Skip Navigation

Nontuberculous Mycobacterial Immune Reconstitution Syndrome in HIV-Infected Patients: Spectrum of Disease and Long-Term Follow-Up

  1. Peter Phillips1,
  2. Simon Bonner3,
  3. Nada Gataric3,
  4. Tony Bai2,
  5. Pearce Wilcox2,
  6. Robert Hogg3,
  7. Michael O'Shaughnessy3, and
  8. Julio Montaner3
  1. 1Divisions of Infectious DiseasesBritish, Columbia, Canada
  2. 2Respirology and British Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, British Columbia, Canada
  3. 3British Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, British Columbia, Canada
  1. Reprints or correspondence: Dr. Peter Phillips, St. Paul's Hospital, Rm. 667, 1081 Burrard St., Vancouver, BC, V6Z 1Y6 (pphillips{at}cfenet.ubc.ca).

  1. Presented in part: 42nd Annual Meeting of the Infectious Diseases Society of America, Boston, Massachusetts, 30 September–3 October 2004 (abstract 883).

 
Next Section

Abstract

Background. The long-term outcome and spectrum of disease of nontuberculous mycobacterial immune reconstitution syndrome have not been described.

Methods. We report the findings of an observational study.

Results. Among 51 patients (43 with Mycobacterium avium complex [MAC] infection, 2 with Mycobacterium genavense infection, and 6 whose samples were smear positive but culture negative) from 1993–2004, the median follow-up period was 29 months. The incidence of nontuberculous mycobacterial immune reconstitution syndrome was 3.5% among patients initiating highly active antiretroviral therapy (HAART) with a baseline CD4+ cell count of <100 cells/µL. Three main clinical presentations were peripheral lymphadenitis (in 17 patients), pulmonary-thoracic disease (in 15 patients), and intra-abdominal disease (in 13 patients). Six other patients had cases that involved joint, spine, prostate, skin, soft tissue, and spontaneously resolving MAC bacteremia. Disease was usually localized. Median CD4+ cell counts before initiation of HAART and at diagnosis were 20 and 120 cells/µL, respectively, and the median reduction in human immunodeficiency virus (HIV) RNA load was 2.5 log10 copies/mL. Intra-abdominal disease was frequently preceded by disseminated MAC infection (in 62% of cases, compared with 6%–33% of cases for other groups; P = .003) and accounted for 16 (43%) of 36 hospitalizations (compared with 5%–35% for other groups; P = .008). The relapse rate was not higher among 10 patients who received no MAC therapy or received MAC therapy for ⩽2 weeks. Prednisone was associated with clinical responses in 8 (89%) of 9 patients with evaluable cases. In total, 7 patients (14%) had 13 subsequent culture-positive MAC events (6 of which were cases of immune reconstitution syndrome, and 7 of which were cases of disseminated MAC infection). Ten patients (20%) died (2 of disseminated MAC infection, 5 of other opportunistic infections, and 3 of HIV-unrelated causes).

Conclusions. Nontuberculous mycobacterial immune reconstitution syndrome has a wide range of clinical presentations and severity. The long-term prognosis is favorable for HAART-adherent patients. Intra-abdominal disease is associated with greater morbidity than is peripheral lymphadenitis. The role of antimycobacterial therapy is uncertain, given the self-limited course of most nonabdominal cases.

Immune reconstitution syndrome (IRS), although uncommon, has been well described in patients before the HIV epidemic, particularly for chronic diseases such as leprosy, tuberculosis, and hepatitis B [1–3]. During the HIV era, a few reports of IRS emerged after the introduction of zidovudine monotherapy [4–6]. However, since the advent of HAART, many more publications have appeared describing patients with paradoxical reactions related to a variety of opportunistic infections [7–13]. A recent review identified 80 reported cases of nontuberculous mycobacterial IRS (NTM-IRS) [14]. The incidence, long-term outcome, and natural history of untreated NTM-IRS have not been previously defined. We report our experience with 51 patients with cases of NTM-IRS during the past decade. The initial findings for 11 of these cases were reported elsewhere [11].

Previous SectionNext Section

Patients and Methods

The study was conducted through the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program, as described in detail elsewhere [15, 16]. Patients were identified by referral and were followed-up prospectively or by review of the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program database. Cases were defined by the development of clinical disease (i.e., symptoms and/or physical signs) associated with all 3 of the following criteria: (1) samples from an inflammatory lesion or of normally sterile body fluid that were smear or culture positive for acid-fast bacilli, (2) a temporal association between the initiation of antiretroviral therapy and the onset of disease, and (3) evidence of a favorable response to antiretroviral therapy, arbitrarily defined as a reduction in HIV RNA load of at least 1 log10 copies/mL or a 50% increase in CD4+ cell count, reaching a level of at least 50 cells/µL. Smear-positive but culture-negative cases were considered to be due to nontuberculous mycobacteria in the absence of a prior documented episode of Mycobacterium tuberculosis infection, because tuberculosis is rarely unmasked by antiretroviral-induced immune reconstitution [3, 14, 17]. Cases were further defined as definite if nontuberculous mycobacteria were demonstrated either in specimens of normally sterile tissue or in respiratory tract specimens in association with discrete endobronchial lesions. Cases in which nontuberculous mycobacteria were isolated from the respiratory tract in association with other pulmonary or thoracic lesions were defined as probable, provided that no other possible etiologies were documented. For patients with previous nontuberculous mycobacterial infection, clinical disease related to NTM-IRS was defined by the presence of new or worsening symptoms or physical signs. Nontuberculous mycobacterial infection was defined as disseminated if the organism was recovered from blood, bone marrow, or liver biopsy specimens; if the organism was only recovered from other sites, the infection was designated as localized infection. Adherence to HAART and MAC therapy was defined by the refill prescription rate, determined on the basis of pharmacy records [18].

The incidence of NTM-IRS was determined by review of the provincial azithromycin prophylaxis program database [19]. In vitro susceptibility testing was performed for selected MAC isolates using the radiometric method (Bactec 12B [Becton Dickinson]; pH, 7.4) [20]. Isolates were considered to be susceptible if the MIC of clarithromycin was ⩽8 µg/mL.

Previous SectionNext Section

Data Analysis

Categorical variables were compared across the 4 different clinical presentation subgroups using contingency tables and χ2 tests of association. Fisher's exact test was used to calculate P values. Continuous variables were compared using the Kruskal-Wallis nonparametric test. Where numerous comparisons were made, the significance level was adjusted using the Bonferroni correction to avoid a type I error.

Previous SectionNext Section

Results

Between 1 January 1993 and 31 December 2004, we identified 57 patients with cases of NTM-IRS. Six patients were excluded from the analysis because follow-up data were unavailable. The remaining 51 patients presented with peripheral lymphadenopathy (17 patients; 33%), pulmonary-thoracic disease (15 patients; 29%), intra-abdominal disease (13 patients; 25%), or miscellaneous sites of infection (6 patients; 12%). There were 47 definite cases (92%); 4 cases of pulmonary-thoracic disease were probable (in patients 23, 24, 25, and 26). Demographic data included a predominance of male sex (47 patients; 92%) and a median age of 36 years (interquartile range, 32–41 years). Of the patients included in the study, 84% were white and non-Hispanic, 6% were aboriginal, 6% were Hispanic, 2% were black, and 2% were Asian. Risk factors for HIV infection included being a man who has sex with men (in 65% of the patients), injection drug use (25%), heterosexual sex (2%), being a man who has sex with men and injection drug use (2%), and having hemophilia (2%), and risk factors were unknown in 2% of cases. AIDS-defining diseases had been previously documented in 30 (59%) of the patients and were most often Pneumocystis jiroveci (formerly carinii) pneumonia (in 14 [27%]) and disseminated MAC infection (in 12 [24%]). Forty-one (80%) of the patients were referred to our clinical service and were followed-up prospectively; the other 10 (20%) were reviewed retrospectively. The median follow-up period was 29 months (interquartile range, 15–58 months).

Between 1 June 1996 and 31 December 1997, the number of patients initiating or changing antiretroviral regimens with a baseline CD4+ cell count of <100 cells/µL who subsequently developed NTM-IRS was 13 (3.5%) of 368; the number of patients initiating or changing antiretroviral regimens with a baseline CD4+ cell count of <50 cells/µL who subsequently developed NTM-IRS was 8 (3.6%) of 220. The median interval from the initiation of HAART to the onset of symptoms (for the 48 cases for which such data was known) was 3 weeks (interquartile range, 1–8 weeks); the median interval from the initiation of HAART to the date of the diagnostic procedure for NTM-IRS was 10 weeks (interquartile range, 6–19 weeks). Antiretroviral regimens, both new (for 34 patients) and revised (for 17 patients), that were temporally associated with the development of NTM-IRS included 2 drugs (7 patients), 3 drugs (38 patients), 4 drugs (4 patients), 6 drugs (1 patient), and 9 drugs (1 patient). Ritonavir-boosted dual protease inhibitor combinations were only counted as a single antiretroviral.

The presenting symptoms are listed in table 1. CD4+ cell counts and HIV RNA loads are presented in table 2. Simultaneous opportunistic diseases were observed in 4 cases, including esophageal candidiasis (in patient 22), 3 probable IRS episodes due to P. jiroveci pneumonia (in patient 21), cryptococcal meningitis (in patient 35), and tuberculosis (in patient 42).

Table 1
View larger version:
Table 1

Symptoms at presentation for 51 patients with nontuberculous mycobacterial immune reconstitution syndrome.

Table 2
View larger version:
Table 2

CD4+ cell counts and HIV RNA loads for 51 patients with nontuberculous mycobacterial immune reconstitution syndrome (NTM-IRS).

Among the 51 patients, 52 diagnostic procedures demonstrated mycobacterial infection, including fine-needle aspiration (27 procedures), open surgical biopsy (8), bronchoscopic examination (7), culture of specimens (6, including 3 of draining sinus specimens, 2 of sputum samples, and 1 of a blood specimen), laparotomy (3), and mediastinoscopic examination (1). Mycobacterial smears of the relevant specimens were positive in 34 (68%) of 50 cases. One case (in patient 51) was diagnosed by blood culture, and mycobacterial smear was not performed. Mycobacterial culture of the relevant clinical specimen as performed in 49 of 51 cases (tissue biopsy specimens from patients 34 and 50 were acid-fast bacilli smear positive but were not cultured). Among the 49 cases, 42 (86%) had positive culture results (40 were positive for MAC, and 2 were positive for Mycobacterium genavense); 6 (12%) had positive acid-fast bacilli smear results but negative culture results; and 1 (2%) had negative acid-fast bacilli smear results and negative culture results, but had been smear and culture positive for MAC 10 weeks earlier, using samples obtained from the same mediastinal nodes just before initiation of HAART (patient 20). Four culture-negative patients (patients 20, 27, 34, and 48) had cases that were presumed to be due to MAC on the basis of simultaneous or previous MAC bacteremia. In total, 44 (86%) of the cases were due to MAC, 2 (4%) were due to M. genavense, and 5 (10%) were due to unknown species.

Antimycobacterial therapy was already being used at the time of NTM-IRS diagnosis in 21 (41%) of the patients, including primary MAC prophylaxis in 11 patients and secondary MAC prophylaxis in 10 patients. Among the 10 patients who developed NTM-IRS during combination antimycobacterial therapy, 8 were culture positive (7 for MAC and 1 for M. genavense), and 5 of 7 MAC isolates remained clarithromycin susceptible. Disease was usually localized. Cultures of blood samples (with or without bone marrow samples) showed no growth for 40 (91%) of 44 patients who underwent sampling at the time of NTM-IRS diagnosis; among the subset who were not receiving antimycobacterial therapy, blood cultures showed no growth for 21 (95%) of 22 patients.

Clinical characteristics are outlined according to the 4 patient groups in tables 3–6. Of cases of peripheral lymphadenopathy (table 3), 7 were supraclavicular, 5 were cervical, 3 were inguinal, 1 was axillary, and 1 was preauricular. Among the pulmonary-thoracic disease group, 3 patients (patients 18, 27, and 30) also developed peripheral lymphadenopathy. Draining sinuses developed in 10 (59%) of 17 patients with peripheral lymphadenopathy but only in 1 (3%) of 34 other patients (patient 27). Sinus drainage continued for a median of 7 months (range, 1–19 months). Residual extensive scarring prompted plastic surgery in 2 patients, both of whom had a favorable result.

Table 3
View larger version:
Table 3

Clinical and laboratory findings for 17 patients with nontuberculous mycobacterial immune reconstitution syndrome (NTM-IRS) who presented with peripheral lymphadenitis.

Table 4
View larger version:
Table 4

Clinical and laboratory findings for 15 patients with nontuberculous mycobacterial immune reconstitution syndrome (NTM–IRS) presenting with pulmonary-thoracic disease.

Table 5
View larger version:
Table 5

Clinical and laboratory findings for 13 patients with nontuberculous mycobacterial immune reconstitution syndrome (NTM-IRS) who presented with intra-abdominal disease.

Table 6
View larger version:
Table 6

Clinical and laboratory findings for 6 patients with nontuberculous mycobacterial immune reconstitution syndrome (NTM-IRS) with miscellaneous presentations.

Among the patients with pulmonary-thoracic disease, CT scan findings included mediastinal lymphadenopathy (10 patients, with hypodense centers in 4), parenchymal infiltrates (7), cavitary lesions (6), lung nodules (4), hilar lymphadenopathy (3), partial or complete lobar/segmental collapse (3), parenchymal tree-in-bud lesions (2), endobronchial nodules (2), and pericardial effusion (1). Acid-fast bacilli smears of 15 (28%) of 53 specimens obtained from 15 patients with pulmonary-thoracic disease had positive results; specimens included 6 fine-needle aspirates, 6 bronchial biopsy specimens, 12 bronchoalveolar lavage specimens, and 29 sputum samples, of which 50%, 0%, 8%, and 38% were smear positive, respectively. Cultures positive for mycobacteria were obtained from 28 (60%) of 47 specimens submitted, including 6 fine-needle aspirates, 12 specimens of bronchoalveolar lavage fluid, and 29 sputum samples, of which 100%, 58%, and 52% had positive culture results, respectively. Bronchoscopic examinations were performed for 13 patients (12 of whom had pulmonary-thoracic disease, and 1 of whom had peripheral lymphadenopathy); in 5 (38%) of these patients, bronchoscopic examination revealed 1–6 endobronchial lesions (either nodular, polypoid, sessile, or necrotic). Partial or complete bronchial obstruction was demonstrated for 4 patients (intrinsic in 3 patients and extrinsic in 1 patient), 3 of whom also had documented endobronchial lesions.

All 13 patients with intra-abdominal disease had imaging that demonstrated intra-abdominal lymphadenopathy (hypodense centers in 7 patients). Intra-abdominal disease presentations also included peritonitis (4 patients), chylous ascites (2), duodenal lesions (2), intestinal obstruction (1), abscess (1), and an adrenal mass (1). Comparison of the different groups showed that intra-abdominal disease was more often associated with prior nontuberculous mycobacterial infection, hospitalization, relapse, and lower CD4+ cell count (table 7). The clinical appearance of the cervical lymphadenopathy and draining sinuses for patient 12, the bronchoscopic findings for patient 18, and the imaging for patients 28, 33, and 47 are illustrated in figures 1–5, respectively.

Table 7
View larger version:
Table 7

Comparison of clinical characteristics of patients with nontuberculous mycobacterial immune reconstitution syndrome (NTM-IRS), by type of NTM-IRS.

Figure 1
View larger version:
Figure 1

Left neck cervical lymphadenopathy with draining sinuses (patient 12)

Figure 2
View larger version:
Figure 2

Polypoid endobronchial lesion (patient 18)

Figure 3
View larger version:
Figure 3

CT scan of a pleural-based cavitary lesion (patient 28)

Figure 4
View larger version:
Figure 4

CT scan of enlarged intra-abdominal lymph nodes with hypodense centers (solid arrows) and chylous ascites (double-line arrow) (patient 33).

Figure 5
View larger version:
Figure 5

MRI of a T10 spinal gibbus deformity, vertebral osteomyelitis, and epidural abscess at the time of nontuberculous mycobacterial immune reconstitution syndrome relapse (patient 47).

Clinical responses and outcomes are outlined in table 8. Antimycobacterial therapy was continued for >2 weeks in 41 patients. Partial or complete resolution of symptoms occurred in all but 1 of 52 episodes among 51 patients (2 episodes occurred in patient 47) (table 7). Duration of symptoms could be determined for 39 (76%) of the patients; the median duration of symptoms was 6 months (range, 0–27 months), with ongoing symptoms at last follow-up in 5 patients. The time to resolution of symptoms following the initiation of new therapy for MAC infection could be determined for 21 episodes; the median time to resolution of symptoms was 6 months (range, 2 weeks to 21 months). However, among 10 patients who received ⩽2 weeks of antimycobacterial therapy, the median duration of symptoms was 3 months (range, 0–23 months). Overall mortality was 20%; 3 patients were lost to follow-up after 23–52 months. Death related to MAC occurred in 2 (4%) of the patients; in both patients, death was related to MAC bacteremia and recurrent CD4+ lymphopenia (CD4+ cell count, <50 cells/µL).

Table 8
View larger version:
Table 8

Clinical responses and outcome for 51 patients with nontuberculous mycobacterial immune reconstitution syndrome (NTM-IRS).

Previous SectionNext Section

Discussion

HAART results in a marked reduction in levels of circulating HIV RNA within 1–2 weeks after initiation of therapy [21]. This reduction in HIV RNA load is associated with an early increase in memory CD4+ cell count [22], followed by an increase in naive CD4+ cell count at 4–6 weeks after therapy initiation, which continues to account for the major portion of the increase in CD4+ cell count over time. The antiretroviral therapy—induced thymic enlargement is considered to be responsible for the naive CD4+ cell response [23]. These quantitative changes are associated with enhanced in vitro proliferative responses to various pathogens, including MAC [24]. The restoration of delayed hypersensitivity responses and cytokine production may be responsible for the inflammatory lesions that have been described in the various IRSs [25].

We have described the clinical presentations, laboratory findings, and outcomes for 51 patients with HIV-related NTM-IRS. Three major presentations, accounting for 88% of cases, were identified, including peripheral lymphadenitis, pulmonary-thoracic disease, and intra-abdominal disease. Although there is no widely accepted clinical definition of HIV-related IRS, we propose the definition outlined above (see Patients and Methods). The temporal association between IRS and initiation of HAART has occasionally not been straightforward, as in our 2 patients with musculoskeletal cases (patients 46 and 47), for whom the intervals between initiation of HAART and the onset of symptoms were ∼1 and ∼2 years, respectively. The late onset of IRS due to MAC has been described elsewhere in patients with bone involvement [26]. Occasionally, patients presenting with NTM-IRS have not yet had a significant increase in CD4+ cell count, despite having a virologic response (patients 5, 17, 22, 37, and 45). Conversely, other individuals whose CD4+ cell count increased may have had a discordant virologic response or, at the time of NTM-IRS diagnosis, may have already discontinued HAART and had a viral rebound. Consequently, we do not consider that both a CD4+ cell and virologic response are required to make the diagnosis, as has been suggested elsewhere [8]. Also, the diagnosis of HIV-related IRS does not depend on an AIDS diagnosis, given that some of the conditions (such as herpes zoster) are not AIDS-defining. HIV-related MAC infection prior to the era of HAART typically presented as disseminated disease with chronic, nonspecific symptoms, such as fever, night sweats, and weight loss, and was often associated with abdominal pain, diarrhea, and cytopenias [27]. Atypical clinical features of HIV-related nontuberculous mycobacterial infection provide important clues to the diagnosis of NTM-IRS and include the presence of localized disease [11, 12], endobronchial lesions [4, 9], massive lymphadenopathy, draining sinuses [11], and atypical infection locations, such as skin or bone [5, 26]. Atypical features were usually present in this case series, but there were several exceptions (patients 1, 34, 42, and 51). Our patients were predominantly white men who have sex with men; however, the results may have differed for other populations.

Sites of disease in this series included all of the major lymph node regions, the thorax, the abdomen, and various other sites of disease. Constitutional symptoms were the most common type of symptom; however, chief complaints related to almost every organ system. Disease severity ranged from asymptomatic lymphadenopathy to vertebral osteomyelitis with spinal cord compression. Approximately one-half of the patients required hospitalization, most often for abdominal or pulmonary-thoracic disease. The median interval from initiation of HAART to the onset of symptoms was 3 weeks; however, the median interval from the onset of symptoms to the date of a diagnostic procedure was 6 weeks. Diagnostic delays were often related to a lack of physician awareness of IRS. The most frequent provisional diagnoses were mycobacterial infection or lymphoma; however, IRS was usually not initially included in the differential diagnosis.

A number of differences were observed between the clinical groups. Fever was more frequent among patients with abdominal or pulmonary-thoracic disease, whereas draining sinuses only occurred in patients with peripheral lymphadenopathy. Patients with abdominal cases were more likely to have previous disseminated MAC infection, lower CD4+ cell counts, and positive blood culture results at the time of NTM-IRS diagnosis, and they had higher rates of both hospitalization and relapse. These observations for patients with abdominal cases may be related to a greater burden of MAC infection before initiation of HAART, in addition to inadequate recovery of cell-mediated immunity [28].

Primary [19] or secondary MAC prophylaxis did not protect against the development of NTM-IRS and was being used by 21 (41%) of the patients at presentation. Although 12 (24%) of the patients initially received antituberculous therapy pending species identification, IRS due to M. tuberculosis is very seldom encountered in the absence of recently documented tuberculosis [3, 14, 17]. In contrast, 38 (75%) of our patients with NTM-IRS had no prior history of mycobacterial disease and appeared to represent an unmasking of subclinical disease. Therapy most often consisted of clarithromycin plus ethambutol but, in most cases, was not temporally associated with symptom resolution. Rifabutin was usually not added to the regimen because of its limited efficacy [29] and concerns regarding antiretroviral drug interactions and polypharmacy. Antimycobacterial therapy was offered to all patients; however, 10 either declined or did not tolerate the regimen. Complete responses in 17 (33%) of the patients appeared to be unrelated to antimycobacterial therapy. Patients who received ⩽2 weeks of antimycobacterial therapy experienced neither a longer duration of symptoms nor a higher relapse rate, compared with those who received prolonged therapy. However, given the observational study design, conclusions cannot be drawn regarding the role of antimycobacterial therapy. Prednisone therapy was usually associated with a favorable symptomatic response; however, 5 of 8 responders experienced relapse when it was tapered or stopped. The chronicity of symptoms for patients with intra-abdominal cases before initiation of corticosteroid therapy suggests that the high relapse rate among such patients was related to the site of disease, rather than being due to the use of corticosteroids. HAART was not interrupted as a management strategy for any of the patients in this series; however, this has been associated with resolution of symptoms in a few reports [7, 8], though it is likely to be more appropriate for patients with IRS associated with a greater risk of life-threatening complications, such as CNS tuberculomas or P. jiroveci pneumonia that is unresponsive to systemic corticosteroids [14, 30]. Overall mortality was 20% after a median follow-up period of 29 months. Death related to MAC occurred in 2 (4%) of the patients and in both cases was related to MAC bacteremia and recurrent CD4+ lymphopenia (CD4+ cell count, <50 cells/µL). This contrasts with a median survival period of 8.7 months for patients with disseminated MAC infection treated with clarithromycin, ethambutol, and rifabutin in the pre-HAART era [31].

The differential diagnosis of clinical deterioration during the first few months of HAART includes adverse drug reactions and various opportunistic diseases; but increasingly, IRS is being recognized in this setting. An early diagnosis of NTM-IRS usually depends on obtaining a fine-needle aspirate or tissue biopsy sample demonstrating the presence of acid-fast bacilli in the inflammatory lesion, combined with an additional determination of CD4+ cell count and HIV RNA plasma load. Many such cases have initially been misdiagnosed as due to tuberculosis or treatment failure of previously diagnosed MAC infection, leading to the inappropriate addition of potentially toxic second-line drugs, such as amikacin or clofazimine, neither of which were associated with clinical or microbiologic responses in randomized trials involving MAC bacteremia [32, 33].

Only 3.5% of our patients with CD4+ cell counts <100 cells/µL developed NTM-IRS after the initiation of HAART. Shelburne et al. [34] observed the development of IRS in 11 (31%) of 35 patients with previously documented MAC infection who received HAART. However, the risk related to any of the various IRS syndromes may be as high as 25% among those patients with CD4+ lymphopenia [35], making it appropriate to counsel patients regarding the possibility of such an event in the same context as the discussion of adverse drug events.

In summary, we have determined the incidence of NTM-IRS and have identified 3 major clinical presentations. A number of distinct differences associated with the intra-abdominal cases have also been outlined, including higher morbidity. The absence of a convincing, temporally related clinical response to specific antimycobacterial therapy among most patients and the generally favorable outcome for those who received little or no antimycobacterial therapy raises questions regarding both the efficacy and necessity of specific treatment in many of these patients. In contrast to HIV-related tuberculosis, when problems develop regarding issues of polypharmacy in the management of NTM-IRS, the priority should be the HAART. The role of prednisone in selected patients is supported by the observation of prompt clinical responses and the recurrence of symptoms on tapering or withdrawal of therapy, particularly in patients with severe intra-abdominal disease. The long-term prognosis is generally favorable, particularly for those who remain adherent to HAART and have nonabdominal disease.

Previous SectionNext Section

Acknowledgments

We thank Kelly Hsu, who helped prepare the manuscript.

Potential conflicts of interest. P.P. has received recent research funding from Pfizer and Merck Frosst Canada; has been a consultant for Pfizer, Merck Frosst Canada, Fujisawa, and Hoffmann—La Roche; and is a member of the speakers' bureau for Pfizer, Merck Frosst Canada, Fujisawa, Hoffmann—La Roche, and Schering-Plough Pharmaceuticals. J.M. has received recent research funding from, has been a consultant for, and is a member of the speakers' bureau for Abbott Laboratories, Aguouron, Boehringer Ingelheim, Bristol Myers-Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann—La Roche, Pfizer, Sanofi Pasteur, Tibotec, and Trimeris. R.H. has received recent research funding from, has been a consultant for, and is a member of the speakers' bureau for Michael Smith Foundation for Health Research (Senior Scholar Award), National Institutes of Health, Canadian Institutes of Health Research, National Research Development Program, Health Canada, GlaxoSmithKline, Bristol Myers-Squibb, Boehringer Ingelheim Pharmaceuticals, Merck Frosst Laboratories, and Agouron Pharmaceuticals. All other authors: no conflicts.

  • Received April 22, 2005.
  • Accepted July 6, 2005.
Previous Section
 

References

  1. ↵
    1. Sharma P,
    2. Kar HK,
    3. Misra RS,
    4. et al
    . Reactional states and neuritis in multibacillary leprosy patients following multidrug therapy with/without immunotherapy with Mycobacterium w antileprosy vaccine. Lepr Rev 2000;71:193-205.
    MedlineWeb of Science
    1. Afghani B,
    2. Lieberman JM
    . Paradoxical enlargement or development of intracranial tuberculomas during therapy: case report and review. Clin Infect Dis 1994;19:1092-9.
    Abstract/FREE Full Text
  3. ↵
    1. Cheng VCC,
    2. Yuen KY,
    3. Chan WM,
    4. et al
    . Immunorestitution disease involving the innate and adaptive response. Clin Infect Dis 2000;30:882-92.
    Abstract/FREE Full Text
  4. ↵
    1. Packer SJ,
    2. Cesario T,
    3. Williams JH Jr
    . Mycobacterium avium complex infection presenting as endobronchial lesions in immunosuppressed patients. Ann Intern Med 1988;109:389-93.
    Abstract/FREE Full Text
  5. ↵
    1. Barbaro DJ,
    2. Orcutt VL,
    3. Coldiron BM
    . Mycobacterium avium-Mycobacterium intracellulare infection limited to the skin and lymph nodes in patients with AIDS. Rev Infect Dis 1989;11:625-8.
    MedlineWeb of Science
  6. ↵
    1. French MAH,
    2. Mallal SA,
    3. Dawkins RL
    . Zidovudine induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients. AIDS 1992;6:1293-7.
    MedlineWeb of Science
  7. ↵
    1. DeSimone JA,
    2. Pomerantz RJ,
    3. Babinchak TJ
    . Inflammatory reactions in HIV-1-infected persons after initiation of active antiretroviral therapy. Ann Int Med 2000;133:447-54.
    Abstract/FREE Full Text
  8. ↵
    1. Shelburne SA III,
    2. Hamill RJ,
    3. Rodriguez-Barradas MC,
    4. et al
    . Immune reconstitution inflammatory syndrome. Emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 2002;81:213-27.
    CrossRefMedline
  9. ↵
    1. Salama C,
    2. Policar M,
    3. Venkataraman M
    . Isolated pulmonary Mycobacterium avium complex infection in patients with human immunodeficiency virus infection: case reports and literature review. Clin Infect Dis 2003;37:e35-40.
    Abstract/FREE Full Text
    1. Shelburne SA,
    2. Hamill RJ
    . The immune reconstitution inflammatory syndrome. AIDS Rev 2003;5:67-79.
    Medline
  11. ↵
    1. Phillips P,
    2. Kwiatowski MB,
    3. Copland M,
    4. et al
    . Mycobacterial lymphadenitis associated with the initiation of combination antiretroviral therapy. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:122-8.
    MedlineWeb of Science
  12. ↵
    1. Race EM,
    2. Adelson-Mitty J,
    3. Kriegal GR,
    4. et al
    . Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease. Lancet 1998;351:252-5.
    CrossRefMedlineWeb of Science
  13. ↵
    1. Desimone JA,
    2. Babinchak TJ,
    3. Kaulback KR,
    4. Pomerantz RJ
    . Treatment of Mycobacterium avium complex immune reconstitution disease in HIV-1-infected individuals. AIDS Patient Care STDS 2003;17:617-22.
    CrossRefMedlineWeb of Science
  14. ↵
    1. Lawn SD,
    2. Bekker LG,
    3. Miller RF
    . Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361-73.
    CrossRefMedlineWeb of Science
  15. ↵
    1. Hogg RS,
    2. Yip B,
    3. Chan KJ,
    4. et al
    . Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA 2001;286:2568-77.
    Abstract/FREE Full Text
  16. ↵
    1. Wood E,
    2. Hogg RS,
    3. Yip B,
    4. Harrigan PR,
    5. O'Shaughnessy MV,
    6. Montaner JS
    . Is there a baseline CD4 cell count that precludes a surival response to modern antiretroviral therapy? AIDS 2003;17:711-20.
    CrossRefMedlineWeb of Science
  17. ↵
    1. Phillips P
    . Immunoresititution disease in relation to infection with Mycobacterium avium complex and to leprosy. Clin Infect Dis 2001;32:845-8.
    FREE Full Text
  18. ↵
    1. Wood E,
    2. Hogg RS,
    3. Yip B,
    4. Harrigan PR,
    5. O'Shaughnessy MV,
    6. Montaner JSG
    . Effect of medication adherence on survival of HIV-infected adults who start highly active antiretroviral therapy when the CD4+ cell count is 0.200 to 0.350 × 109 cells/L. Ann Intern Med 2003;139:810-6.
    Abstract/FREE Full Text
  19. ↵
    1. Phillips P,
    2. Chan K,
    3. Hogg R,
    4. et al
    . Azithromycin prophylaxis for Mycobacterium avium complex during the era of highly active antiretroviral therapy: evaluation of a provincial program. Clin Infect Dis 2002;34:371-8.
    Abstract/FREE Full Text
  20. ↵
    1. Craft JC,
    2. Notario GF,
    3. Grosset JH,
    4. et al
    . Clarithromycin resistance and susceptibility patterns of Mycobacterium avium strains isolated during prophylaxis for disseminated infection in patients with AIDS. Clin Infect Dis 1998;27:807-12.
    Abstract/FREE Full Text
  21. ↵
    1. Pakker N,
    2. Roos M,
    3. Van Leeuwnen R,
    4. et al
    . Patterns of T-cell repopulation, virus load reduction, and restoration of T-cell function in HIV-infected persons during therapy with different antiretroviral agents. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16:318-26.
    MedlineWeb of Science
  22. ↵
    1. Autran B,
    2. Carcelaint G,
    3. Li TS,
    4. et al
    . Positive effects of combined antiretroviral therapy on CD4+ T-cell homeostasis in advanced HIV disease. Science 1997;277:112-6.
    Abstract/FREE Full Text
  23. ↵
    1. Smith K,
    2. Valdez H,
    3. Landay A,
    4. et al
    . Thymic size and lymphocyte restoration in patients with HIV infection after 48 weeks of zidovudine, lamivudine, and ritonavir therapy. J Infect Dis 2000;181:141-7.
    Abstract/FREE Full Text
  24. ↵
    1. Havlir DV,
    2. Schrier RD,
    3. Torriani FJ,
    4. Chervenak K,
    5. Hwang JY,
    6. Boom WH
    . Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in human immunodeficiency virus-infected subjects. J Infect Dis 2000;182:1658-63.
    Abstract/FREE Full Text
  25. ↵
    1. French MA,
    2. Price P,
    3. Stone SF
    . Immune restoration disease after antiretroviral therapy. AIDS 2004;18:1615-27.
    CrossRefMedlineWeb of Science
  26. ↵
    1. Aberg JA,
    2. Chin-Hong PV,
    3. McCutchan,
    4. et al
    . Localized osteomyelitis due to Mycobacterium avium complex in patients with human immunodeficiency virus receiving highly active antiretroviral therapy. Clin Infect Dis 2002;35:e8-13.
    Abstract/FREE Full Text
  27. ↵
    1. Horsburg CR
    . Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med 1991;324:1332-8.
    MedlineWeb of Science
  28. ↵
    1. Cinti SK,
    2. Kaul DR,
    3. Sax PE,
    4. et al
    . Recurrence of Mycobacterium avium infection in patients receiving highly active antiretroviral therapy and antimycobacterial agents. Clin Infect Dis 2000;30:511-4.
    Abstract/FREE Full Text
  29. ↵
    1. Gordin FM,
    2. Sullam PM,
    3. Shafran SD,
    4. et al
    . A randomized, placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex. Clin Infect Dis 1999;28:1080-5.
    Abstract/FREE Full Text
  30. ↵
    1. Wislez M,
    2. Bergot E,
    3. Antoine M,
    4. et al
    . Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 2001;164:847-51.
    Abstract/FREE Full Text
  31. ↵
    1. Shafran SD,
    2. Singer J,
    3. Zarowny DP,
    4. et al
    . A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996;335:377-83.
    CrossRefMedlineWeb of Science
  32. ↵
    1. Parenti DM,
    2. Williams Pl,
    3. Hafner R,
    4. et al
    . A phase II/III trial of antimicrobial therapy with or without amikacin in the treatment of disseminated Mycobacterium avium infection in HIV-infected individuals. AIDS 1998;12:2439-46.
    CrossRefMedlineWeb of Science
  33. ↵
    1. Chaisson RE,
    2. Keiser P,
    3. Pierce M,
    4. et al
    . Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic Mycobacterium avium disease in patients with HIV infection. AIDS 1997;11:311-7.
    CrossRefMedlineWeb of Science
  34. ↵
    1. Shelburne SA,
    2. Visnegarwala F,
    3. Darcourt J,
    4. et al
    . Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005;19:399-406.
    MedlineWeb of Science
  35. ↵
    1. French MA,
    2. Lenzo N,
    3. John M,
    4. et al
    . Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000;1:107-15.
    CrossRefMedline
| Table of Contents

This Article

  1. Clin Infect Dis. (2005) 41 (10): 1483-1497. doi: 10.1086/497269
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 54 (5)
  1. Clinical Infectious Diseases
  1. Alert me to new issues

Most