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Published ahead of print on February 13, 2003, doi:10.1164/rccm.200206-563OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1279-1282, (2003)
© 2003 American Thoracic Society

Histoplasmosis after Treatment with Anti–Tumor Necrosis Factor-{alpha} Therapy

Karen L. Wood, Chadi A. Hage, Kenneth S. Knox, Martin B. Kleiman, Aruna Sannuti, Richard B. Day, L. Joseph Wheat and Homer L. Twigg, III

Divisions of Pulmonary and Critical Care, and Infectious Disease, Department of Medicine and Department of Pediatrics, Infectious Disease, Indiana University School of Medicine, Indianapolis, Indiana

Correspondence and requests for reprints should be addressed to Homer L. Twigg III, M.D., 1001 West Tenth Street, OPW 425 Indianapolis, IN 46202. E-mail: htwig{at}iupui.edu


   ABSTRACT
TOP
 ABSTRACT
CASE REPORTS
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Anti–tumor necrosis factor-{alpha} (TNF-{alpha}) antibodies are frequently used to treat inflammatory diseases. However, these drugs also have immunosuppressive effects. We report on three patients who developed disseminated histoplasmosis on therapy with TNF-{alpha} inhibitors. In vitro assays were used to characterize the role of these agents in host defense against Histoplasma capsulatum. Intracellular proliferation of H. capsulatum was measured in alveolar macrophages and peripheral monocytes of normal volunteers in the presence and absence of the TNF-{alpha} antibody, infliximab. Both infliximab and control antibody enhanced fungal growth in monocytes and alveolar macrophages, suggesting this was a nonspecific antibody response. Despite similar intracellular fungal loads in the presence of both antibodies, lymphocyte proliferation in response to blood monocytes and alveolar macrophages infected with H. capsulatum was inhibited by the addition of physiologic doses of infliximab, whereas control antibody had no effect. The production of H. capsulatum–induced interferon-{gamma} and TNF-{alpha} was assessed in 5-day cultures containing lymphocytes and alveolar macrophages or monocytes. Interferon-{gamma} secretion was significantly reduced in the presence of infliximab. In summary, patients receiving anti–TNF-{alpha} therapy are at risk for developing disseminated histoplasmosis. This may be due to a defect in the TH1 arm of cellular immunity.

Key Words: histoplasmosis • tumor necrosis factor-{alpha} • anti–tumor necrosis factor-{alpha} antibodies • interferon-{gamma}

Therapies directed against tumor necrosis factor-{alpha} (TNF-{alpha}) have been proven efficacious in decreasing the pathologic inflammatory response in rheumatoid arthritis (1) and Crohn's disease (2). As with many antiinflammatory agents, these therapies functionally immunosuppress the patient, increasing the risk of infection (3–5). Histoplasmosis is the most prevalent endemic mycosis in the U.S. (6) and a common opportunistic infection (7). Immunosuppressed patients are at high risk for severe infection with diffuse pulmonary disease and/or progressive dissemination (8, 9). Murine models have demonstrated that cell-mediated immunity, including TNF-{alpha} secretion, plays a critical role in the host defense against Histoplasma capsulatum (10–13). Thus, TNF-{alpha} inhibitors could potentially interfere with host responses to H. capsulatum in humans. We report three patients from Indiana who developed histoplasmosis after initiation of therapy with TNF-{alpha} inhibitors, provide evidence for the importance of TNF-{alpha} in the immune response to H. capsulatum, and propose guidelines for management.


   CASE REPORTS
TOP
 ABSTRACT
 CASE REPORTS
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Case 1
A 50-year-old white male with rheumatoid arthritis receiving methotrexate 10 mg once a week and methylprednisolone 8 mg daily was started on infliximab injections at 3 mg/kg monthly. Ten weeks after the start of therapy, he began to experience dyspnea and cough and was hospitalized for severe respiratory failure, requiring mechanical ventilation. Chest radiograph showed bilateral reticulonodular infiltrates; complete blood cell count was normal. Bronchoalveolar lavage fluid contained yeast forms resembling H. capsulatum, confirmed by culture. Histoplasma urine antigen was 10.3 U (>= 1 U is positive), complement fixation titers were 1:2,048 to the mycelial (M) antigen and 1:256 to the yeast (Y) antigen (>= 1:8 is positive), and immunodiffusion revealed both H and M bands (detection of any band is positive). Amphotericin B lipid complex 5 mg/kg/day was given for 11 days, followed by itraconazole 200 mg/day. Respiratory function improved, but he required ventilatory support despite 60 days of anti-fungal therapy.

Case 2
A 17-year-old white female with juvenile rheumatoid arthritis, treated with infliximab 300 mg monthly for 8 months, azathioprine 50 mg daily, and prednisone 5 mg daily, was admitted with cough, fever, chills, nausea, and vomiting. On examination she appeared ill with fever and tachypnea. Complete blood count and chest radiograph were normal. Symptoms persisted with empiric antibiotic treatment. Workup demonstrated a Histoplasma urine antigen of 4.3 U, complement fixation titers of 1:64 to the M antigen, and an M band on immunodiffusion. Amphotericin B was initiated and immunosuppressive therapy was discontinued. Leukopenia and thrombocytopenia developed in the first week of treatment and subsequently resolved. She received amphotericin B for 5 weeks before changing to itraconazole 200 mg/day. She is currently asymptomatic. This was the index case for a large outbreak of histoplasmosis resulting from contaminated soil in proximity to the patient's high school.

Case 3
A 50-year-old white female with rheumatoid arthritis receiving etanercept 25 mg twice weekly for more than 1 year and methotrexate 10 mg weekly for 3 years presented with complaints of fever, sweats, headache, cough, dyspnea, nausea, and vomiting for 3 weeks. The patient was a teacher in the school attended by the patient in CASE 2. Laboratory studies revealed elevated liver function tests and normal complete blood count. Chest radiograph showed bilateral diffuse reticulonodular infiltrates. Cerebrospinal fluid was normal. Workup demonstrated a Histoplasma urine antigen of 3.1 U, complement fixation titers of less than 1:8 to the M antigen and 1:32 to the Y antigen, and an M band on immunodiffusion. Itraconazole 200 mg twice daily was started on Day 20 after presentation; etanercept and methotrexate were stopped. She responded to therapy with oral itraconazole; her fever resolved and cough and fatigue improved.


   METHODS
TOP
 ABSTRACT
 CASE REPORTS
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Bronchoscopy with bronchoalveolar lavage and phlebotomy was performed on healthy volunteers. Bronchoalveolar lavage fluid was processed and alveolar macrophages were obtained as previously described (14). Peripheral blood mononuclear cells were obtained by Ficoll-Hypaque gradient centrifugation. After adherence to plastic for 1 hour, nonadherent cells were removed and lymphocytes were purified by rosetting with sheep red blood cells for 2 hours. Adherent monocytes were harvested by gentle scraping. Alveolar macrophages and peripheral monocytes were plated at 5 x 104 cells per well in 96-well plates. A fungistatic assay was performed as previously described (15). Briefly, 5 x 103 H. capsulatum yeasts (clinical isolate IU-CT; Indianapolis, IN) in 5% fetal calf serum RPMI with 10 µg/ml gentamicin were placed in each well with monocytes or macrophages, in the presence of anti–TNF-{alpha} antibodies (infliximab; Centocor, Inc., Malvern, PA) or a human IgG control (Calbiochem, San Diego, CA) at concentrations ranging from 0.1 to 10 µg/ml. After 24 hours, supernatants were removed, 50 µl [3H] leucine (1.5 µCi; New England Nuclear, Boston, MA; specific activity > 140 Ci/mol) and 5 µl of 10x yeast nitrogen broth were added. Eighteen hours later, 50 µl of L-leucine and 50 µl of sodium hypochlorite were added, and cells were harvested with an automated harvester and counted in a liquid scintillation counter. This assay has been shown to reflect actual proliferation of H. capsulatum and not simply increased uptake of labeled organisms (15). Lymphoproliferation experiments were performed as previously described (16). Briefly, monocytes or macrophages were incubated with or without autologous purified blood lymphocytes, live H. capsulatum, and 1 µg/ml infliximab or control IgG in 20% fetal calf serum RPMI with 10 µg/ml gentamicin for 5 days. Supernatants were harvested and 10 µl of 0.1 mCi/ml of [3H] thymidine (specific activity 6.7 Ci/mol; New England Nuclear) was added. Eighteen hours later, sodium hypochlorite was added and the cells harvested. All supernatants were frozen and used for cytokine measurements. All proliferation experiments were performed in triplicate. Importantly, for these 6-day assays, both infliximab and the control antibody were shown in control experiments to have no effect on cell viability.

TNF-{alpha}, IFN-{gamma}, interleukin (IL)-10, and IL-4 measurements were performed using commercially available enzyme-linked immunosorbent assay kits (Quantikine Colorimetric Sandwich ELISA kits; R&D Systems, Minneapolis, MN) following the manufacturer's directions. The lower limit of detection of these kits was 8.0 pg/ml for IFN-{gamma}, 0.12 pg/ml for TNF-{alpha}, 0.13 pg/ml for IL-4, and 0.5 pg/ml for IL-10.

Statistics
Data are shown as the mean ± standard error (SEM). All data sets were tested for normality and found to be non-normally distributed. Non-normal data sets were first analyzed using an analysis of variance on the ranked data. The {alpha}-level for significance was set at 0.1 due to the small number of subjects available for analysis. When significant differences were identified, a Duncan's post-hoc analysis was performed to separate effects.


   RESULTS
TOP
 ABSTRACT
 CASE REPORTS
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Proliferation of H. capsulatum in alveolar macrophages and monocytes was determined by the incorporation of [3H] leucine in four normal volunteers in the presence and absence of infliximab or control antibody at various concentrations from 0.1 to 10 µg/ml. Although there is a modest increase in H. capusulatum growth in monocytes and macrophages in the presence of either antibody, there was no difference between the two, suggesting this was a nonspecific antibody response. In Figure 1 , we show the data in alveolar macrophages at an antibody concentration of 1 µg/ml, which is the concentration used for all subsequent experiments. This concentration is also comparable to plasma concentrations found after therapeutic dosing of infliximab. Thus, differences in all subsequent immunologic assays are not the result of increased fungal growth in the presence of infliximab versus control antibody.



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  		Figure 1. Intracellular growth of Histoplasma capsulatum (HC) in alveolar macrophages (AM). AM were exposed to live H. capsulatum in the presence of infliximab or control human IgG antibody as described in METHODS. Growth of HC was measured by incorporation of radioactive leucine 18 hours after infection. HC growth increases modestly after exposure to both antibodies. No difference is noted between the uptake and growth of HC in AMs treated with either infliximab or control IgG antibody (n = 4).

 
To assess the effect of TNF-{alpha} inhibitors on lymphoproliferative responses to intracellular H. capsulatum, lymphocyte proliferation measured by [3H] thymidine incorporation was determined in the presence and absence of 1.0 µg/ml infliximab. Table 1 demonstrates that in three out of four individuals, circulating lymphocytes proliferated in response to H. capsulatum when co-cultured with monocytes or alveolar macrophages. When alveolar macrophages were used as the antigen presenting cell, proliferation was completely inhibited by the addition of 1.0 µg/ml infliximab. Interestingly, infliximab had no effect on H. capsulatum–induced lymphoproliferation when monocytes were used as the antigen presenting cell. The control antibody had no effect on H. capsulatum–induced lymphoproliferation when either macrophages or monocytes were used as the accessory cell.


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  		TABLE 1. Lymphocyte proliferation in response to histoplasma capsulatum in the presence and absence of infliximab and control antibody

 
We next assessed the production of various cytokines in response to histoplasmosis infection. Table 2 demonstrates that IFN-{gamma} and TNF-{alpha} were produced in response to infection with H. capsulatum. This response was only observed in wells with an antigen presenting cell and lymphocytes in the presence of organisms. Importantly, cultures of lymphocytes or macrophages alone plus H. capsulatum demonstrated very little cytokine production (data not shown). A ranked analysis of variance showed statistically significant differences in IFN-{gamma} and TNF-{alpha} production between interventions. H. capsulatum induced IFN-{gamma} and TNF-{alpha} secretion in cultures of lymphocytes plus monocytes or alveolar macrophages. This response was almost completely inhibited by infliximab in macrophage–lymphocyte cultures and was significantly inhibited in monocyte–lymphocyte cultures. Control IgG antibody had no effect on H. capsulatum–induced cytokine secretion. H. capsulatum induced small amounts of IL-10 and IL-4 secretion, though this was minimal compared with IFN-{gamma} and TNF-{alpha} secretion. Infliximab had a small, nonsignificant effect on secretion of IL-10 and IL-4 as well. Interestingly, individuals who had a brisk lymphoproliferative response to H. capsulatum produced the most TNF-{alpha} and IFN-{gamma}. Although the one individual who had no lymphoproliferation in response to H. capsulatum had the lowest cytokine secretion, there was still a clear preference for production of TH1 cytokines. These results suggest that H. capsulatum induces primarily a TH1 cytokine response, which is inhibited by anti-TNF antibodies regardless of whether the immune response is primary (as evidenced by low cytokine production and lymphoproliferation) or secondary (high cytokine production and lymphoproliferation). These results also demonstrate that the generation of a TH1 response requires interaction between accessory cells and T cells in response to H. capsulatum antigens.


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  		TABLE 2. Cytokine production in response to histoplasma in the presence and absence of infliximab

 

   DISCUSSION
TOP
 ABSTRACT
 CASE REPORTS
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We report three patients with disseminated histoplasmosis, which occurred while receiving TNF-{alpha} inhibitors for rheumatoid arthritis and juvenile rheumatoid arthritis. We further demonstrate in an in vitro model of histoplasmosis that exposure of lymphocytes and alveolar macrophages to H. capsulatum results in T cell proliferation and secretion of IFN-{gamma} and TNF-{alpha}, cytokines typical of a TH1 response. Intracellular growth of H. capsulatum in monocytes and alveolar macrophages is enhanced equally in the presence of anti–TNF-{alpha} antibodies and control IgG antibodies. However, only antibodies to TNF-{alpha} specifically inhibit T cell proliferation. Finally, anti–TNF-{alpha} antibodies, but not control antibodies, completely abrogate the H. capsulatum–induced TH1 response in alveolar macrophage cultures and significantly inhibit the response in monocyte cultures. Thus, these data provide evidence that the increased incidence of disseminated histoplasmosis in patients receiving anti–TNF-{alpha} therapy results from inhibition of an appropriate TH1 response.

Despite the recognition that TNF-{alpha} and IFN-{gamma} are important in host defense against H. capsulatum, previous studies have shown that exogenously administered cytokines do not enhance the fungistatic activity of human monocytes/macrophages (15, 17). Our results demonstrating that anti–TNF-{alpha} antibodies were no different than control human IgG in their effect on macrophage fungistatic activity supports this concept. In fact, our observation that infliximab significantly impairs H. capsulatum–induced lymphoproliferation and IFN-{gamma} secretion without affecting macrophage fungistatic activity suggests that TNF-{alpha} is more important as a regulator of the cellular immune response than as a direct mediator of macrophage phagocytic function. The role of TNF-{alpha} in cellular immune responses is complex. Whereas TNF-{alpha} is clearly important in initiating an inflammatory and cellular immune response, recent work suggests that it may also possess anti-inflammatory and immunosuppressive properties in established infections, possibly through inhibition of IL-12 production (18). However, in our model of acute infection, inhibition of TNF-{alpha} appears to have a detrimental effect on the initial TH1 response to H. capsulatum.

The lymphoproliferative response to H. capsulatum tended to be greatest when monocytes were used as the antigen presenting cell. Despite this response, the inhibitory effect of infliximab on lymphoproliferation was greatest in alveolar macrophage cultures. This observation supports extensive prior investigations demonstrating that alveolar macrophages are poor accessory cells as compared with blood monocytes (19). It is also intriguing that the H. capsulatum–induced IFN-{gamma} response is more completely inhibited by infliximab in alveolar macrophage cultures than monocyte cultures. These findings suggest that the lung may be uniquely susceptible to the immunosuppressive effects of anti–TNF-{alpha} antibodies.

In addition to our 3 patients, 12 cases of histoplasmosis occurring in patients taking TNF-{alpha} inhibitors have been reported in the literature (4, 5, 20). Together, infections occurred in 13 patients receiving infliximab and in 2 receiving etanercept. Eleven of the 12 outside cases of histoplasmosis were diagnosed by tissue biopsy. Our three cases were diagnosed noninvasively by antigen detection and serologic methods—antigenuria is present in 92% of patients with disseminated histoplasmosis and can be seen with primary infection after intense exposure. Measurement of Histoplasma antigen in the urine and blood is a rapid, noninvasive technique that can aid in the diagnosis of histoplasmosis in patients with disseminated histoplasmosis (21). We believe that it may also prove useful in the setting of patients receiving TNF-{alpha} inhibitors.

On the basis of epidemiologic data and our in vitro work, it would seem prudent to withhold TNF-{alpha} inhibitors in patients being treated for histoplasmosis. Chronic antifungal maintenance therapy may be needed if TNF-{alpha} inhibiting therapy is resumed. Itraconazole maintenance therapy prevents relapse of histoplasmosis in persons with AIDS (22) and would be expected to be effective in patients who reinstitute TNF-{alpha} inhibiting therapy. If chronic maintenance therapy is not implemented, urine antigen screening at 3-month intervals may be performed to look for recurrence.

Screening for exposure to H. capsulatum before beginning anti–TNF-{alpha} therapy would also seem reasonable. It is already standard of care to screen for tuberculosis with placement of a PPD before starting therapy with many immunosuppressive agents. However, it is unclear whether remote exposure to H. capsulatum predicts risk of recurrent infection. Modes of acquisition of active infection in immunocompromised hosts may include exogenous exposure or reactivation of latent infection. However, numerous studies have shown that histoplasmosis in immunosuppressed patients is relatively uncommon, even in endemic areas (9, 23, 24). These data suggest that reactivation of "latent" infection during immunosuppression is rare, and exogenous exposure of nonimmune or previously infected hosts is the more common mode of acquisition. Furthermore, screening for histoplasmosis using skin test reactivity or serology has not been shown to predict which immunosuppressed patients will develop active infection (24–26). Thus screening for histoplasmosis in patients about to start immunosuppressive therapy, including anti–TNF-{alpha} antibodies, is not recommended at this time.

In summary, patients receiving anti–TNF-{alpha} therapy are at risk for developing severe histoplasmosis. This may be due to impairment of the normal TH1 immune response to H. capsulatum. Patients starting anti–TNF-{alpha} should be followed closely for the development of granulomatous infections, including histoplasmosis.


   FOOTNOTES
 
Supported by Department of Veteran's Affairs (L.J.W.) and National Institutes of Health grant RO1 HL59834 (H.L.T.).

Received in original form June 6, 2002; accepted in final form February 10, 2003


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 ABSTRACT
 CASE REPORTS
 METHODS
 RESULTS
 DISCUSSION
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S. D. Roberts, D. S. Wilkes, R. A. Burgett, and K. S. Knox
Refractory Sarcoidosis Responding to Infliximab
Chest, November 1, 2003; 124(5): 2028 - 2031.
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S Ehlers
Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF
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Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2003 American Thoracic Society