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Histoplasmosis-Induced Hemophagocytic Syndrome: A Case Series and Review of the Literature

Histoplasmosis-Induced Hemophagocytic Syndrome: A Case Series and Review of the Literature MA JO R A R T IC LE Histoplasmosis-Induced Hemophagocytic Syndrome: A Case Series and Review of the Literature 1 1 2 2 3 Jennifer Leigh Townsend, Satish Shanbhag, John Hancock, Kathryn Bowman, and Ank E. Nijhawan 1 2 3 Johns Hopkins Bayview Medical Center, Baltimore, Maryland; University of Texas Southwestern, and Parkland Health and Hospital System, Dallas, Texas Background. Histoplasmosis-associated hemophagocytic lymphohistiocytosis (HLH) is a relatively rare disor- der for which data are limited regarding optimal treatment and clinical outcomes in adults. We describe the clinical features, treatment, and outcomes of patients with histoplasmosis-associated HLH at our institution. Methods. We performed a retrospective chart review of all inpatients at Parkland Hospital diagnosed with HLH associated with Histoplasma capsulatum from 2003 to 2013. Results. Eleven cases of histoplasmosis-associated HLH over this time period were identified. Nine of eleven cases were males (82%). Nine of these patients had human immunodeficiency virus (HIV)/acquired immune defi- ciency syndrome (AIDS), 1 was a renal transplant patient on immunosuppressants, and the other had no document- ed immunocompromise. The most common HLH criteria were splenomegaly (n = 10), fever (n = 10), and ferritin >500 ng/dL (n = 9). Urine Histoplasma antigen was positive in every patient tested (n = 9 of 9), and most antibodies for Histoplasma were positive if checked (n = 4 of 5). A majority of patients received liposomal amphotericin B (n = 9) with an average treatment duration of 11 days, and 5 patients also received prednisone, intravenous immu- noglobulin (IVIG), or both. Overall, 5 patients died within 30 days (45.5%), and 7 patients died within 90 days (63.6%). Of the 5 patients that received immunosuppression, 4 died (80%), whereas in the group not given additional immunosuppression (n = 5), 2 died (40%). Conclusions. Histoplasmosis-associated HLH among adults is a lethal disease of highly immunocompromised patients, especially patients with HIV/AIDS. Clinical features such as splenomegaly, elevated ferritin, and cytopenias should prompt evaluation for HLH in this population. Further data are needed to define the role of immunosup- pression, IVIG, and highly active antiretroviral therapy in treating this condition. Keywords. disseminated histoplasmosis; hemophagocytic syndrome; HIV. Hemophagocytic syndrome, also called hemophagocytic megaly, and cytopenias. A majority of cases occur in chil- lymphohistiocytosis (HLH), is a rare syndrome charac- dren and are triggered by primary genetic disorders (“pri- terized by a hyperstimulated but ineffective immune mary HLH”) that cause defects in cytotoxic functioning response with characteristic signs of fever, hepatospleno- of natural killer (NK) and T lymphocytes. In adults, “sec- ondary HLH” can be triggered by hematologic malignan- cies and autoimmune diseases, but more often it occurs Received 24 March 2015; accepted 14 April 2015. with various bacterial infections, fungi, and viruses [1, Presented in part: Infectious Diseases Society of America Meeting, 2014, 2]. Although aggressive chemotherapy treatment proto- Philadelphia, PA. Correspondence: Jennifer L. Townsend, MD, 5200 Eastern Ave, MFL Center cols and allogeneic stem cell transplant have been shown Tower #381, Baltimore, MD 21224 (holmseyj@gmail.com; jholme27@jhmi.edu). to decrease mortality in children with HLH due to a Open Forum Infectious Diseases genetic predisposition, optimal treatment of infection- © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Societyof America. This is an Open Access article distributed under the terms related HLH in adults is not clear [3, 4]. Some physicians of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http:// treat only the underlying infection, whereas others use creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work immune suppression in addition to antimicrobials. The is not altered or transformed in any way, and that the work is properly cited. For literature presents scant evidence regarding the efficacy commercial re-use, please contact journals.permissions@oup.com. DOI: 10.1093/ofid/ofv055 of chemotherapy in infection-related HLH. Histoplasma-Induced HLH: A Case Series OFID 1 � � Rather than a disease on its own, HLH can be viewed as an 26 cases report using antifungal therapy in addition to immune immune derangement and hypercytokinemia caused by various suppression. The remainder did not diagnose the condition pre- triggers. Under normal conditions, intracellular infections are mortem or did not detail a treatment regimen. The paucity of controlled by a complex interaction of cell types, to which NK data highlights the need for reporting of more cases in the cur- cells are central. In HLH, defects in NK cell cytotoxicity result in rent era to examine whether any treatments can aid in survival a positive feedback loop of uncontrolled intracellular infection, of these patients. ongoing immune activation, and a lack of immune down- In this study, we sought: (1) to identify cases of histoplasmo- regulation. Without NK cell removal of cytotoxic T lympho- sis-associated HLH at our large urban safety net hospital, (2) to cytes (CTLs), a sustained increase in activated lymphocytes describe the clinical characteristics of patients with histoplas- generates a cytokine storm and unopposed macrophage activa- mosis-induced HLH including diagnostic criteria, and (3) to tion that damage end organs of the host [5, 6]. describe the treatment regimens and clinical outcomes of this Clinical and laboratory findings in HLH include markers of study population. immune activation as well as end organ damage. High levels of tumor necrosis factor (TNF)-α production by macrophages stim- METHODS ulates fever and inhibits the ability of lipoprotein lipase to remove triglycerides from the serum. Activated macrophages phagocy- We performed a retrospective chart review of cases of tose erythrocytes and scavenge heme, but they also secrete ferritin histoplasma-associated HLH at Parkland Hospital in Dallas, and contribute to hyperferritinemia. Cytopenias are not just a re- Texas, a large urban hospital that is the sole public safety net sult of hemophagocytosis, but they also related to suppression of provider in Dallas County. Records were reviewed from Decem- normal hematopoiesis by cytokines. Macrophages may also se- ber 2003 to February 2013. Cases were identified searching the crete plasminogen activators that accelerate the conversion of results of bone marrow biopsy specimens from 2003 to 2013 for plasminogen to plasmin, causing hyperfibrinolysis and leading the key term “hemophagocytosis.” This was the time period to characteristically low fibrinogen levels. Soluble interleukin during which the pathology department electronically coded (IL)-2 receptor, which is secreted by activated macrophages and cases in a searchable database. The reports of bone marrow lymphocytes, is extremely high in HLH as well [5]. specimens with mention of hemophagocytosis were reviewed In cases of secondary HLH, the pathophysiology is thought to for evidence of histoplasmosis infection and absence of malig- be from temporary acquired immunodeficiency states that result nancy. The last case that did not have a bone marrow specimen in NK cell defects. In HLH, the perforin-mediated killing func- was included because the patient was seen by the authors as an tion is blocked leading to an accumulation of activated T lym- inpatient consultation during the time of the review, and the pa- phocytes and activated histiocytes with increasingly high levels tient was found to have evidence of HLH by laboratory criteria. of cytokines. Human immunodeficiency virus (HIV), for in- This study was approved by the UT Southwestern Medical Cen- stance, is known to cause NK cell defects, which may explain ter Institutional Review Board. the higher incidence of HLH in HIV patients [7–11]. Patients were excluded from review if they were <18 years of With the understanding that HLH is a result of defective NK age, and if no clinical records were available. Record review was cell function, it becomes clear that intracellular organisms are via paper charts, which often contained limited data, and the uniquely positioned to trigger HLH, because NK cells are essen- electronic medical record for patients after 2006. Patients tial for clearing infected somatic cells and activated CTL. All of were considered to have possible (4 of 8 criteria) or confirmed the pathogens currently described as triggers of HLH are either (5 of 8 criteria) HLH according to the HLH-2004 criteria: (1) intracellular or facultatively intracellular, including viruses Fever; (2) Splenomegaly; (3) Cytopenias affecting 2/3 cell (Epstein-Barr virus [EBV], cytomegalovirus, HIV), parasites lines in the peripheral blood; (4) Hypertriglyceridemia and/or (malaria,leishmania),mycobacteria,fungi,and bacteria hypofibrinogenemia; (5) Hemophagocytosis in the spleen, (Babesia, Listeria, Coxiella). Without functioning NK cells, a bone marrow, or lymph nodes, with no evidence of malignancy; host suffers a double defect of an exuberant but ineffective im- (6) Low or absent NK cell activity (not available at our facility); mune response that damages the host without clearing the (7) Ferritin >500 ng/dL; (8) Soluble IL-2 receptor >2400 U/mL infection. (not available at our facility) [3]. Patients were considered to The existing treatment and outcomes data for histoplas- have disseminated Histoplasma capsulatum if any of the follow- mosis-associated HLH in adults consist of 27 reported cases ing were true as per Infectious Diseases Society of America (summarized in Table 1). Seventeen of the cases occurred in guidelines: (1) cultures from sputum or a sterile body site HIV patients, a majority from before the era of highly active an- (bone marrow, lymph node, biopsy specimen) grew H capsula- tiretroviral therapy (HAART). The mortality rate for all report- tum; (2) biopsy specimens contained granulomas with yeast ed cases was 10 of 26 (38%). Treatment is not always detailed, morphologically consistent with Hcapsulatum;or(3) urine but half of cases report using antifungal therapy alone. Five of or serum Histoplasma antigen was positive [30]. 2 OFID Townsend et al � � a Table 1. Previous Cases of Histoplasma-Associated HLH Reported in the Literature Author Year Underlying Disease CD4 Treatment Outcome Majluf-Cruz [12] 1993 HIV NR Fluconazole Survived HIV NR Amphotericin B Survived HIV NR none Died Keller [13] 1994 CMC N/A Amphotericin B Survived Koduri [14] 1995 None N/A Amphotericin B/solumedrol Died Koduri [15] 1995 HIV 36 ART/Amphotericin B/ IVIG × 2d Died HIV 4 ART/Amphotericin B/ IVIG × 2d Died HIV 6 ART/Amphotericin B/ IVIG × 2d Died HIV 22 ART/Amphotericin B/ IVIG × 2d Survived HIV 32 ART/Amphotericin B Survived HIV 44 ART/Amphotericin B Survived Chemlal [16] 1997 HIV 34 NR NR Kumar [17] 2000 None N/A None Died HIV NR None Died Rao [18] 2002 CLL N/A Amphotericin B Survived Masri [19] 2003 Heart transplant N/A Amphotericin B Survived Gil-Brusola [20] 2007 HIV 39 None Died Guiot [21] 2007 HIV 66 Abelcet × 36d –> itraconazole Survived Sanchez [22] 2007 HIV NR Amphotericin B × 6 wks Survived Wang [23] 2007 CKD/ fungal endocarditis N/A None Died Phillips [24] 2008 Sarcoidosis on chronic N/A NR Survived steroids De Lavaissiere [25] 2009 HIV NR ART/IVIG × 2 g/Amphotericin B × 4 wks –> itraconazole Survived Lo [26] 2010 Renal transplant N/A Ambisome × 2 wks –> itraconazole; reduced Survived immunosuppression (IS) Renal transplant N/A Amphotericin B × 1 wk –> itraconazole; reduced IS Survived Van Koeveringe [27] 2010 CLL N/A Amphotericin B Survived Vaid [28] 2011 HIV 153 Antifungal and ART Died Chandra [29] 2012 HIV NR Ketoconazole Survived Abbreviations: ART, antiretroviral therapy; CKD, chronic kidney disease; CLL, chronic lymphocytic leukemia; CMC, chronic mucocutaneous candidiasis; HIV, human immunodeficiency virus; HLH, hemophagocytic lymphohistiocytosis; IVIG, intravenous immunoglobulin; N/A, not applicable; NR, not reported. Underlying disease, treatment, and outcomes. For all patients meeting inclusion criteria, data were collected marrow biopsy but met other laboratory criteria for HLH. on patient demographics, comorbidities, presence of fever, pres- Cases occurred between December 2003 and February 2013. ence of organomegaly, laboratory values (complete blood The demographics and clinical characteristics of these patients counts, ferritin, lactate dehydrogenase [LDH], triglycerides, are presented in Table 2. A majority of the patients had HIV (9 fibrinogen), microbiologic data, diagnostic procedures (bone of 11). One was a renal transplant recipient, and the other had marrow biopsy, bronchoscopy), treatment course (antifungal no known immunosuppression. A majority were male (9 of 11), medication, chemotherapy), and outcomes (survival to hospital with a mean age of 43.9 years. The majority of HIV patients discharge). Immunosuppression included corticosteroids, TNF were not on HAART at diagnosis (6 of 9), and the mean CD4 inhibitors, calcineurin inhibitors, cytotoxic chemotherapy, in- count was very low at 14.3. The average time between admission travenous immunoglobulin (IVIG), and methotrexate. and bone marrow biopsy was 9 days (range, 3–15). Antifungal start dates were not routinely available. Results of the microbiology and radiologic testing done RESULTS during inpatient evaluation are shown in Table 3.The most Eleven cases of histoplasmosis-associated HLH were identified: consistent diagnostic finding was a positive urine Histoplasma 10 patients with hemophagocytosis on bone marrow examina- antigen, which was positive in 100% of the specimens that tion, and 1 patient reported by the Infectious Disease consult were sent (9 of 9). Eight patients had H capsulatum visualized service at the time of our search who did not undergo a bone on bone marrow biopsy (Figure 1), 7 had positive blood cultures Histoplasma-Induced HLH: A Case Series OFID 3 � � Table 2. Characteristics of Patients With Histoplasmosis-Induced HLH, 2003–2013 Immunosuppressive Case Country of Medications at ART at Time Number Age Gender Ethnicity Origin HIV Diagnosis CD4 Count HIV VL of dx 1 31 Female Hispanic Mexico Yes No 1 None Yes 2 53 Male Non-Hispanic/White USA Yes No 6 205 000 Yes 3 33 Female Non-Hispanic/Black USA Yes No 1 750 000 No 4 47 Male Hispanic Mexico No Yes N/A N/A N/A 5 28 Male Non-Hispanic/Black USA Yes No Unknown Unknown Yes 6 60 Male Hispanic Unknown No Yes N/A N/A N/A 7 44 Male Hispanic Unknown Yes No 2 190 000 No 8 52 Male Non-Hispanic/White USA Yes No 16 6 440 000 No 9 52 Male Non-Hispanic/White USA Yes No 16 6 440 000 No 10 32 Male Hispanic El Salvador Yes No 50 >10 000 000 Yes 11 51 Male Non-Hispanic/White USA Yes No 9 6036 No Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; HLH, hemophagocytic lymphohistiocytosis; N/A, not applicable; VL, viral load. for H capsulatum, and 4 had intracellular yeast seen on periph- activity were not available. All patients had fever documented eral smear (Figure 2). A bronchoalveolar lavage specimen from except for 2 patients, who had sparse medical records available. one of the patients is shown in Figure 3. On chest radiography, Cytopenias were universal and severe, with most patients having the most common finding was bilateral infiltrates (6 of 11), but platelet counts <50 × 10 /µL. The mean ferritin level was ex- other findings included pleural effusions (n = 5), pulmonary tremely high at 30 722 ng/mL (range, 1713–100 000+). All but nodules (n = 3) (Figure 4), lymphadenopathy (n = 4), pneumo- one patient had documented splenomegaly. thorax (n = 1), cardiomegaly (n = 3), and pulmonary edema From the available treatment data, the most commonly (n = 1). reported treatment regimen was liposomal amphotericin B Specific laboratory values included in the HLH-2004 criteria (n = 9) for a mean of 11 days (range, 3–21), followed by oral are reported in Table 4. Soluble IL-2 receptor levels and NK cell antifungals (most commonly itraconazole) for 3–12 months Table 3. Microbiologic and Radiologic Findings in Patients With Histoplasma-Associated HLH Bone Histoplasma Histoplasma Urine Case Marrow on Peripheral Bone Marrow With Antibody Histoplasma Sites Growing Number With Yeast Smear Hemophagocytosis (<1:8) Ag (<2.0 EIA) Histoplasma CXR Findings 1 Yes Yes Yes N/A N/A Blood, bone marrow, BI, B effusions, CM 2 Yes Yes Yes Positive Positive None BI, LAD 3 No No Yes N/A >13 Blood Hemothorax, right pneumothorax 4 No No Yes Positive Positive None BI, L effusion 5 Yes Yes Yes N/A >13 Blood, bone marrow Clear 6 Yes No Yes N/A >13 Bone marrow, skin CM 7 Yes No Yes N/A 11 Sputum, blood Edema, BI, effusions 8 Yes No Yes Positive >19 Bone marrow Miliary nodules, effusions, LAD 9 Yes No Yes N/A >19 Blood, bone marrow Miliary nodules 10 Yes No Yes Positive N/A Respiratory blood, CM, BI, nodules, L bone marrow effusion 11 No Yes Not done Negative 4.9 Respiratory, blood, BI, nodules gastric tissue Abbreviations: Ag, antigen; B, bilateral; BI, bilateral infiltrates; CM, cardiomegaly; EIA, enzyme immunoassay; HLH, hemophagocytic lymphohistiocytosis; L, Left; LAD, lymphadenopathy; N/A, not applicable (not reported). Complement fixation titer, ARUP laboratories. 4 OFID Townsend et al � � Figure 1. Gomori methenamine silver stain of bone marrow, 40×. Intra- Figure 3. Bronchoalveolar lavage specimen showing intracellular yeast. cellular yeast consistent with Histoplasma capsulatum. Wright stain, 1000×. (n = 5) (see Table 5). Three patients died during the initial am- whereas in the group not given additional immunosuppression photericin course. (n = 5), 2 died (40%). The remaining patient survived but his In addition, 2 HIV patients received steroids, 1 received IVIG treatment course was not available for review. Overall 30-day alone, and 1 received steroids in addition to IVIG. One renal mortality was high (5 of 11 patients, 45.5%). Four patients transplant patient continued on his home regimen of prednis- died during the admission (within 16 days), while one patient olone and tacrolimus, whereas the other renal transplant patient died 7 months later. There was not a significant difference in had no documented immunosuppressive treatment. One pa- mortality between patients who did or did not receive immuno- tient was started on HAART during the admission, whereas 4 suppression (P = .24, 2 tailed Fisher’s exact test) although the others were continued on their outpatient HAART regimens. comparison was underpowered. One patient presented with HLH within 3 weeks of starting HAART, which is consistent with an immune reconstitution in- DISCUSSION flammatory syndrome (IRIS). Of the 5 patients that received immunosuppression during We report eleven cases of Histoplasma-associated HLH, the admission (including prednisone, IVIG, or both), 4 died (80%), largest case series of this clinical phenomenon that has been reported to date. The relatively large number of Histoplasma- associated HLH cases at our hospital, compared with the num- ber of cases reported at other institutions in the literature, may be Figure 2. Peripheral blood smear showing intracellular yeast. 100× oil. Figure 4. Chest computed tomography with mixed pattern of large and Modified Wright-Giemsa stain. small nodules. Histoplasma-Induced HLH: A Case Series OFID 5 � � Table 4. Clinical Features and Diagnostic Criteria for HLH-2004 Platelet Nadir Peak Ferritin Case T During Hemoglobin Nadir (150–450 (30.0–400.0 LDH (135– HLH max Number Admission Rash Splenomegaly (12.4–17.3 g/dL) ×10 /µL) ng/mL) 225 U/L) Criteria 1 39.8 No Yes 6 12 Unknown 1336 5 of 8 2 38.6 No Yes 7.1 9 >16 500 971 5 of 8 3 37 No Yes 6 48 1713 227 4 of 8 4 39.2 No Yes 5.9 16 >16 500 1815 6 of 8 5 37.3 No Yes 7.3 70 >16 500 1277 4 of 8 6 38.5 Yes No 8.8 45 Unknown 971 5 of 8 7 39.9 No Yes 6.3 <5 >16 500 1402 5 of 8 8 38.7 No Yes 7 4 4392 402 6 of 8 9 39.4 No Yes 7 4 4400 402 5 of 8 10 101.9 No Yes 5.7 7 >100 000 2517 5 of 8 11 39.5 No Yes 5.7 10 >100 000 8004 5 of 8 Abbreviations: HLH, hemophagocytic lymphohistiocytosis; LDH, lactate dehydrogenase; T, temperature. due to the geographic overlap of histoplasmosis and HIV as well prevalent than we found in our series, given our somewhat lim- as the under-recognition of this condition in other settings [31, ited case finding strategy. In addition, while many clinicians rec- 32]. We hypothesize that this condition may be even more ognize that disseminated histoplasmosis causes high fevers, an Table 5. Treatment and outcomes of Histoplasma-associated hemophagocytic lymphohistiocytosis Liposomal Oral HAART Survival amphotericin antifungal Immuno HAART at Immuno started from Case Antifungal drug B duration duration suppressive time of suppressive during Outcome admission Number used (days) (days) treatment diagnosis duration admission at 30 days (days) 1 Liposomal Unknown 0 days None Yes None No Died 16 amphotericin B 2 Liposomal 14 Unknown None Yes None Yes Alive 2168 amphotericin B; itraconazole 3 Liposomal 21 >1 year Prednisone 20 mg No Unknown No Died 221 amphotericin PO daily B; fluconazole 4 Itraconazole 0 Unknown None N/A None N/A Alive 44 5 Unknown Unknown Unknown Unknown Yes Unknown Unknown Alive 3560 6 Liposomal Unknown Unknown Prednisolone 10 N/A 5 months N/A Alive 2849 amphotericin mg po BID, B; voriconazole Tacrolimus 1.5 mg PO daily 7 Liposomal 16 12 weeks None No None No Alive 86 amphotericin B; itraconazole 8 Liposomal 5 0 days IVIG × 1; No 9 days No Died 9 amphotericin prednisone 40 B; itraconazole BID 9 Liposomal 3 Unknown IVIG 1gm × 1 No 1 day No Died 9 amphotericin B; itraconazole 10 Liposomal 18 >1 year None Yes None No Alive 408 amphotericin B; itraconazole 11 Liposomal 11 0 days Prednisone 40 mg No 11 days Yes Died 13 amphotericin B PO BID; solumedrol 60 mg IV q6hrs Abbreviations: HAART, Highly active antiretroviral therapy; IVIG, intravenous immunoglobulin. 6 OFID Townsend et al � � elevated LDH, and a high ferritin, they may not consider HLH in not receiving HIV treatment at the time of developing HLH, it this clinical scenario. In our series, the mean time from presen- also may precipitate HLH. In our series, one patient presented tation to bone marrow was >1 week, which may have led to treat- with HLH within 3 weeks of starting HAART, which is consistent ment delays. It remains to be seen if early diagnosis could lead to with an immune reconstitution inflammatory syndrome (IRIS). improved outcomes with earlier institution of antimicrobial and Prior publications have reported HLH as a manifestation of IRIS possibly immunsuppressive therapy. in HIV-positive patients, 2 with HIV alone, 1 associated with leish- In our series, uncontrolled HIV was the dominant risk factor mania, 1 with EBV, and 1 with lymphoma [25, 38–43]. As with for this condition, while renal transplant patients are also at risk other chronic fungal and mycobacterial diseases that have a strong [33]. HIV patients may be uniquely vulnerable to HLH given potential to cause IRIS, it may be reasonable to wait for the acute the depletion of NK cells in HIV, which has been connected phase of HLH to resolve before instituting HIV treatment. to multiple manifestations of immune dysregulation [20, 34, There remains considerable controversy surrounding treat- 35]. Thepredominanceofmales is difficult to explain, as no ment of adult patients with HLH related to infectious triggers. gender predilection has been reported for HLH or histoplasmo- Our comparison between patients who did or did not receive sis, but may be related to a higher prevalence of HIV in males in additional immunosuppression detected more survivors in the Dallas. Guidelines do not recommend routinely screening for non-immunosuppression group, although the analysis is under- disseminated histoplasmosis in HIV patients before starting powered and may reflect treatment bias of individuals who were HAART [36], noris thisdoneinrenal transplant patients. more ill. Additional data, even if retrospective, must be com- However, it may be reasonable to screen patients with severe piled to help guide decisions in this difficult-to-treat group. anemia or thrombocytopenia with a urine histoplasma antigen, This study has several limitations. First, our search strategy especially those planned for intense immunosuppression, so focused on bone marrow biopsy results, which may have missed that their infection might be recognized and treated prior to patients with histoplasmosis-associated HLH who did not un- immunosuppression. dergo bone marrow biopsy. Nonetheless, we were able to iden- One interesting clinical finding in our series that has not been tify 11 cases over an approximately 10-year period, which is the described previously is the occurrence of a cardiopulmonary largest case series of histoplasmosis-associated HLH to date. syndrome in patients with HLH. Several patients had either car- Second, the medical records from patients occurring before im- diomegaly, pleural effusions, or pulmonary edema on their plementation of the electronic medical record had less detailed chest radiographs. A high output state related to anemia in information about treatment regimens. Finally, because this is a these patients may be contributing, possibly in addition to the retrospective review with a small sample size, no conclusions cytokine storm causing leaky vasculature. can be reached on the impact of different treatment regimens Treatment for the triggering condition is recommended as on clinical outcomes. Prospective treatment studies would be first line therapy for patients with HLH, although indications ideal, but they are unlikely given the rarity of this disease. for initiating chemotherapy directed at HLH is less clear in the adult population with the sporadic (rather than inherited CONCLUSIONS form) of the disease. Although all patients in our series received antifungal treatment with amphotericin products and/or azole Histoplasma-associated HLH was relatively common at our treatment, there was wide variability on whether or not immu- large urban safety net hospital in Dallas, Texas, and uncon- nomodulation was used. None of the patients in this series were trolled HIV patients make up the majority of patients, whereas treated with the chemotherapy protocols such as those recom- solid organ transplant patients also seem to be at risk. Key fea- mended for HLH in children (etoposide, dexamethasone with tures that should prompt evaluation for this condition are sple- or without intrathecal therapy),although half of patients in nomegaly, an extremely elevated ferritin, and cytopenias in an our series received steroids, IVIG, or both. Given the small sam- immunocompromised patient. Fungal blood cultures and urine ple size, no benefit or harm could be attributed to IVIG or ste- Histoplasma antigen are high-yield tests in this setting for diag- roids. Since a majority of tissue damage is caused by cytotoxic nosing H capsulatum as the underlying trigger for HLH. The lymphocytes, therapiessuchascorticosteroids and cytotoxic mortality rate is high despite the use of antifungal agents and chemotherapies such as those used in children make sense as immune suppression. More data on treatment for this condition strategies to control the inflammation, but have not been estab- are needed in adults. The role and timing of HAART initiation lished in adults. More targeted immunosuppression in macro- in treatment of this condition remains unclear. phage activation syndrome (a similar pathologic process) is being evaluated in studies underway using cytokine antagonists Acknowledgments and IL-1 receptor antagonists [37]. Disclaimer. The content is solely the responsibility of the authors and The role of HAART for treatment of this condition is not does not necessarily represent the official views of the National Institutes of clear. Although HAART may improve outcomes in patients Health. Histoplasma-Induced HLH: A Case Series OFID 7 � � Financial support. This study was supported by the National Center for 20. Gil-Brusola A, Peman J, Santos M, et al. Disseminated histoplasmosis Advancing Translational Sciences of the National Institutes of Health with hemophagocytic syndrome in a patient with AIDS: description (award Number KL2TR001103; to A. 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Histoplasmosis-Induced Hemophagocytic Syndrome: A Case Series and Review of the Literature

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© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
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Abstract

MA JO R A R T IC LE Histoplasmosis-Induced Hemophagocytic Syndrome: A Case Series and Review of the Literature 1 1 2 2 3 Jennifer Leigh Townsend, Satish Shanbhag, John Hancock, Kathryn Bowman, and Ank E. Nijhawan 1 2 3 Johns Hopkins Bayview Medical Center, Baltimore, Maryland; University of Texas Southwestern, and Parkland Health and Hospital System, Dallas, Texas Background. Histoplasmosis-associated hemophagocytic lymphohistiocytosis (HLH) is a relatively rare disor- der for which data are limited regarding optimal treatment and clinical outcomes in adults. We describe the clinical features, treatment, and outcomes of patients with histoplasmosis-associated HLH at our institution. Methods. We performed a retrospective chart review of all inpatients at Parkland Hospital diagnosed with HLH associated with Histoplasma capsulatum from 2003 to 2013. Results. Eleven cases of histoplasmosis-associated HLH over this time period were identified. Nine of eleven cases were males (82%). Nine of these patients had human immunodeficiency virus (HIV)/acquired immune defi- ciency syndrome (AIDS), 1 was a renal transplant patient on immunosuppressants, and the other had no document- ed immunocompromise. The most common HLH criteria were splenomegaly (n = 10), fever (n = 10), and ferritin >500 ng/dL (n = 9). Urine Histoplasma antigen was positive in every patient tested (n = 9 of 9), and most antibodies for Histoplasma were positive if checked (n = 4 of 5). A majority of patients received liposomal amphotericin B (n = 9) with an average treatment duration of 11 days, and 5 patients also received prednisone, intravenous immu- noglobulin (IVIG), or both. Overall, 5 patients died within 30 days (45.5%), and 7 patients died within 90 days (63.6%). Of the 5 patients that received immunosuppression, 4 died (80%), whereas in the group not given additional immunosuppression (n = 5), 2 died (40%). Conclusions. Histoplasmosis-associated HLH among adults is a lethal disease of highly immunocompromised patients, especially patients with HIV/AIDS. Clinical features such as splenomegaly, elevated ferritin, and cytopenias should prompt evaluation for HLH in this population. Further data are needed to define the role of immunosup- pression, IVIG, and highly active antiretroviral therapy in treating this condition. Keywords. disseminated histoplasmosis; hemophagocytic syndrome; HIV. Hemophagocytic syndrome, also called hemophagocytic megaly, and cytopenias. A majority of cases occur in chil- lymphohistiocytosis (HLH), is a rare syndrome charac- dren and are triggered by primary genetic disorders (“pri- terized by a hyperstimulated but ineffective immune mary HLH”) that cause defects in cytotoxic functioning response with characteristic signs of fever, hepatospleno- of natural killer (NK) and T lymphocytes. In adults, “sec- ondary HLH” can be triggered by hematologic malignan- cies and autoimmune diseases, but more often it occurs Received 24 March 2015; accepted 14 April 2015. with various bacterial infections, fungi, and viruses [1, Presented in part: Infectious Diseases Society of America Meeting, 2014, 2]. Although aggressive chemotherapy treatment proto- Philadelphia, PA. Correspondence: Jennifer L. Townsend, MD, 5200 Eastern Ave, MFL Center cols and allogeneic stem cell transplant have been shown Tower #381, Baltimore, MD 21224 (holmseyj@gmail.com; jholme27@jhmi.edu). to decrease mortality in children with HLH due to a Open Forum Infectious Diseases genetic predisposition, optimal treatment of infection- © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Societyof America. This is an Open Access article distributed under the terms related HLH in adults is not clear [3, 4]. Some physicians of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http:// treat only the underlying infection, whereas others use creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work immune suppression in addition to antimicrobials. The is not altered or transformed in any way, and that the work is properly cited. For literature presents scant evidence regarding the efficacy commercial re-use, please contact journals.permissions@oup.com. DOI: 10.1093/ofid/ofv055 of chemotherapy in infection-related HLH. Histoplasma-Induced HLH: A Case Series OFID 1 � � Rather than a disease on its own, HLH can be viewed as an 26 cases report using antifungal therapy in addition to immune immune derangement and hypercytokinemia caused by various suppression. The remainder did not diagnose the condition pre- triggers. Under normal conditions, intracellular infections are mortem or did not detail a treatment regimen. The paucity of controlled by a complex interaction of cell types, to which NK data highlights the need for reporting of more cases in the cur- cells are central. In HLH, defects in NK cell cytotoxicity result in rent era to examine whether any treatments can aid in survival a positive feedback loop of uncontrolled intracellular infection, of these patients. ongoing immune activation, and a lack of immune down- In this study, we sought: (1) to identify cases of histoplasmo- regulation. Without NK cell removal of cytotoxic T lympho- sis-associated HLH at our large urban safety net hospital, (2) to cytes (CTLs), a sustained increase in activated lymphocytes describe the clinical characteristics of patients with histoplas- generates a cytokine storm and unopposed macrophage activa- mosis-induced HLH including diagnostic criteria, and (3) to tion that damage end organs of the host [5, 6]. describe the treatment regimens and clinical outcomes of this Clinical and laboratory findings in HLH include markers of study population. immune activation as well as end organ damage. High levels of tumor necrosis factor (TNF)-α production by macrophages stim- METHODS ulates fever and inhibits the ability of lipoprotein lipase to remove triglycerides from the serum. Activated macrophages phagocy- We performed a retrospective chart review of cases of tose erythrocytes and scavenge heme, but they also secrete ferritin histoplasma-associated HLH at Parkland Hospital in Dallas, and contribute to hyperferritinemia. Cytopenias are not just a re- Texas, a large urban hospital that is the sole public safety net sult of hemophagocytosis, but they also related to suppression of provider in Dallas County. Records were reviewed from Decem- normal hematopoiesis by cytokines. Macrophages may also se- ber 2003 to February 2013. Cases were identified searching the crete plasminogen activators that accelerate the conversion of results of bone marrow biopsy specimens from 2003 to 2013 for plasminogen to plasmin, causing hyperfibrinolysis and leading the key term “hemophagocytosis.” This was the time period to characteristically low fibrinogen levels. Soluble interleukin during which the pathology department electronically coded (IL)-2 receptor, which is secreted by activated macrophages and cases in a searchable database. The reports of bone marrow lymphocytes, is extremely high in HLH as well [5]. specimens with mention of hemophagocytosis were reviewed In cases of secondary HLH, the pathophysiology is thought to for evidence of histoplasmosis infection and absence of malig- be from temporary acquired immunodeficiency states that result nancy. The last case that did not have a bone marrow specimen in NK cell defects. In HLH, the perforin-mediated killing func- was included because the patient was seen by the authors as an tion is blocked leading to an accumulation of activated T lym- inpatient consultation during the time of the review, and the pa- phocytes and activated histiocytes with increasingly high levels tient was found to have evidence of HLH by laboratory criteria. of cytokines. Human immunodeficiency virus (HIV), for in- This study was approved by the UT Southwestern Medical Cen- stance, is known to cause NK cell defects, which may explain ter Institutional Review Board. the higher incidence of HLH in HIV patients [7–11]. Patients were excluded from review if they were <18 years of With the understanding that HLH is a result of defective NK age, and if no clinical records were available. Record review was cell function, it becomes clear that intracellular organisms are via paper charts, which often contained limited data, and the uniquely positioned to trigger HLH, because NK cells are essen- electronic medical record for patients after 2006. Patients tial for clearing infected somatic cells and activated CTL. All of were considered to have possible (4 of 8 criteria) or confirmed the pathogens currently described as triggers of HLH are either (5 of 8 criteria) HLH according to the HLH-2004 criteria: (1) intracellular or facultatively intracellular, including viruses Fever; (2) Splenomegaly; (3) Cytopenias affecting 2/3 cell (Epstein-Barr virus [EBV], cytomegalovirus, HIV), parasites lines in the peripheral blood; (4) Hypertriglyceridemia and/or (malaria,leishmania),mycobacteria,fungi,and bacteria hypofibrinogenemia; (5) Hemophagocytosis in the spleen, (Babesia, Listeria, Coxiella). Without functioning NK cells, a bone marrow, or lymph nodes, with no evidence of malignancy; host suffers a double defect of an exuberant but ineffective im- (6) Low or absent NK cell activity (not available at our facility); mune response that damages the host without clearing the (7) Ferritin >500 ng/dL; (8) Soluble IL-2 receptor >2400 U/mL infection. (not available at our facility) [3]. Patients were considered to The existing treatment and outcomes data for histoplas- have disseminated Histoplasma capsulatum if any of the follow- mosis-associated HLH in adults consist of 27 reported cases ing were true as per Infectious Diseases Society of America (summarized in Table 1). Seventeen of the cases occurred in guidelines: (1) cultures from sputum or a sterile body site HIV patients, a majority from before the era of highly active an- (bone marrow, lymph node, biopsy specimen) grew H capsula- tiretroviral therapy (HAART). The mortality rate for all report- tum; (2) biopsy specimens contained granulomas with yeast ed cases was 10 of 26 (38%). Treatment is not always detailed, morphologically consistent with Hcapsulatum;or(3) urine but half of cases report using antifungal therapy alone. Five of or serum Histoplasma antigen was positive [30]. 2 OFID Townsend et al � � a Table 1. Previous Cases of Histoplasma-Associated HLH Reported in the Literature Author Year Underlying Disease CD4 Treatment Outcome Majluf-Cruz [12] 1993 HIV NR Fluconazole Survived HIV NR Amphotericin B Survived HIV NR none Died Keller [13] 1994 CMC N/A Amphotericin B Survived Koduri [14] 1995 None N/A Amphotericin B/solumedrol Died Koduri [15] 1995 HIV 36 ART/Amphotericin B/ IVIG × 2d Died HIV 4 ART/Amphotericin B/ IVIG × 2d Died HIV 6 ART/Amphotericin B/ IVIG × 2d Died HIV 22 ART/Amphotericin B/ IVIG × 2d Survived HIV 32 ART/Amphotericin B Survived HIV 44 ART/Amphotericin B Survived Chemlal [16] 1997 HIV 34 NR NR Kumar [17] 2000 None N/A None Died HIV NR None Died Rao [18] 2002 CLL N/A Amphotericin B Survived Masri [19] 2003 Heart transplant N/A Amphotericin B Survived Gil-Brusola [20] 2007 HIV 39 None Died Guiot [21] 2007 HIV 66 Abelcet × 36d –> itraconazole Survived Sanchez [22] 2007 HIV NR Amphotericin B × 6 wks Survived Wang [23] 2007 CKD/ fungal endocarditis N/A None Died Phillips [24] 2008 Sarcoidosis on chronic N/A NR Survived steroids De Lavaissiere [25] 2009 HIV NR ART/IVIG × 2 g/Amphotericin B × 4 wks –> itraconazole Survived Lo [26] 2010 Renal transplant N/A Ambisome × 2 wks –> itraconazole; reduced Survived immunosuppression (IS) Renal transplant N/A Amphotericin B × 1 wk –> itraconazole; reduced IS Survived Van Koeveringe [27] 2010 CLL N/A Amphotericin B Survived Vaid [28] 2011 HIV 153 Antifungal and ART Died Chandra [29] 2012 HIV NR Ketoconazole Survived Abbreviations: ART, antiretroviral therapy; CKD, chronic kidney disease; CLL, chronic lymphocytic leukemia; CMC, chronic mucocutaneous candidiasis; HIV, human immunodeficiency virus; HLH, hemophagocytic lymphohistiocytosis; IVIG, intravenous immunoglobulin; N/A, not applicable; NR, not reported. Underlying disease, treatment, and outcomes. For all patients meeting inclusion criteria, data were collected marrow biopsy but met other laboratory criteria for HLH. on patient demographics, comorbidities, presence of fever, pres- Cases occurred between December 2003 and February 2013. ence of organomegaly, laboratory values (complete blood The demographics and clinical characteristics of these patients counts, ferritin, lactate dehydrogenase [LDH], triglycerides, are presented in Table 2. A majority of the patients had HIV (9 fibrinogen), microbiologic data, diagnostic procedures (bone of 11). One was a renal transplant recipient, and the other had marrow biopsy, bronchoscopy), treatment course (antifungal no known immunosuppression. A majority were male (9 of 11), medication, chemotherapy), and outcomes (survival to hospital with a mean age of 43.9 years. The majority of HIV patients discharge). Immunosuppression included corticosteroids, TNF were not on HAART at diagnosis (6 of 9), and the mean CD4 inhibitors, calcineurin inhibitors, cytotoxic chemotherapy, in- count was very low at 14.3. The average time between admission travenous immunoglobulin (IVIG), and methotrexate. and bone marrow biopsy was 9 days (range, 3–15). Antifungal start dates were not routinely available. Results of the microbiology and radiologic testing done RESULTS during inpatient evaluation are shown in Table 3.The most Eleven cases of histoplasmosis-associated HLH were identified: consistent diagnostic finding was a positive urine Histoplasma 10 patients with hemophagocytosis on bone marrow examina- antigen, which was positive in 100% of the specimens that tion, and 1 patient reported by the Infectious Disease consult were sent (9 of 9). Eight patients had H capsulatum visualized service at the time of our search who did not undergo a bone on bone marrow biopsy (Figure 1), 7 had positive blood cultures Histoplasma-Induced HLH: A Case Series OFID 3 � � Table 2. Characteristics of Patients With Histoplasmosis-Induced HLH, 2003–2013 Immunosuppressive Case Country of Medications at ART at Time Number Age Gender Ethnicity Origin HIV Diagnosis CD4 Count HIV VL of dx 1 31 Female Hispanic Mexico Yes No 1 None Yes 2 53 Male Non-Hispanic/White USA Yes No 6 205 000 Yes 3 33 Female Non-Hispanic/Black USA Yes No 1 750 000 No 4 47 Male Hispanic Mexico No Yes N/A N/A N/A 5 28 Male Non-Hispanic/Black USA Yes No Unknown Unknown Yes 6 60 Male Hispanic Unknown No Yes N/A N/A N/A 7 44 Male Hispanic Unknown Yes No 2 190 000 No 8 52 Male Non-Hispanic/White USA Yes No 16 6 440 000 No 9 52 Male Non-Hispanic/White USA Yes No 16 6 440 000 No 10 32 Male Hispanic El Salvador Yes No 50 >10 000 000 Yes 11 51 Male Non-Hispanic/White USA Yes No 9 6036 No Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; HLH, hemophagocytic lymphohistiocytosis; N/A, not applicable; VL, viral load. for H capsulatum, and 4 had intracellular yeast seen on periph- activity were not available. All patients had fever documented eral smear (Figure 2). A bronchoalveolar lavage specimen from except for 2 patients, who had sparse medical records available. one of the patients is shown in Figure 3. On chest radiography, Cytopenias were universal and severe, with most patients having the most common finding was bilateral infiltrates (6 of 11), but platelet counts <50 × 10 /µL. The mean ferritin level was ex- other findings included pleural effusions (n = 5), pulmonary tremely high at 30 722 ng/mL (range, 1713–100 000+). All but nodules (n = 3) (Figure 4), lymphadenopathy (n = 4), pneumo- one patient had documented splenomegaly. thorax (n = 1), cardiomegaly (n = 3), and pulmonary edema From the available treatment data, the most commonly (n = 1). reported treatment regimen was liposomal amphotericin B Specific laboratory values included in the HLH-2004 criteria (n = 9) for a mean of 11 days (range, 3–21), followed by oral are reported in Table 4. Soluble IL-2 receptor levels and NK cell antifungals (most commonly itraconazole) for 3–12 months Table 3. Microbiologic and Radiologic Findings in Patients With Histoplasma-Associated HLH Bone Histoplasma Histoplasma Urine Case Marrow on Peripheral Bone Marrow With Antibody Histoplasma Sites Growing Number With Yeast Smear Hemophagocytosis (<1:8) Ag (<2.0 EIA) Histoplasma CXR Findings 1 Yes Yes Yes N/A N/A Blood, bone marrow, BI, B effusions, CM 2 Yes Yes Yes Positive Positive None BI, LAD 3 No No Yes N/A >13 Blood Hemothorax, right pneumothorax 4 No No Yes Positive Positive None BI, L effusion 5 Yes Yes Yes N/A >13 Blood, bone marrow Clear 6 Yes No Yes N/A >13 Bone marrow, skin CM 7 Yes No Yes N/A 11 Sputum, blood Edema, BI, effusions 8 Yes No Yes Positive >19 Bone marrow Miliary nodules, effusions, LAD 9 Yes No Yes N/A >19 Blood, bone marrow Miliary nodules 10 Yes No Yes Positive N/A Respiratory blood, CM, BI, nodules, L bone marrow effusion 11 No Yes Not done Negative 4.9 Respiratory, blood, BI, nodules gastric tissue Abbreviations: Ag, antigen; B, bilateral; BI, bilateral infiltrates; CM, cardiomegaly; EIA, enzyme immunoassay; HLH, hemophagocytic lymphohistiocytosis; L, Left; LAD, lymphadenopathy; N/A, not applicable (not reported). Complement fixation titer, ARUP laboratories. 4 OFID Townsend et al � � Figure 1. Gomori methenamine silver stain of bone marrow, 40×. Intra- Figure 3. Bronchoalveolar lavage specimen showing intracellular yeast. cellular yeast consistent with Histoplasma capsulatum. Wright stain, 1000×. (n = 5) (see Table 5). Three patients died during the initial am- whereas in the group not given additional immunosuppression photericin course. (n = 5), 2 died (40%). The remaining patient survived but his In addition, 2 HIV patients received steroids, 1 received IVIG treatment course was not available for review. Overall 30-day alone, and 1 received steroids in addition to IVIG. One renal mortality was high (5 of 11 patients, 45.5%). Four patients transplant patient continued on his home regimen of prednis- died during the admission (within 16 days), while one patient olone and tacrolimus, whereas the other renal transplant patient died 7 months later. There was not a significant difference in had no documented immunosuppressive treatment. One pa- mortality between patients who did or did not receive immuno- tient was started on HAART during the admission, whereas 4 suppression (P = .24, 2 tailed Fisher’s exact test) although the others were continued on their outpatient HAART regimens. comparison was underpowered. One patient presented with HLH within 3 weeks of starting HAART, which is consistent with an immune reconstitution in- DISCUSSION flammatory syndrome (IRIS). Of the 5 patients that received immunosuppression during We report eleven cases of Histoplasma-associated HLH, the admission (including prednisone, IVIG, or both), 4 died (80%), largest case series of this clinical phenomenon that has been reported to date. The relatively large number of Histoplasma- associated HLH cases at our hospital, compared with the num- ber of cases reported at other institutions in the literature, may be Figure 2. Peripheral blood smear showing intracellular yeast. 100× oil. Figure 4. Chest computed tomography with mixed pattern of large and Modified Wright-Giemsa stain. small nodules. Histoplasma-Induced HLH: A Case Series OFID 5 � � Table 4. Clinical Features and Diagnostic Criteria for HLH-2004 Platelet Nadir Peak Ferritin Case T During Hemoglobin Nadir (150–450 (30.0–400.0 LDH (135– HLH max Number Admission Rash Splenomegaly (12.4–17.3 g/dL) ×10 /µL) ng/mL) 225 U/L) Criteria 1 39.8 No Yes 6 12 Unknown 1336 5 of 8 2 38.6 No Yes 7.1 9 >16 500 971 5 of 8 3 37 No Yes 6 48 1713 227 4 of 8 4 39.2 No Yes 5.9 16 >16 500 1815 6 of 8 5 37.3 No Yes 7.3 70 >16 500 1277 4 of 8 6 38.5 Yes No 8.8 45 Unknown 971 5 of 8 7 39.9 No Yes 6.3 <5 >16 500 1402 5 of 8 8 38.7 No Yes 7 4 4392 402 6 of 8 9 39.4 No Yes 7 4 4400 402 5 of 8 10 101.9 No Yes 5.7 7 >100 000 2517 5 of 8 11 39.5 No Yes 5.7 10 >100 000 8004 5 of 8 Abbreviations: HLH, hemophagocytic lymphohistiocytosis; LDH, lactate dehydrogenase; T, temperature. due to the geographic overlap of histoplasmosis and HIV as well prevalent than we found in our series, given our somewhat lim- as the under-recognition of this condition in other settings [31, ited case finding strategy. In addition, while many clinicians rec- 32]. We hypothesize that this condition may be even more ognize that disseminated histoplasmosis causes high fevers, an Table 5. Treatment and outcomes of Histoplasma-associated hemophagocytic lymphohistiocytosis Liposomal Oral HAART Survival amphotericin antifungal Immuno HAART at Immuno started from Case Antifungal drug B duration duration suppressive time of suppressive during Outcome admission Number used (days) (days) treatment diagnosis duration admission at 30 days (days) 1 Liposomal Unknown 0 days None Yes None No Died 16 amphotericin B 2 Liposomal 14 Unknown None Yes None Yes Alive 2168 amphotericin B; itraconazole 3 Liposomal 21 >1 year Prednisone 20 mg No Unknown No Died 221 amphotericin PO daily B; fluconazole 4 Itraconazole 0 Unknown None N/A None N/A Alive 44 5 Unknown Unknown Unknown Unknown Yes Unknown Unknown Alive 3560 6 Liposomal Unknown Unknown Prednisolone 10 N/A 5 months N/A Alive 2849 amphotericin mg po BID, B; voriconazole Tacrolimus 1.5 mg PO daily 7 Liposomal 16 12 weeks None No None No Alive 86 amphotericin B; itraconazole 8 Liposomal 5 0 days IVIG × 1; No 9 days No Died 9 amphotericin prednisone 40 B; itraconazole BID 9 Liposomal 3 Unknown IVIG 1gm × 1 No 1 day No Died 9 amphotericin B; itraconazole 10 Liposomal 18 >1 year None Yes None No Alive 408 amphotericin B; itraconazole 11 Liposomal 11 0 days Prednisone 40 mg No 11 days Yes Died 13 amphotericin B PO BID; solumedrol 60 mg IV q6hrs Abbreviations: HAART, Highly active antiretroviral therapy; IVIG, intravenous immunoglobulin. 6 OFID Townsend et al � � elevated LDH, and a high ferritin, they may not consider HLH in not receiving HIV treatment at the time of developing HLH, it this clinical scenario. In our series, the mean time from presen- also may precipitate HLH. In our series, one patient presented tation to bone marrow was >1 week, which may have led to treat- with HLH within 3 weeks of starting HAART, which is consistent ment delays. It remains to be seen if early diagnosis could lead to with an immune reconstitution inflammatory syndrome (IRIS). improved outcomes with earlier institution of antimicrobial and Prior publications have reported HLH as a manifestation of IRIS possibly immunsuppressive therapy. in HIV-positive patients, 2 with HIV alone, 1 associated with leish- In our series, uncontrolled HIV was the dominant risk factor mania, 1 with EBV, and 1 with lymphoma [25, 38–43]. As with for this condition, while renal transplant patients are also at risk other chronic fungal and mycobacterial diseases that have a strong [33]. HIV patients may be uniquely vulnerable to HLH given potential to cause IRIS, it may be reasonable to wait for the acute the depletion of NK cells in HIV, which has been connected phase of HLH to resolve before instituting HIV treatment. to multiple manifestations of immune dysregulation [20, 34, There remains considerable controversy surrounding treat- 35]. Thepredominanceofmales is difficult to explain, as no ment of adult patients with HLH related to infectious triggers. gender predilection has been reported for HLH or histoplasmo- Our comparison between patients who did or did not receive sis, but may be related to a higher prevalence of HIV in males in additional immunosuppression detected more survivors in the Dallas. Guidelines do not recommend routinely screening for non-immunosuppression group, although the analysis is under- disseminated histoplasmosis in HIV patients before starting powered and may reflect treatment bias of individuals who were HAART [36], noris thisdoneinrenal transplant patients. more ill. Additional data, even if retrospective, must be com- However, it may be reasonable to screen patients with severe piled to help guide decisions in this difficult-to-treat group. anemia or thrombocytopenia with a urine histoplasma antigen, This study has several limitations. First, our search strategy especially those planned for intense immunosuppression, so focused on bone marrow biopsy results, which may have missed that their infection might be recognized and treated prior to patients with histoplasmosis-associated HLH who did not un- immunosuppression. dergo bone marrow biopsy. Nonetheless, we were able to iden- One interesting clinical finding in our series that has not been tify 11 cases over an approximately 10-year period, which is the described previously is the occurrence of a cardiopulmonary largest case series of histoplasmosis-associated HLH to date. syndrome in patients with HLH. Several patients had either car- Second, the medical records from patients occurring before im- diomegaly, pleural effusions, or pulmonary edema on their plementation of the electronic medical record had less detailed chest radiographs. A high output state related to anemia in information about treatment regimens. Finally, because this is a these patients may be contributing, possibly in addition to the retrospective review with a small sample size, no conclusions cytokine storm causing leaky vasculature. can be reached on the impact of different treatment regimens Treatment for the triggering condition is recommended as on clinical outcomes. Prospective treatment studies would be first line therapy for patients with HLH, although indications ideal, but they are unlikely given the rarity of this disease. for initiating chemotherapy directed at HLH is less clear in the adult population with the sporadic (rather than inherited CONCLUSIONS form) of the disease. Although all patients in our series received antifungal treatment with amphotericin products and/or azole Histoplasma-associated HLH was relatively common at our treatment, there was wide variability on whether or not immu- large urban safety net hospital in Dallas, Texas, and uncon- nomodulation was used. None of the patients in this series were trolled HIV patients make up the majority of patients, whereas treated with the chemotherapy protocols such as those recom- solid organ transplant patients also seem to be at risk. Key fea- mended for HLH in children (etoposide, dexamethasone with tures that should prompt evaluation for this condition are sple- or without intrathecal therapy),although half of patients in nomegaly, an extremely elevated ferritin, and cytopenias in an our series received steroids, IVIG, or both. Given the small sam- immunocompromised patient. Fungal blood cultures and urine ple size, no benefit or harm could be attributed to IVIG or ste- Histoplasma antigen are high-yield tests in this setting for diag- roids. Since a majority of tissue damage is caused by cytotoxic nosing H capsulatum as the underlying trigger for HLH. The lymphocytes, therapiessuchascorticosteroids and cytotoxic mortality rate is high despite the use of antifungal agents and chemotherapies such as those used in children make sense as immune suppression. More data on treatment for this condition strategies to control the inflammation, but have not been estab- are needed in adults. The role and timing of HAART initiation lished in adults. More targeted immunosuppression in macro- in treatment of this condition remains unclear. phage activation syndrome (a similar pathologic process) is being evaluated in studies underway using cytokine antagonists Acknowledgments and IL-1 receptor antagonists [37]. Disclaimer. The content is solely the responsibility of the authors and The role of HAART for treatment of this condition is not does not necessarily represent the official views of the National Institutes of clear. Although HAART may improve outcomes in patients Health. Histoplasma-Induced HLH: A Case Series OFID 7 � � Financial support. This study was supported by the National Center for 20. Gil-Brusola A, Peman J, Santos M, et al. Disseminated histoplasmosis Advancing Translational Sciences of the National Institutes of Health with hemophagocytic syndrome in a patient with AIDS: description (award Number KL2TR001103; to A. 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Published: Apr 1, 2015

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