0
Communications to the Editor |

Etanercept or Mycobacterium Lung Injury? FREE TO VIEW

Kevin Fennelly; Michael D. Iseman
Author and Funding Information

Affiliations: New Jersey Medical School-UMDNJ Newark, NJ National Jewish Medical and Research Center Denver, CO,  Marietta Pulmonary Medicine Marietta, GA

Correspondence to: Michael D. Iseman, MD, National Jewish Medical and Research Center, Clinical Mycobacteriology Service, Infectious Diseases Section Office, J201 Annex Bldg, 1400 Jackson St, Denver, CO 80206; e-mail: isemanm@njc.org



Chest. 2003;124(3):1174-1175. doi:10.1378/chest.124.3.1174
Text Size: A A A
Published online

To the Editor:

We have significant questions regarding the recent report “Lung Injury Linked to Etanercept Injury” (November 2002).1 The authors’ final diagnosis was drug-induced lung injury due to etanercept, but we suggest that the data are more consistent with either hypersensitivity pneumonitis or miliary infection, both probably related to Mycobacterium avium complex. The clinical presentation, pathology, findings of loosely cohesive noncaseating granulomas, and resolution after administration of prednisone therapy are consistent with hypersensitivity pneumonitis, possibly in response to inhaled Mycobacterium avium-intracellulare complex (MAC). Hypersensitivity pneumonitis associated with exposures to nontuberculous mycobacteria has been associated with exposures in hot tubs2 or to metalworking fluids. No environmental or occupational history was provided in the case description. Had the patient used a hot tub or had other potential exposures? Alternatively, the multifocal pulmonary lesions and noncaseating granulomas in the skin lesions are also consistent with disseminated mycobacterial infection. There was no mention of special stains or cultures of the skin lesions, which would have been helpful in establishing this diagnosis. The authors did not address reports of reactivation tuberculosis associated with tumor necrosis factor (TNF)-α inhibitors. Although most cases have been associated with infliximab,3 etanercept has been associated with 11 cases of tuberculosis, 3 of which (27%) were disseminated, and 5 of which (45%) were fatal.4 Of note, etanercept has been associated with eight cases of nontuberculous mycobacterial disease as well.5 Could miliary MAC resolve without antibiotic therapy? Yes, based on analogy to the involution of MAC with reconstitution of immunity in AIDS or hairy-cell leukemia.

Given the increasing use of immunomodulatory agents, including the TNF-α inhibitors, clinicians must maintain a high index of suspicion for mycobacterial disease. We are not aware of data on the number of arthritis patients using hot tubs, but this practice may pose a risk for patients receiving TNF-α inhibitory therapy.

Peno-Green, L, Lluberas, G, Kingsley, T, et al (2002) Lung injury linked to etanercept therapy.Chest122,1858-1860. [PubMed] [CrossRef]
 
Embil, J, Warren, P, Yarkus, M, et al Pulmonary illness associated with exposure toMycobacterium aviumcomplex in hot tub water: hypersensitivity pneumonitis or infection?Chest1997;111,813-816. [PubMed]
 
Keane, J, Gershon, S, Wise, RP, et al Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.N Engl J Med2001;345,1098-1104. [PubMed]
 
Day, R Adverse reactions to TNF-alpha inhibitors in rheumatoid arthritis.Lancet2002;359,540-541. [PubMed]
 
Cush, JJ, Matteson, EL. FDA advisory committee reviews safety of TNF inhibitors: ACR Hotline. 2001; American College of Rheumatology. Atlanta, GA:.
 
To the Editor:

We are honored by the interest of Iseman and Fennely in our case, and we respect their vast knowledge and experience with acid-fast bacilli (AFB) and granulomatous inflammation. Teasing through the differential diagnosis for granulomatous lung inflammation can be challenging. Conclusions often are fraught with controversy,1 particularly when microorganisms are not identified in tissue stains. Temporal relationships in the clinical history help to define the likelihood of an applicable diagnosis. The clinical response to treatment provides important clues, either supporting or refuting the initial diagnosis. For these reasons, the diagnostician needs to be open to all potential possibilities.

The choice was made not to begin therapy with antibiotics. This decision was based on the results of biopsy stains and on the patient’s clinical presentation. Testing of a lung biopsy specimen demonstrated no AFB and the clinical presentation did not strongly favor the presence of Mycobacterium avium complex (MAC) infection. The skin biopsy was not performed for approximately 1 week after the lung biopsy. The conclusion of “sarcoidosis” as the diagnosis was rendered by the dermatologist who reviewed the skin biopsy results. But, our inquiry could not definitively determine whether AFB stains were performed on these specimens. The interventions described in our report2 were well underway by the time that the BAL culture became available 6 weeks after the bronchoscopy. The clinical response to these interventions was favorable during the weeks prior to obtaining the culture results, with no signs present to suggest infection.

Temporal events favored the presence of a drug effect over infection. Symptoms began 2 months after the beginning of treatment with etanercept, which seemed early for the development of disseminated MAC infection. Reports from the HIV literature3 derived from the early 1990s stated that the mean period of time until the appearance of disseminated MAC infection was at least 8 months after making the diagnosis of HIV. Another observation seen was the distinct two-tiered improvement, which was possibly not emphasized adequately with the original report.2 A clear improvement first occurred during the week immediately after stopping etanercept therapy, with no additional clinical change demonstrated until prednisone was added.

Inhibitors of tumor necrosis factor and corticosteroids have been shown to impair defense mechanisms directed toward mycobacterial infection.45 Even if immunity was restored after stopping etanercept therapy, the effect was transient since prednisone was implemented by week 4. Under these conditions, a spontaneous and sustained remission of disseminated MAC would be unlikely. Admittedly, treatment with steroids can impact the illness severity of mycobacterial infection, for which reason it is sometimes used as an adjunct to antimicrobial therapy.6 Complete resolution of the pathology extending from mycobacterial disease would not be expected with prednisone alone, unless the Mycobacterium was linked to hypersensitivity pneumonitis.

Our patient had no exposure to hot tubs or swimming pools, which have been linked to MAC hypersensitivity pneumonitis.7 Moreover, the case descriptions of this relatively new entity appear to be comparable to extrinsic allergic alveolitis. A major characteristic of extrinsic allergic alveolitis is that the pathology is limited to lung tissue.8 For our patient, the granulomatous inflammation was systemic, seen in specimens from both lung and skin biopsies. The combination of systemic pathology with no inhalation exposures strongly argues against a diagnosis of mycobacterial hypersensitivity pneumonitis.

In summary, our case is unique to those reporting MAC hypersensitivity pneumonitis in that the inflammation was systemic. Discriminating between disseminated MAC infection and drug-induced injury can be more of a challenge. In retrospect, blood cultures may have been helpful and are recommended for future cases presenting in a similar manner. The temporal features, along with the response to the therapeutic interventions, favor a diagnosis of etanercept-induced lung injury. The MAC isolated in our case is more likely to represent colonization.

References
Casey, MB, Tazilaar, HD, Myers, JL Noninfectious lung pathology in patients with Crohn’s disease.Am J Surg Pathol2003;27,213-221. [PubMed] [CrossRef]
 
Peno-Green, LA, Lluberas, G, Kingsley, T, et al Lung injury linked to etanercept therapy.Chest2002;122,1858-1860. [PubMed]
 
Mandell, GL, Bennett, JE, Dolin, R Principles and practice of infectious diseases 5th ed.2000,2621 Churchill Livingstone. Philadelphia, PA:
 
Bermudez, LE, Young, LS Tumor necrosis factor, alone or in combination with IL-2, but not IFN-γ, is associated with macrophage killing of Mycobacterium avium complex.1988;140,3006-3016
 
Sathe, SS, Tsigler, D, Saral, A, et al Pentoxifylline impairs macrophage defense against Mycobacterium avium complex.J Infect Dis1995;172,863-866. [PubMed]
 
Dorman, SE, Heller, HM, Basgoz, NO, et al Adjunctive corticosteroid therapy for patients whose treatment for disseminated Mycobacterium avium complex infection has failed.Clin Infect Dis1998;26,682-686. [PubMed]
 
Embil, J, Warren, P, Yakrus, M, et al Pulmonary illness associated with exposure to Mycobacterium-avium complex in hot tub water.Chest1997;111,813-816. [PubMed]
 
Fraser, RS, Paré, PD, Coleman, N, et al Diagnosis of diseases of the chest 4th ed.1999,2361-2375 WB Saunders. Philadelphia, PA:
 

Figures

Tables

References

Peno-Green, L, Lluberas, G, Kingsley, T, et al (2002) Lung injury linked to etanercept therapy.Chest122,1858-1860. [PubMed] [CrossRef]
 
Embil, J, Warren, P, Yarkus, M, et al Pulmonary illness associated with exposure toMycobacterium aviumcomplex in hot tub water: hypersensitivity pneumonitis or infection?Chest1997;111,813-816. [PubMed]
 
Keane, J, Gershon, S, Wise, RP, et al Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.N Engl J Med2001;345,1098-1104. [PubMed]
 
Day, R Adverse reactions to TNF-alpha inhibitors in rheumatoid arthritis.Lancet2002;359,540-541. [PubMed]
 
Cush, JJ, Matteson, EL. FDA advisory committee reviews safety of TNF inhibitors: ACR Hotline. 2001; American College of Rheumatology. Atlanta, GA:.
 
Casey, MB, Tazilaar, HD, Myers, JL Noninfectious lung pathology in patients with Crohn’s disease.Am J Surg Pathol2003;27,213-221. [PubMed] [CrossRef]
 
Peno-Green, LA, Lluberas, G, Kingsley, T, et al Lung injury linked to etanercept therapy.Chest2002;122,1858-1860. [PubMed]
 
Mandell, GL, Bennett, JE, Dolin, R Principles and practice of infectious diseases 5th ed.2000,2621 Churchill Livingstone. Philadelphia, PA:
 
Bermudez, LE, Young, LS Tumor necrosis factor, alone or in combination with IL-2, but not IFN-γ, is associated with macrophage killing of Mycobacterium avium complex.1988;140,3006-3016
 
Sathe, SS, Tsigler, D, Saral, A, et al Pentoxifylline impairs macrophage defense against Mycobacterium avium complex.J Infect Dis1995;172,863-866. [PubMed]
 
Dorman, SE, Heller, HM, Basgoz, NO, et al Adjunctive corticosteroid therapy for patients whose treatment for disseminated Mycobacterium avium complex infection has failed.Clin Infect Dis1998;26,682-686. [PubMed]
 
Embil, J, Warren, P, Yakrus, M, et al Pulmonary illness associated with exposure to Mycobacterium-avium complex in hot tub water.Chest1997;111,813-816. [PubMed]
 
Fraser, RS, Paré, PD, Coleman, N, et al Diagnosis of diseases of the chest 4th ed.1999,2361-2375 WB Saunders. Philadelphia, PA:
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543