—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 3 - Immune Reconstitution Inflammatory Syndrome

Joanne L. Wright
University of British Columbia
Vancouver, BC, Canada


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Clinical History
The patient was a 41 year old gay male who was HIV positive and fulfilled the criteria for AIDS. He had been placed on HAART (Highly Active Anti-Retroviral Therapy) for 5 weeks.

The patient presented with cough, fever, malaise, and weight loss. He did not have hemoptysis. The CD4 count was greater than 100.

The CT scan showed bilateral infiltrates associated with bronchial thickening and bronchial obstruction. A bronchoscopy was performed and found bronchial nodules of soft yellow tan tissue. A biopsy of the nodules was performed.


Case 3 - Figure 1 - Low power demonstrating multiple biopsy fragments.
Case 3 - Figure 2 - One of the biopsy fragments containing a diffuse infiltrate of macrophages.



Case 3 - Figure 3 - Biopsy fragments containing small granulomata
Case 3 - Figure 4 - Biopsy fragments containing small granulomata

Diagnosis: Immune reconstitution inflammatory syndrome

Lesions of the Airway Due to Mycobacterium
Obstructing endobronchial lesions by MAC in the immune competent are extremely rare with only isolated cases described in children [1], and in adults as isolated lesions [2], or as a part of disseminated disease [3]. In immune compromised individuals (usually with AIDS), tuberculosis remains an important pathogen, and airways lesions have been described due to either Mycobacterium tuberculosis, or Mycobacterium avium intracellulare [4].

The introduction of protease inhibitors and the use of combination drug regimes known as highly active anti-retroviral therapy (HAART) has changed the outcome in patients with AIDS, and has altered the spectrum of disease in these patients. However, in a sub-group of these patients, HAART therapy is associated with a paradoxical deterioration in clinical status in the face of improved CD4 lymphocyte counts and evidence of decreased viral replication. This complex is the result of the return of immune status with an associated active (and often dramatic) inflammatory response to previously treated and/or incubating pathogens, and has been termed the immune reconstitution inflammatory syndrome (IRIS) [5].

Although lymphadenitis is probably the most common presentation of IRIS, HAART therapy can uncover MAC or M-TB lesions in more unusual sites, including the airways, with the production of obstructing endobronchial lesions. These lesions are not necessarily temporally related to the induction of HAART therapy; although characteristically, the reaction appears within the first few weeks of therapy, they have also been reported to occur after several years therapy.

The histology of the airway lesions in these patients reflects the restoration of cell mediated immunity. Initially, there are abundant collections of macrophages with or without large numbers of organisms. PMN and lymphocytes may be present. Granulomata are a feature of established T-cell function, and may show caseation when the reaction is secondary to M-TB. Pathologists should be alert to the possibility of IRIS in this setting. The lack of organisms should not detract from suggesting this condition.

It is important to make the diagnosis of immune reconstitution inflammatory syndrome for the following reasons:

  1. Further diagnostic endeavors can be limited
  2. Treatment with HAART does not have to be altered
  3. It is generally not necessary to institute anti-TB therapy, although steroids may be required
  4. The patient can be reassured that this is a good prognostic sign

Airway Disease Due to Mycobacterium avium complex in the Immune Competent Patient
There are two distinct presentations of infections with MAC in the immune competent subject [6]. The traditional presentation involves progressive apical fibrocavitary lesions in middle-aged males with histories of heavy smoking and alcohol abuse. More recently, a second, slowly progressive, presentation has been recognized in middle-aged to elderly non-smoking females which involves bilateral nodular lesions in the center of the lung lobules associated with cylindrical bronchiectasis.

The specific association of this pattern in the lingular and middle lobe segments has been termed the "Lady Windermere Syndrome" as it was believed that the disease arose from MAC "colonizing" inspissated mucus in individuals who deliberately suppressed their cough [7] (see footnote). The original article described six women with isolated pulmonary MAC, two additional patients were added in the appendix, one of whom did admit to cough suppression. This hypothesis was supported by an additional case report [8], and subsequent publications (reviewed in [9] have characterized this type of presentation. As noted above, the patients tend to be almost exclusively female. They present with chronic cough which may or may not be productive, associated with the nonspecific constitutional symptoms of fever, weight loss, night sweats, dyspnea, and chest pain. Chronic sinusitis was common in one series [10]. Many of the patients were thin, and thoracic abnormalities such as pectus excavatum and scoliosis were noted.

Review of the literature has also demonstrated a common radiology and physiological pattern [9]. On CT scan, nodular, well circumscribed, and centrilobular infiltrates with a "tree in bud" appearance are characteristic. The upper lobes, or middle lobe and lingula were the most common sites affected, although any lobe could be involved. Cylindrical bronchiectasis was multifocal. Most important, the apical cavitary pattern was not present. Inspiration-expiration film comparison demonstrated airtrapping, Pulmonary function testing confirmed this finding and was associated with decrements in FEF25-75.

The pathophysiology inherent in the Lady Windermere syndrome relates to the concept that MAC is able to colonize an airway [9]. MAC has been shown to adhere to fibronectin in the matrix exposed by damaged epithelium. This type of "colonization" would also support the association of MAC with COPD, bronchiectasis, cystic fibrosis and prior mycobacterial disease, and would also provide some support for the idea of mucus inspissation due to cough suppression. However, there is also no question that MAC is able to induce bronchiectasis by its inflammatory reaction [11]. Thus, whether the airway lesions are prior to or due to infection by MAC remains controversial. What is not controversial, however, is that this presentation and the subsequent clinical course is quite different from the standard cavitary disease presentation.

Footnote:
The name is derived from the play "Lady Windermere's Fan" by Oscar Wilde (London, Routledge, Chapman, and Hall, 1966). In the play (Act 1 Scene 1) Lady Windermere states "How do you do Lord Darlington. No I can't shake hands with you. My hands are all wet with the roses". This was considered as a sign of extreme fastidiousness. Readers of the play might also recognize that this statement might also be interpreted as a sign of Lady Windermere's displeasure with Lord Darlington.

References

  1. Litman, D. A., U. K. Shah, and B. R. Pawel. 2000. Isolated endobronchial atypical mycobacterium in a child: a case report and review of the literature. Internationa Journal of Pediatric Oto Rhino Laryngology 55:65-68.
  2. Fukuoka, K., Y. Nakano, A. Nakajima, S. Hontsu, and H. Kimura. 2003. Endobronchial lesions involved in Mycobacterium avium infection. Resp Med 2003:1261-1264.
  3. Shih, J.-Y., H.-C. Wang, I.-P. Chiang, P.-C. Yang, and K.-T. Luh. 1997. Endobronchial lesions in a non-AIDS patient with disseminated Mychbacterium avium-intracellulare infection. Eur Respir J 10:497-499.
  4. Wolff, A. J. and A. E. O'Donnell. 2003. HIV-related pulmonary infections: a review of the recent literature. Curr Opin Pulm Med 9:210-214.
  5. Shelburne, S. A. and R. J. Hamill. 2003. The immune reconstitution inflammatory syndrome. AIDS Review 5:67-79.
  6. American Thoracic Society. 1997. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 156:S1-S25.
  7. Reich, J. M. and R. E. Johnson. 1992. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern: the Lady Windermere syndrome. Chest 101:1605-1610.
  8. Dhillon, S. S. and C. Watanakunakorn. 2000. Lady Windermere Syndrome: Middle lobe bronchiectasis and Mycobacterium avium complex infection due to voluntary cough suppression. Clinical Infectious Disease 30:572-575.
  9. Chalermskulrat, W., J. G. Gilbey, and J. F. Donohue. 2002. Nontuberculous mycobacteria in women, young and old. Clin Chest Med 23:675-686.
  10. Kubo, K., Y. Yamazaki, T. Hachiya, M. Hayasaka, T. Honda, M. Hasegawa, and S. Sone. 1998. Mycobacterium avium-intracellulare pulmonary infection in patients without known predisposing lung disease. Lung 176:381-391.
  11. Fujita, J., Y. Ohtsuki, E. Shigeto, I. Suemitsu, I. Yamadori, S. Bandoh, M. Shiode, K. Nishimura, T. Hirayama, T. Matsushima, H. Kukunaga, and T. Ishida. 2003. Pathological findings of bronchiectases caused by Mycobacterium avium intracellulare complex. Resp Med 97:933-938.