Histoplasmosis on TNF Blockers

1. Histoplasmosis on TNF Blockers C. Hage Indiana University School of Medicine L.J. Wheat MiraVista Diagnostics

2. LB Edwards ARRD 1969 Histoplasmosis on TNF Blockers Endemic distribution of H. capsulatum in the US , based on histoplasmin skin test positivity in Navy recruits (LB Edwards ARRD 1969;99:1-18)Endemic distribution of H. capsulatum in the US , based on histoplasmin skin test positivity in Navy recruits (LB Edwards ARRD 1969;99:1-18)

3. Microconidia Infectious  Hage SRCCM 2008 Microconidia measure 2-3 microns and deposited in alveoli upon inhalation, causing localized pulmonary infection when the inoculum is low and the patient is not immunosuppressed. Pulmonary histo usually manifested by hilar or mediastinal adenopathy and focal infiltrate. Scattered infiltrates and nodules may occur with larger exposure. Microconidia measure 2-3 microns and deposited in alveoli upon inhalation, causing localized pulmonary infection when the inoculum is low and the patient is not immunosuppressed. Pulmonary histo usually manifested by hilar or mediastinal adenopathy and focal infiltrate. Scattered infiltrates and nodules may occur with larger exposure.

4. Yeast Pathogenic Newman Sem Res Infec 2001 Development of cellular immunity during the first month of infection prevents progression and permits clearance of the infection. Progressive dissemination more likely in individuals with reduced immunity. Development of cellular immunity during the first month of infection prevents progression and permits clearance of the infection. Progressive dissemination more likely in individuals with reduced immunity.

5. TNF Activates Macrophage Cell-mediated immunity plays a critical role in the host defense against H. capsulatum, and requires dendritic cells, which process antigens for stimulation of specific CD4 and CD8 lymphocytes; TH1 cytokines (interferon-?, TNF-?); interleukin 12 and 18; and activated macrophages [1]   Reference List   1. Cutler JE, Deepe GS, Jr., and Klein BS. Advances in combating fungal diseases: vaccines on the threshold. Nat Rev Microbiol 2007; 5:13-28.  Cell-mediated immunity plays a critical role in the host defense against H. capsulatum, and requires dendritic cells, which process antigens for stimulation of specific CD4 and CD8 lymphocytes; TH1 cytokines (interferon-?, TNF-?); interleukin 12 and 18; and activated macrophages [1]   Reference List   1. Cutler JE, Deepe GS, Jr., and Klein BS. Advances in combating fungal diseases: vaccines on the threshold. Nat Rev Microbiol 2007; 5:13-28.  

6. TNF Role in Granuloma Chadi Hage Mature granuloma in histoplasmosisMature granuloma in histoplasmosis

7. Anti-TNF? “Loose” Granuloma Chadi Hage Anti-TNF prevents the development of a well-organized granulomaAnti-TNF prevents the development of a well-organized granuloma

8. Key Findings  Wallis summarizes results of AERS reports from January 1998 through September 2002 and Winthrop reports a survey done through the Emerging Infection Network. Reasons for the high ratio of histoplasmosis to tuberculosis in the Winthrop report may include a lower incidence of tuberculosis in the United States and the effectiveness of screening and treating tuberculosis before beginning TNF blockers. Hage has reviewed the experience at the Indiana University medical center, where there have been over 20 cases of histoplasmosis in patients receiving TNF blockers (manuscript being prepared). Wallis summarizes results of AERS reports from January 1998 through September 2002 and Winthrop reports a survey done through the Emerging Infection Network. Reasons for the high ratio of histoplasmosis to tuberculosis in the Winthrop report may include a lower incidence of tuberculosis in the United States and the effectiveness of screening and treating tuberculosis before beginning TNF blockers. Hage has reviewed the experience at the Indiana University medical center, where there have been over 20 cases of histoplasmosis in patients receiving TNF blockers (manuscript being prepared).

9. Reported Cases See notes Among cases reported in more detail, pneumonia and progressive disseminated disease (PDH) were present in 70-80% [1-8]   Reference List   1. Wood KL, Hage CA, Knox KS et al. Histoplasmosis after Treatment with Anti-TNF-{alpha} Therapy. Am J Respir Crit Care Med 2003; 167:1279-82. 2. Sawalha AH, Lutz BD, Chaudhary NA, Kern W, Harley JB, and Greenfield RA. Panniculitis: A Presenting Manifestation of Disseminated Histoplasmosis in a Patient with Rheumatoid Arthritis. J Clin Rheumatol 2003; 9:259-62. 3. Galandiuk S and Davis BR. Infliximab-induced disseminated histoplasmosis in a patient with Crohn's disease. Nat Clin Pract Gastroenterol Hepatol 2008; 5:283-7. 4. Goulet CJ, Moseley RH, Tonnerre C, Sandhu IS, and Saint S. Clinical problem-solving. The unturned stone. N Engl J Med 2005; 352:489-94. 5. Zhang Z, Correa H, and Begue RE. Tuberculosis and treatment with infliximab. N Engl J Med 2002; 346:623-6. 6. Nakelchik M and Mangino JE. Reactivation of histoplasmosis after treatment with infliximab. Am J Med 2002; 112:78-9. 7. Jain VV, Evans T, and Peterson MW. Reactivation histoplasmosis after treatment with anti-tumor necrosis factor alpha in a patient from a nonendemic area. Respir Med 2006; 100:1291-3. 8. Narayana N, Gifford R, Giannini P, and Casey J. Oral histoplasmosis: An unusual presentation. Head Neck 2008.    Among cases reported in more detail, pneumonia and progressive disseminated disease (PDH) were present in 70-80% [1-8]   Reference List   1. Wood KL, Hage CA, Knox KS et al. Histoplasmosis after Treatment with Anti-TNF-{alpha} Therapy. Am J Respir Crit Care Med 2003; 167:1279-82. 2. Sawalha AH, Lutz BD, Chaudhary NA, Kern W, Harley JB, and Greenfield RA. Panniculitis: A Presenting Manifestation of Disseminated Histoplasmosis in a Patient with Rheumatoid Arthritis. J Clin Rheumatol 2003; 9:259-62. 3. Galandiuk S and Davis BR. Infliximab-induced disseminated histoplasmosis in a patient with Crohn's disease. Nat Clin Pract Gastroenterol Hepatol 2008; 5:283-7. 4. Goulet CJ, Moseley RH, Tonnerre C, Sandhu IS, and Saint S. Clinical problem-solving. The unturned stone. N Engl J Med 2005; 352:489-94. 5. Zhang Z, Correa H, and Begue RE. Tuberculosis and treatment with infliximab. N Engl J Med 2002; 346:623-6. 6. Nakelchik M and Mangino JE. Reactivation of histoplasmosis after treatment with infliximab. Am J Med 2002; 112:78-9. 7. Jain VV, Evans T, and Peterson MW. Reactivation histoplasmosis after treatment with anti-tumor necrosis factor alpha in a patient from a nonendemic area. Respir Med 2006; 100:1291-3. 8. Narayana N, Gifford R, Giannini P, and Casey J. Oral histoplasmosis: An unusual presentation. Head Neck 2008.    

10. Misdiagnosis Crohn’s Goulet NEJM 2005 Goulet NEJM 2005;352:489. 20 yo but life-long diarrhea. Dgn Crohn’s and treated with steroids. Two recent doses of infliximab. Goulet noted that is important to R/O infection in workup Crohn’s. Recommended Histo antigen. Question of IRIS causing worsening after held steroids and started ampho B.Goulet NEJM 2005;352:489. 20 yo but life-long diarrhea. Dgn Crohn’s and treated with steroids. Two recent doses of infliximab. Goulet noted that is important to R/O infection in workup Crohn’s. Recommended Histo antigen. Question of IRIS causing worsening after held steroids and started ampho B.

11. Buccal and Colon Ulcers www.infdiseasesconsultants.com/idcase6.php Gastrointestinal ulcers caused by histoplasmosis in a patient treated with adalimumab, courtesy of Dr. William Muth, and described in more detail on his websiteGastrointestinal ulcers caused by histoplasmosis in a patient treated with adalimumab, courtesy of Dr. William Muth, and described in more detail on his website

12. Cutaneous Lesions A variety of skin lesions have been described in patients receiving TNF blockers who have disseminated histoplasmosis. Some have developed necrotic findings after stopping the TNF blocker, suggesting IRIS. A variety of skin lesions have been described in patients receiving TNF blockers who have disseminated histoplasmosis. Some have developed necrotic findings after stopping the TNF blocker, suggesting IRIS.

13. Other Sites CNS and adrenal involvement may be seen in PDH and have been reported in patients receiving TNF blockers (Wheat, unpublished closed(. CNS and adrenal involvement may be seen in PDH and have been reported in patients receiving TNF blockers (Wheat, unpublished closed(.

14. Mode of Acquisition Controversy exists as to the mode of acquisition of histoplasmosis in these patients, however. Histoplasmosis could represent 1). newly acquired primary infection, 2). reinfection caused by a loss of immunity during immunosuppression, 3). progression of undiagnosed “smoldering” histoplasmosis that was present when the TNF blocker was initiated, or 4). reactivation of “latent” histoplasmosis. Controversy exists as to the mode of acquisition of histoplasmosis in these patients, however. Histoplasmosis could represent 1). newly acquired primary infection, 2). reinfection caused by a loss of immunity during immunosuppression, 3). progression of undiagnosed “smoldering” histoplasmosis that was present when the TNF blocker was initiated, or 4). reactivation of “latent” histoplasmosis.

15. Doesn’t Reactivate Among nearly 600 transplant patients in Indianapolis, where three large outbreaks of histoplasmosis had occurred during the preceding 20 years, not one developed histoplasmosis [1]. Similarly, among over 600 children given chemotherapy for malignancy in Memphis, none developed histoplasmosis [2].     Reference List: 1. Vail GM, Young RS, Wheat LJ, Filo RS, Cornetta K, and Goldman M. Incidence of histoplasmosis following allogeneic bone marrow transplant or solid organ transplant in a hyperendemic area. Transpl Infect Dis 2002; 4:148-51. 2. Hughes WT. Hematogenous histoplasmosis in the immunocompromised child. J Pediatr 1984; 105:569-75.  Among nearly 600 transplant patients in Indianapolis, where three large outbreaks of histoplasmosis had occurred during the preceding 20 years, not one developed histoplasmosis [1]. Similarly, among over 600 children given chemotherapy for malignancy in Memphis, none developed histoplasmosis [2].     Reference List: 1. Vail GM, Young RS, Wheat LJ, Filo RS, Cornetta K, and Goldman M. Incidence of histoplasmosis following allogeneic bone marrow transplant or solid organ transplant in a hyperendemic area. Transpl Infect Dis 2002; 4:148-51. 2. Hughes WT. Hematogenous histoplasmosis in the immunocompromised child. J Pediatr 1984; 105:569-75.  

16. “No …endogenous reinfection” Straub & Schwarz AJCVP 1955 Calcified mediastinal lymph nodes caused by histoplasmosis. Straub and Schwarz evaluated calcified granuloma in the long and mediastinal lymph nodes of consecutive autopsies in Cincinnati, Ohio. They found no evidence for viable organisms based upon fungal culture and injection of the material into mice. They concluded that endogenous reinfection was unlikely in histoplasmosis, in contrast to tuberculosis, because organisms persisting in granuloma are not viable.Calcified mediastinal lymph nodes caused by histoplasmosis. Straub and Schwarz evaluated calcified granuloma in the long and mediastinal lymph nodes of consecutive autopsies in Cincinnati, Ohio. They found no evidence for viable organisms based upon fungal culture and injection of the material into mice. They concluded that endogenous reinfection was unlikely in histoplasmosis, in contrast to tuberculosis, because organisms persisting in granuloma are not viable.

17. When to Consider Patients should be questioned about possible exposure or evidence for active or recent past histoplasmosis before beginning TNF blockers. Role of serology or antigen detection screening is unclear, but testing should be considered for evaluation of possible exposure or symptoms. Patients should be questioned about possible exposure or evidence for active or recent past histoplasmosis before beginning TNF blockers. Role of serology or antigen detection screening is unclear, but testing should be considered for evaluation of possible exposure or symptoms.

18. Avoid & Report Exposure Patients should be educated about their risk for developing histoplasmosis and when to suspect it (link to MVD website, Appendix 2). Additional guidance on patient education is provided in the FDA alert (link).Patients should be educated about their risk for developing histoplasmosis and when to suspect it (link to MVD website, Appendix 2). Additional guidance on patient education is provided in the FDA alert (link).

19. Consequences of Failure to Consider Histo Excellent methods for diagnosis are available, but first the disease must be suspected. In this case the diagnosis was not suspected and testing was not performed before death. But cultures gone before death returned positive for Histoplasma after the patient died, and widespread histoplasmosis was observed at autopsy. Excellent methods for diagnosis are available, but first the disease must be suspected. In this case the diagnosis was not suspected and testing was not performed before death. But cultures gone before death returned positive for Histoplasma after the patient died, and widespread histoplasmosis was observed at autopsy.

20. Wheat EOBT 2006 Direct Examination H & E stain shows clear space around the yeast, which represents cytoplasmic shrinkage rather than a true capsule, leading to the species name, “capsulatum”. The typical narrow neck bud is demonstrated in the GMS stain. H & E stain shows clear space around the yeast, which represents cytoplasmic shrinkage rather than a true capsule, leading to the species name, “capsulatum”. The typical narrow neck bud is demonstrated in the GMS stain.

21. PA Connolly, CVI 2007 Mvista® Histo Antigen EIA Sensitivity in disseminated histoplasmosis in patients with AIDS and specificity in controls using the MVista® Histoplasma antigen EIA. And then publish that is the sensitivity appears to be 90 to 95% in patients with histoplasmosis complicating TNF blocker therapy (Hage, unpublished) Sensitivity in disseminated histoplasmosis in patients with AIDS and specificity in controls using the MVista® Histoplasma antigen EIA. And then publish that is the sensitivity appears to be 90 to 95% in patients with histoplasmosis complicating TNF blocker therapy (Hage, unpublished)

22. Diagnosis in Anti-TNF therapy Wheat, unpublished Results of diagnostic test in 19 patients for whom antigen testing was done at MiraVista Diagnostics. Other tests were performed in the minority of patients: culture, 5/10 positive; histopathology, 4/7 positive; serology, 12/14 positive.Results of diagnostic test in 19 patients for whom antigen testing was done at MiraVista Diagnostics. Other tests were performed in the minority of patients: culture, 5/10 positive; histopathology, 4/7 positive; serology, 12/14 positive.

23. Hage Resp Med 2006 Histo Antigen in BAL The sensitivity for diagnosis of pulmonary histoplasmosis may be improved by testing BAL for Histoplasma antigen (Hage Resp Med 2006). Antigen was detected in BAL in 84% of cases, increasing to 92% following concentration of the BAL. The sensitivity for diagnosis of pulmonary histoplasmosis may be improved by testing BAL for Histoplasma antigen (Hage Resp Med 2006). Antigen was detected in BAL in 84% of cases, increasing to 92% following concentration of the BAL.

24. Treatment Johnson AIM 2002 The only double-blind randomized trial evaluating treatment for histoplasmosis compared desoxycholate amphotericin B to liposomal amphotericin B in patients with AIDS complicated by moderately severe or severe PDH. Patients received amphotericin B for seven to 14 days followed by itraconazole for 10 weeks, and then received chronic suppressive treatment with itraconazole. Johnson Ann Int Med 2002;137:105 The only double-blind randomized trial evaluating treatment for histoplasmosis compared desoxycholate amphotericin B to liposomal amphotericin B in patients with AIDS complicated by moderately severe or severe PDH. Patients received amphotericin B for seven to 14 days followed by itraconazole for 10 weeks, and then received chronic suppressive treatment with itraconazole. Johnson Ann Int Med 2002;137:105

25. Outcome L-AmB vs D-AmB Johnson AIM 2002 Response was significantly better with liposomal amphotericin B MF desoxycholate amphotericinB. This is only study showing any lipid AmB formulation to be superior to D-AmB.Response was significantly better with liposomal amphotericin B MF desoxycholate amphotericinB. This is only study showing any lipid AmB formulation to be superior to D-AmB.

26. Important Questions Observational studies and controlled trials are needed to evaluate several important questions in management of patients with histoplasmosis complicating TNF blocker therapy.Observational studies and controlled trials are needed to evaluate several important questions in management of patients with histoplasmosis complicating TNF blocker therapy.

27. Highlights Wheat IDSA guideline CID 2007