019
Published01 Oct 2019


Background. Histoplasmosis is an endemic fungal disease with diverse clinical presentations. Histoplasmosis-associated hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with limited data regarding treatment and outcome. We described the clinical features, treatment, and outcomes of five patients in our institution with histoplasmosis-associated HLH. This review also summarizes the current literature about presentation, treatment, and outcome of this infection-related HLH entity. Methods. We searched the electronic medical records for patients with histoplasmosis-associated HLH at our institution from 1/1/2006 to 9/30/2017. Diagnosis of HLH was confirmed by chart review using the HLH-04 criteria. We also searched the current literature for case reports and case series. Results. Five cases of histoplasmosis-associated HLH were included from our institution. All five patients were diagnosed after 2010. The literature review yielded 60 additional cases of histoplasmosis-associated HLH. The most common underlying condition was HIV in 61% of cases. The majority of histoplasmosis patients (81%) were treated with amphotericin B formulations. Documented specific treatments for HLH were as follows: nine patients received steroids only, six patients received intravenous immunoglobulin (IVIG) only, three patients received dexamethasone and etoposide, two patients received etoposide, dexamethasone, and cyclosporine, two patients received steroids and IVIG, and one patient received Anakinra and IVIG. The inpatient case fatality rate was 31% with most of the deaths occurring within two weeks of hospital admission. Conclusions. Histoplasmosis-associated HLH among adults is an uncommon but serious complication with high associated mortality. Early antifungal therapy with a lipid formulation amphotericin B is critical. The initiation of immunosuppressive therapy with regimens like HLH-04 in this disease entity should be individualized.

1. Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a rare but often life-threatening syndrome of excessive immune activation. Primary HLH is triggered by genetic disorders and usually manifests in children below the age of 18 months. The term secondary (acquired) HLH has generally been used to describe cases in adults without known genetic predisposition and a clear trigger for HLH. This trigger is often an infection or an alteration in immune homeostasis (e.g., malignancy, rheumatologic conditions, or immunodeficiency syndromes) [1]. HLH may present as a single episode of disease or recurrent episodes. Histoplasmosis-associated HLH is a relatively rare disorder with limited data about treatment [2, 3]. We describe the clinical features, treatment, and outcomes of cases seen at the University of Kansas Medical Center (KUMC). In addition, we reviewed the current literature about diagnosis and treatment of histoplasmosis-associated HLH.

2. Methods

We searched our medical informatics HERON (Healthcare Enterprise Repository for Ontological Narration) database for the following ICD9/ICD10 terms: “hemophagocytic syndrome,” “hemophagocytosis,” “hemophagocytic lymphohistiocytosis” or “macrophage activation syndrome” and “histoplasmosis” or “disseminated histoplasmosis.” We included patients older than 18 years and seen at our institution from 1/1/2006 to 9/30/2017. All patients who satisfied the HLH-04 criteria [4] for a diagnosis of HLH (i.e., 5 of 8 criteria) and confirmed to have histoplasmosis by retrospective chart review were included. HLH-04 criteria include (1) fever; (2) splenomegaly; (3) cytopenia in two or more cell lines; (4) hypertriglyceridemia (triglyceride level ≥265 mg/dL or hypofibrinogenemia (fibrinogen level ≤150 mg/dL); [5] hemophagocytosis in the bone marrow, spleen, or lymph nodes; [6] hyperferritinemia (ferritin level ≥500 ng/mL); [7] impaired NK cell function; and [8] elevated soluble CD25 (soluble IL-2 receptor alpha) two standard deviations above age-adjusted laboratory-specific norms. This study was approved by the University of Kansas Medical Center institutional board review.

3. Literature Review

We searched PubMed for “histoplasmosis” and “hemophagocytic syndrome,” “histoplasmosis” and “secondary hemophagocytic syndrome,” “histoplasmosis induced hemophagocytic syndrome,” “disseminated histoplasmosis” and “hemophagocytic syndrome,” “HLH” and “histoplasmosis,” and “histoplasma associated HLH.” Few papers were only available by a Google search. We included all case reports/series with a published abstract in English.

4. Results

We identified five cases of histoplasmosis-associated HLH. The clinical characteristics are summarized in Table 1. All patients had disseminated histoplasmosis and were immunosuppressed. Human immunodeficiency virus (HIV) infection was the underlying condition in 2/5 patients (40%); the diagnosis of HIV in both patients was new. The other three patients were on steroids in addition to other immunosuppressive agents. There was a male predominance 4/5 (80%). All patients 5/5 (100%) had positive blood cultures for histoplasma, and the histoplasma antigen (blood or urine) was above the limit of quantification. Histoplasma was seen on bone marrow (BM) biopsy in 3/4 (75%) patients.

Case #YearAgeGenderRaceComorbid conditionsImmunosuppressive agentYeast in BMUrine histoplasma AgSites growing histoplasmaCXR findings

1201148MWhiteHIV/CD4 count 50NoneYesAbove LoQBloodNo infiltrates
2201448FWhiteMCTDHCQ/prednisone 10 mg dailyNoAbove LoQBloodLAD without infiltrates
3201675MWhiteCrohn’sInfliximab/azathioprine/prednisoneYesN/A (serum Ag: above LoQ)Blood and BMNo infiltrates
4201746MAfrican AmericanSarcoidPrednisoneYesAbove LoQBlood and BMDiffuse infiltrate
5201741MWhiteHIV/CD4 count 10NoneN/AAbove LoQBloodDiffuse infiltrate

M: male; F: female; HIV: human immunodeficiency virus; MCTD: mixed connective tissue disease; N/A: not applicable, BM: bone marrow; dexa: dexamethasone; CXR: chest X-ray; Ag: antigen; LAD: lymphadenopathy; LoQ: limit of quantification; HCQ: hydroxychloroquine.

Four patients (80%) met at least 5 out of 8 criteria for the diagnosis of HLH as shown in Table 2. The IL2-receptor, cytopenia, and ferritin criteria were met in all five patients. Peak ferritin level was above the limit of quantification in 4/5 (80%) patients. One patient met only four criteria, but the hematology consulting team felt that it was highly likely secondary HLH.

Case #FeverCytopenia (2 lines)IL2-receptor (pg/mL)Peak triglycerides (mg/dL)BM with hemophagocytosisSplenomegalyPeak ferritin (ng/mL)Nadir fibrinogen (mg/dL)


The treatment and outcomes are shown in Table 3. Most patients were started on liposomal amphotericin B for at least 2 weeks and then transitioned to an oral azole. One patient received only voriconazole. Three out of five patients survived to hospital discharge.

Case #Antifungal drugHLH specific treatmentOutcome (hospital discharge)

1Liposomal amphotericin B for 2 weeks, then itraconazole for 12 monthsNoneSurvived
2Liposomal amphotericin B for 4 weeks, then oral azoles for 4 yearsDexamethasone 10 mg/m2 for 2 daysSurvived
3Voriconazole PO (discharged to hospice, patient preference)NoneDischarged to hospice
4Liposomal amphotericin B for 2 weeks then itraconazole for 4 monthsDexamethasone 10 mg/m2Survived
5Liposomal amphotericin B for 2 weeks then oral azolesNoneDied (day 43)

Notes. BM: bone marrow, IL: interleukin, N/A: not applicable.

The literature review yielded 60 cases from 39 papers; most of them were case reports and few were case series. Table 4 summarizes the patients baseline characteristics, treatment used, diagnostic tests for histoplasmosis, and outcomes. Five papers were published before 2000, and 18 papers were published since 2015. We report five patients at our institution from 1/1/2006 to 9/30/2017 (Table 1). All 5 cases at KUMC were diagnosed after 2010. Adding our five cases to the 60 reported previously, the median age of cases was 41 years and 72% (37/52) were men. The most common underlying immunosuppressive condition was HIV in 62% (36/58). Six patients had solid organ transplant, and there was no clear underlying immunodeficiency described in seven patients. In eleven patients, there was no mention of the host immune status.

AuthorYearCountryAge, genderUnderlying diseaseCD4TreatmentHistoplasma diagnosisOutcome

Majluf-Cruz et al. [5]1993Mexico37 y, MHIVNRFluconazoleLiver BxSurvived
49 y, MHIVNRAmphotericin BBM BxSurvived
36 y, MHIVNRNoneBM BxDied (N/A)

Keller and Kurtzberg [6]1994USA6 yChronic mucocutaneous candidiasisN/AAmphotericin BBM Cx/blood Cx/BAL CxSurvived

Koduri et al. [7]1995USANRNoneN/AAmphotericin B/solumedrolNRDied (NR)

Koduri et al. [8]1995USANRHIV36Amphotericin B/IVIG × 2dBlood smear/BM path and CxDied (NR)
HIV4Amphotericin B/IVIG × 2dBlood smear/BM path/BM Cx/CSF CxDied (HD 6)
HIV6Amphotericin B/IVIG × 2dBlood smear/BM path and CxDied (NR)
HIV22Amphotericin B/IVIG × 2dBM path and Cx/skin CxSurvived
HIV32Amphotericin BBM path and CxSurvived
HIV44Amphotericin BBM path and CxSurvived

Chemlal et al. [9]1997Africa50 yHIV34NRBlood Cx/BM and skin pathNR

Kumar et al. [10]2000India50 y, MNoneN/ANoneSplenic aspirate smearsDied (within 48 hours)

40 y, MHIVNRNoneLN BxDied (within 48 hours)

Rao et al. [1]2002USA68 y, MCLL on cyclophosphamide and fludarabineN/AAmphotericin BBM and lung Bx (path)Survived

Masri et al. [11]2003USA47 y, MHeart transplantN/ALiposomal amphotericin BBM (path and Cx)/peripheral smear/lung Bx (path and Cx)Survived

Gil-Brusola et al. [12]2007Ecuador33 y, MHIV/disseminated TB39NoneBlood smear/BM pathDied (HD 18)

Guiot et al. [13]2007Puerto Rico43 y, MHIV/ileal perforation66Liposomal amphotericin B for 21 days/itraconazoleGI (path)/BAL (cytology)/BM path and Cx, histoplasma PCRSurvived

Sanchez et al. [14]2007USA61 y, MHIV/pulmonary TB4Amphotericin BBlood and BM (? Cx or path)Survived

Wang et al. [15]2007USA52 y, MHCV, CKDN/ANone (postmortem diagnosis)Autopsy diagnosis/postmortem blood and spleen CxDied (HD 12)

Phillips et al. [16]2008USA69 y, MSarcoidosis on chronic steroidsN/AAmphotericin B/steroids/etoposide/cyclosporineBM path and Cx/blood smearSurvived

De Lavaissiere et al. [17]2009France33 y, MHIVNRAmphotericin B/itraconazole/ART/IVIGBlood and BM (Cx or path?)Survived

Lo et al. [18]2010USA22 y, FRenal transplantN/ALiposomal amphotericin for 2 weeks/itraconazoleBM path/Blood Cx/urine AgSurvived
USA18 y, MRenal transplantN/ALiposomal amphotericin B for 1 week/itraconazoleLN path/BM Cx/urine AgSurvived

van Koeveringe and Brouwer [19]2010Holland50 y, MCLL-alemtuzumab/fludarabine/cyclophosphamideN/ADexamethasone/cyclosporine/etoposide/amphotericin BBM path confirmed by PCR and cultureSurvived

Vaid and Patel [20]2011UK25 y, MHIV153AntifungalSkin/BM/oral mucosa pathDied (NR)

Chandra et al. [21]2012India38 y, FHIVNRKetoconazoleNRSurvived

Nieto-Rios et al. [22]2012Colombia30 y, FRenal transplantN/AAmphotericin B/itraconazoleBlood CxSurvived

41 y, FRenal transplantN/ANone (died the same day of positive Cx)Blood CxDied (HD 3)

Telfer and Gulati [23]2012USA28 y, MHIV12VoriconazoleBM path/urine AgDied (NR)

Huang [24]2014Guatemala25 y, MHIV4Antifungals/dexamethasoneUrine Ag/BM pathSurvived

Subedee and van Sickels [25]2015USA42 y, FHIV40Liposomal amphotericin B/itraconazoleUrine Ag/BM pathSurvived

Rajput et al. [26]2015Canada64 y, F.CKD, SCDN/AAntifungal therapyBM and blood CxSurvived

Kashifet al. [27]2015USA34 y, MSCDN/AAmphotericin B/itraconazole/dexamethasone/etoposideLN BxDied (HD 8)

Castelliet al. [28]2015Mexico32 y, MHIV3Liposomal amphotericin B × 2 weeks/itraconazole/dexamethasone/etoposideBAL Cx/Blood Cx/BM CxSurvived

Mukherjee and Basu [29]2015India52, MCOPD, Type II DMN/AAmphotericin BAutopsyDied (NR)

Townsend et al. [30]2015Mexico31 y, FHIV1Liposomal amphotericin BBlood and BM CxDied (HD 16)
USA53 y, MHIV6Liposomal amphotericin B × 14 d/itraconazoleUrine AgSurvived
USA33 y, FHIV1Liposomal amphotericin B × 21 d/fluconazoleBlood Cx/urine AgSurvived
Mexico47 y, MImmunosuppressive treatmentItraconazoleUrine AgSurvived
USA28 y, MHIVN/ANRBlood Cx/BM Cx/urine AgSurvived
USA60 y, MImmunosuppressive treatmentN/ALiposomal amphotericin B/voriconazole/steroids/tacrolimusBM path/skin Bx/urine AgSurvived
USA44 y, MHIV2Liposomal amphotericin B × 16 d/itraconazoleSputum and blood Cx/urine AgSurvived
USA52 y, MHIV16Liposomal amphotericin B × 6 d/itraconazole/steroids/IVIGBM Cx and urine AgDied (HD 9)
USA52 y, MHIV16Liposomal amphotericin B × 3 d/itraconazole/IVIGBlood Cx/BM path/urine AgDied (HD 9)
El Salvador32 y, MHIV50Liposomal amphotericin B × 18 d/itraconazoleBlood, sputum, and BM CxSurvived
USA51 y, MHIV9Liposomal amphotericin B/steroidsSputum, blood, gastric tissue CxDied (HD 13)

De and Nath [31]2015India40 y, MHealthyN/AAmphotericin B deoxy/itraconazoleBM BxSurvived
32 y, MHealthyN/AAmphotericin B/itraconazoleBM BxSurvived

Sonavane et al. [32]2016India43 y, FHealthyN/AAmphotericin B/itraconazoleBM BxSurvived

Nieto et al. [33]2016Colombia33 y, MHIVN/AAmphotericin B/steroidsNRSurvived

Ferguson-Paulet al. [34]2016USA6 months, FMRSA bacteremiaN/ALiposomal amphotericin B/itraconazole/etoposide/steroidsUrine serum Ag/BM and CSF CxSurvived

Daoand He [35]2016USA21 y, MCrohn diseaseN/AAntifungal therapyBM (cx and path)/Blood and BAL CxSurvived

Schulze et al. [36]2016Germany59 y, FSteroids for suspected IBDN/ALiposomal amphotericin B/posaconazole/steroidsColon, liver, LN, lung path/blood CxSurvived

Gómez-Espejo et al. [37]2017Venezuela23 y, MHIV7Liposomal amphotericin B/dexamethasone/IVIGLiver BxSurvived

Karthik Bommanan et al. [38]2017India32 y, MHealthyN/AAmphotericin BBM Bx pathSurvived

Souto Filho et al. [39]2017Brazil40 y, FSLEN/AAmphotericin B/steroidsBM Bx pathDied (within 48 hrs)

Ocon et al. [40]2017Guyana49 y, MHIV7Liposomal amphotericin B/ART/IVIG/anakinraBlood cxSurvived

Loganantharajet al. [41]2017Dominican Republic46 y, MHIV54Liposomal amphotericin BUrine Ag/LN bxSurvived

Huapaya et al. [42]2017USA46 y, MKidney transplantN/AAmphotericin BUrine and serum Ag/BAL cytologySurvived

Abbreviations: y, year; M, male; F, female; HIV, human immunodeficiency virus; NR, not reported; BM, bone marrow; N/A, not applicable; BAL, bronchoalveolar lavage; ART, antiretroviral therapy; IVIG, intravenous immunoglobulin; d, days; wks, weeks; Cx, culture, Bx, biopsy; path, histopathology; CSF, cerebrospinal fluid; CLL, chronic lymphocytic leukemia, TB, tuberculosis; GI, gastrointestinal; PCR, polymerase chain reaction; HCV, hepatitis C virus; CKD, chronic kidney disease; Ag, antigen; LN, lymph node; MCTD, mixed connective tissue disease; HD, hospital day; IBD: inflammatory bowel disease.

The median CD4 count in HIV patients was 17 cells/μL. The majority of patients had disseminated histoplasmosis. Five patients were diagnosed by either lymph node biopsy or histoplasma urine Ag only and not proven to have disseminated histoplasmosis.

Initial antifungal treatment consisted of amphotericin B formulation in 48 cases and only azoles in four cases. The specific treatment for HLH was as follows: nine patients received steroids only, six patients received intravenous immunoglobulin (IVIG) only, three patients received dexamethasone and etoposide, two patients received etoposide, dexamethasone, and cyclosporine, two patients received steroids and IVIG, and one patient received Anakinra and IVIG.

The overall inpatient case fatality rate was 31% (20/64) and 37% (13/35) among HIV patients. The mortality rate was 25.0% (12/48) in patients who received amphotericin B, 20% (1/5) in patients who received steroids and etoposide with or without cyclosporine (all received amphotericin B), 62% (5/8) in patients who received IVIG, and 31% (5/16) in patients who received steroids. One patient received Anakinra and IVIG and survived. Only 14/21 patients had available date of death; of those, 10 patients died within two weeks of admission and four patients died at hospital days 16, 18, 43, and 44.

5. Discussion

Histoplasmosis-associated HLH is rare but likely underdiagnosed given the nonspecific clinical and laboratory presentation. The diagnosis is challenging because high fever, peripheral blood cytopenia, splenomegaly, and elevated ferritin are very common in patients with disseminated histoplasmosis. We report the second largest case series of histoplasmosis-induced HLH. About half of the cases (29/60) were reported after 2014, and all five cases at our institution were diagnosed after 2010. This may be explained by an increased awareness of this entity. Almost all cases of histoplasmosis-associated HLH occurred in patients with disseminated histoplasmosis. Most patients were relatively young. HIV and its numerous related opportunistic infections remain the most common underlying immunodeficiency that triggers HLH, but the recent literature showed an increasing number of non-HIV patients (organ transplant, patients receiving chemotherapy, or other immunosuppressive treatments). This is likely caused by the recent increase in disseminated histoplasmosis among non-HIV infected patients [43, 44]. Only few patients had no clear underlying immunodeficiency. The male predominance may be related in part to the higher incidence and prevalence of HIV in men in the United States.

Human immunodeficiency virus (HIV) could trigger hemophagocytic syndrome by itself, or secondary to ART initiation or opportunistic infections [45]. In a retrospective study to evaluate the triggers of HLH among HIV patients in Brazil, opportunistic infections were the most common factors (59%) including Mycobacterium (34%), Cytomegalovirus (14%), and Cryptococcus neoformans (11%) [46].

Macrophage activation syndrome (MAS) is a form of HLH that is usually associated with rheumatologic diseases and inflammatory bowel diseases (IBD). In a review of literature of 50 cases of HLH or MAS, the association between HLH and IBD was thought to be secondary to infections, the effect of immunosuppressive therapy, and the potential presence of a genetic susceptibility [47]. The majority of cases were Crohn’s disease (CD) rather than ulcerative colitis; this was attributed to the more frequent use of immunomodulators in CD.

The number of patients in each treatment group and the noncontrolled nature of this review hinder making conclusions about the most effective therapy. Patients who received amphotericin B had a slightly lower case fatality rate compared to the whole group. It is unclear if the addition of etoposide and steroids was helpful, but 4/5 patients with such regimen survived. We suggest starting a lipid formulation of amphotericin B as soon as possible, as recommended by the Infectious Diseases Society of America guidelines [48] for the treatment of moderate to severe disseminated histoplasmosis. There are limited data to establish the best treatment protocol and the role of immunosuppressive therapy and IVIG for histoplasma-associated HLH [1].

The treatment of secondary HLH is most effective when the inciting disease can be treated and controlled. If effective histoplasmosis treatment fails to demonstrate improvement after 48–72 hours, clinicians often consider initiation of immunosuppressive therapy with regimens such as the HLH-94 protocol [49]. Once clinical improvement is noted, we believe immunosuppressive therapy can be tapered, and the full protocol is often not required.

We report a small number of cases at our institution and it is possible that we could have missed cases in our retrospective search. In published case reports and case series, some data were lacking and few articles were not in English.

6. Conclusions

Histoplasmosis-associated HLH among adults is an uncommon but serious disease with high mortality. The clinical and laboratory findings that should prompt evaluation for HLH are splenomegaly, highly elevated ferritin, and cytopenia in an immunocompromised patient with disseminated histoplasmosis. The delay in diagnosis of HLH may affect outcomes and patients with suspected HLH should have a prompt hematology consultation. HLH appears to be a disease of excessive immune activation, and the optimal treatment and duration of immunosuppressive therapy remains unknown. Early antifungal therapy with a lipid formulation amphotericin B is critical. Multicenter prospective studies are needed to help define the role and duration of immunosuppressive therapy for this disease.

Conflicts of Interest

The authors declare that they have no conflicts of interest.


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