Theodore K. Marras

Isolation prevalence of pulmonary non-tuberculous mycobacteria in Ontario, 1997–2003

Background: The prevalence of pulmonary non-tuberculous mycobacteria (NTM) infection is reportedly increasing. A study was undertaken of the “isolation prevalence” of pulmonary NTM in Ontario, Canada between 1997 and 2003 and the frequency of pulmonary NTM “disease”. Methods: In a retrospective cohort, the “isolation prevalence” was studied by reviewing all positive NTM culture results from the Tuberculosis and Mycobacteriology Laboratory, Ministry of Health and Long-Term Care in Toronto from 1997 to 2003. This laboratory identifies at least 90% of NTM isolates in Ontario, Canada. Prevalence was compared between years using a negative binomial model. To study the frequency of “disease” (defined by American Thoracic Society criteria), the records of patients who had an isolate in 2003 and had been assessed at our hospital were reviewed. Results: 22 247 pulmonary isolates were obtained from 10 231 patients. The “isolation prevalence” of all species (excluding Mycobacterium gordonae) was 9.1/100 000 in 1997, rising to 14.1/100 000 by 2003 (p<0.0001) with a mean annual increase of 8.4%. Similar increases were observed for individual species. 200 patients assessed at our institution were studied using American Thoracic Society criteria for “disease”. Microbiological criteria were fulfilled by 37%. Of patients with adequate data, 74% fulfilled clinical criteria, 77% fulfilled radiological criteria and 33% fulfilled all criteria. Conclusions: The “isolation prevalence” of pulmonary NTM has significantly and rapidly increased in Ontario; a sizeable proportion of patients are likely to have “disease”.

The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study

A significant knowledge gap exists concerning the geographical distribution of nontuberculous mycobacteria (NTM) isolation worldwide. To provide a snapshot of NTM species distribution, global partners in the NTM-Network European Trials Group (NET) framework (www.ntm-net.org), a branch of the Tuberculosis Network European Trials Group (TB-NET), provided identification results of the total number of patients in 2008 in whom NTM were isolated from pulmonary samples. From these data, we visualised the relative distribution of the different NTM found per continent and per country. We received species identification data for 20 182 patients, from 62 laboratories in 30 countries across six continents. 91 different NTM species were isolated. Mycobacterium avium complex (MAC) bacteria predominated in most countries, followed by M. gordonae and M. xenopi. Important differences in geographical distribution of MAC species as well as M. xenopi, M. kansasii and rapid-growing mycobacteria were observed. This snapshot demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents. These differences in species distribution may partly determine the frequency and manifestations of pulmonary NTM disease in each geographical location. Species distribution among nontuberculous mycobacteria isolates from pulmonary specimens is geographically diverse http://ow.ly/npu6r

Pulmonary Nontuberculous Mycobacterial Disease, Ontario, Canada, 1998–2010

We measured the prevalence and temporal trends of pulmonary nontuberculous mycobacterial disease among residents of Ontario, Canada, during 1998–2010. Five-year prevalence increased from 29.3 cases/100,000 persons in 1998–2002 to 41.3/100,000 in 2006–2010 (p<0.0001). Improved laboratory methods did not explain this increase, suggesting a surge in disease prevalence.

The Importance of Nontuberculous Mycobacterial Lung Disease

In this issue of the Journal (pp. 1066–1074), investigators from the National Institutes of Health (NIH) report a distinctive morphotype among a selected cohort of 63 patients with nontuberculous mycobacterial (NTM) lung disease (1). Consistent with other recently published series, the great majority were middle-aged white females (2, 3). Prominent features included being tall and slender, and having scoliosis, pectus excavatum, and mitral valve prolapse. A higher than anticipated number of these patients had mutations of the CFTR genes. Extensive assessment of cell-mediated immunity did not identify deficits. Previously alluded to as ‘‘Lady Windermere’s syndrome’’ by Reich and Johnson (too ‘‘fastidious’’ to cough effectively), this current cohort did not appear unwilling to cough (4). Case series of NTM lung disease from North America, Europe, and Japan were published sporadically in the latter half of the 20th century. Males with underlying chronic obstructive pulmonary disease or pneumoconiosis constituted the bulk of the patients in these reports (5). However, in 1989, a group from Philadelphia reported 21 cases, 17 females, of Mycobacterium avium complex (MAC) lung disease occurring in patients without obvious predispositions (6). Since then, there has been increasing awareness among clinicians of NTM lung infections, with an apparent but unexplained predilection for slender women (7). Nontuberculous mycobacteria, especially MAC, are found widely distributed in the environment, with recovery of strains consistent with human pathogenic isolates (8, 9). Assuming that exposure to such organisms must be nearly universal, the question of mechanisms of vulnerability is compelling, particularly among women presenting with this infection, most of whom have led medically ‘‘blameless’’ lives. The clear identification of phenotypic features in this NIH study provides several hypothesisgenerating leads. Although broad, systematic data have not been compiled, there is a perception among many clinicians and public health tuberculosis (TB) workers that new cases of NTM lung disease may significantly exceed case rates for TB in their communities or regions. The best data for North America come from Ontario where a single laboratory identifies more than 90% of the NTM isolates in the province. This system has provided an opportunity to study the epidemiology of NTM infection at a truly population-based level. Although adequate clinical information regarding the presence of disease, or advanced infection, is lacking in the Ontario laboratory database, it was observed that nontuberculous mycobacteria were far more frequently isolated from pulmonary specimens than was M. tuberculosis (10). Conservatively assuming that 20–40% of pulmonary NTM isolates are associated with disease (11), the incidence of new cases of pulmonary NTM disease in Ontario presumably approximates the incidence of TB. Rather than comparing ‘‘incidence’’ ratios for NTMs and TB, determining the number of patients who experience clinical illness and undergo therapy in any given timeframe (i.e., prevalence) may be a more accurate way to assess the burdens on the community and the health system. In 2004, there were roughly 14,500 new cases of TB reported in the United States (12). Centers for Disease Control and Prevention data indicated that roughly 82% of patients completed therapy within 12 months, and relapse rates have been consistently less than 5% with modern regimens. By contrast, patients with pulmonary MAC usually suffer through long periods of clinical illness before a diagnosis is made; they are then recommended to take 18 months of three-drug therapy and have a nearly 50% likelihood of recurrence that entails retreatment. While treatment duration ranges from 6 to 9 months for most cases of TB in the United States and Canada, most patients become asymptomatic within weeks of commencing therapy. By contrast, we believe that symptomatic disease duration for pulmonary NTM is likely an order of magnitude greater. In 2003, there were 657 cases of TB reported in the province of Ontario, corresponding to an incidence rate of 5.4 per 100,000. In contrast, we estimate that there were likely 420 new cases of pulmonary NTM disease in Ontario in the same year, corresponding to an incidence rate of 3.5 per 100,000. Preliminary prevalence estimates have been made, assuming that the disease duration for TB is 8 months and for pulmonary NTM is within the range of 4 to 10 years. Using these estimates, the prevalence of TB in Ontario was 3.6 per 100,000 in 2003, whereas the contemporary prevalence of pulmonary NTM disease was in the range of 14 to 35 per 100,000. Using this model, the burden of TB may be expected to steadily decline in industrialized nations with mature TB programs. Data from the United States, Canada, and several West European nations describe steadily declining numbers of indigenous TB cases, with the preponderance of new cases occurring among foreign-born individuals. By contrast, the prevalence of NTM disease may be expected to steadily increase. The Ontario experience has reflected a slow but steady decrease in cases of TB, an annual decrement of 4%, whereas rates of NTM isolation increases at an annual rate of 8% (12). This comparison between TB and NTM disease is not intended to be adversarial but to call attention to a burgeoning medical challenge. The medications for NTM infections are expensive, typically difficult to tolerate, and often entail intravenous administration. Many of these patients require physically demanding and time-consuming bronchial hygiene. Limited experience suggests that some of these patients might benefit from resectional lung surgery (13). These observations make it imperative that more extensive research be done on the epidemiology, sources of infection, risk factors, treatment, and prevention of NTM lung disease. Cases of NTM lung disease are no longer just ‘‘curiosities’’ but may well be the leading edge of a major public health problem. The time for action is now.

Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation

Pneumocystis carinii pneumonia (PCP) poses a serious risk to allogeneic bone marrow transplant (BMT) patients, who are often intolerant of trimethoprim‐sulfamethoxazole (TMP‐SMX), the traditional first‐line prophylactic agents. There are limited published data supporting the use of aerosolized pentamidine (AP) prophylaxis in the BMT population. We assessed the effectiveness of AP in BMT recipients by reviewing the experience at our center. We divided our review into four time periods from January 1990 to March 2000, during which approximately 700 BMTs were performed. The first period includes patients receiving AP treatments from January 1990 to July 1997 (baseline), the second from August 1997 to July 1998 (pre‐outbreak), the third from August 1998 to October 1999 (outbreak), and the fourth from November 1999 to March 2000 (post‐outbreak). At our center, TMP‐SMX is the first‐line agent for PCP prophylaxis, which is routinely continued for at least one year, or for the duration of enhanced immunosuppression. During the baseline period, 505 BMTs were performed and 192 patients (38%) received AP for part of their time at risk. Six patients (3%) experienced toxicities requiring discontinuation of AP. Three cases of PCP were diagnosed over 1114 patient‐months of treatment in the baseline period. During the last 42 months of the baseline period, 2/154 patients receiving AP and 2 of an estimated 293 patients receiving exclusively oral prophylaxis developed breakthrough PCP (p = 0.61). During the outbreak period, 9 of 180 patients receiving AP developed PCP compared to none in the group receiving exclusively oral prophylaxis. Either changes in our AP protocol during the pre‐outbreak period or pentamidine resistance may have led to this failure of prophylaxis. There were no further cases during the 5‐month post‐outbreak period. Our observed overall breakthrough rate was 12 cases out of 439 patients (2.7%). Our study shows that AP is an effective and well‐tolerated second‐line agent in preventing PCP post BMT and we recommend its continued use in this regard. However, it should be administered using a well‐studied protocol, and only when TMP‐SMX is not tolerated.

Increased risk of mycobacterial infections associated with anti-rheumatic medications

Rationale Anti-tumour necrosis factor (TNF) agents and other anti-rheumatic medications increase the risk of TB in rheumatoid arthritis (RA). Whether they increase the risk of infections with nontuberculous mycobacteria (NTM) is uncertain. Objectives To determine the effect of anti-TNF therapy and other anti-rheumatic drugs on the risk of NTM disease and TB in older patients with RA. Methods Population-based nested case–control study among Ontario seniors aged ≥67 years with RA who were prescribed at least one anti-rheumatic medication between 2001 and 2011. We identified cases of TB and NTM disease microbiologically and identified drug exposures using linked prescription drug claims. We estimated ORs using conditional logistic regression, controlling for several potential confounders. Measurements and main results Among 56 269 older adults with RA, we identified 37 cases of TB and 211 cases of NTM disease; each case was matched to up to 10 controls. Individuals with TB or NTM disease were both more likely to be using anti-TNF therapy (compared with non-use); adjusted ORs (95% CIs) were 5.04 (1.27 to 20.0) and 2.19 (1.10 to 4.37), respectively. Exposure to leflunomide and other anti-rheumatic drugs with high immunosuppressing potential also were associated with both TB and NTM disease, while oral corticosteroids and hydroxychloroquine were associated with NTM disease. Conclusions Anti-TNF use is associated with increased risk of both TB and NTM disease, but appears to be a relatively greater risk for TB. Several other anti-rheumatic drugs were also associated with mycobacterial infections.

Risk of Mycobacterial Infections Associated With Rheumatoid Arthritis in Ontario, Canada

OBJECTIVE Patients with rheumatoid arthritis (RA) are at increased risk of TB. Little is known about the risk of nontuberculous mycobacteria (NTM) disease in these patients. We sought to ascertain the rate of NTM infection and TB in all residents of Ontario, Canada, with and without RA. METHODS In a cohort study, all Ontarians aged ≥ 15 years in January 2001 were followed until December 2010. Individuals with RA were identified using a validated algorithm to search hospitalization and physician billing claims. We linked Public Health Ontario Laboratory data to identify all cases of laboratory-confirmed TB and NTM disease. Analysis was performed using Cox proportional hazards regression. RESULTS We identified 113,558 Ontarians with RA and 9,760,075 Ontarians without RA. Relative to the non-RA group, adjusted hazard ratios (HRs) and 95% CIs for TB (1.92, [1.50-2.47]) and NTM disease (2.07, [1.84-2.32]) demonstrated increased risks in the RA group. Among those with RA, per 100,000 person-years, NTM disease (HR, 41.6; 95% CI, 37.1-46.5) was more common than TB (HR, 8.5; 95% CI, 6.5-10.8). After full adjustment, people with RA who developed NTM disease were 1.81 times as likely to die than uninfected people with RA. CONCLUSIONS Mycobacterial infections are more common in Ontarians with RA, with NTM disease more likely than TB. NTM disease is associated with an increased risk of death in patients with RA. Given the rising rates of NTM disease worldwide, determining whether this risk is due to the use of immunosuppressive medications vs RA itself is an important objective for future research.

Pneumonia severity index in the immunocompromised

BACKGROUND The pneumonia severity index (PSI) accounts for many comorbidities, but not immunosuppression. OBJECTIVES To document the utility of the PSI to predict mortality in immunocompromised patients (IP) with community-acquired pneumonia (CAP). METHODS Charts of 284 patients with immunosuppression and CAP were reviewed, and these patients were compared with a contemporary sample of non-IP with CAP. The ability of the PSI to predict mortality was assessed by using multiple logistic regression. Discrimination of the PSI was studied by using the concordance index. RESULTS Thirty-nine of 284 IP died. Mortality varied according to the etiology of the immunosuppression. Patients with HIV, solid organ transplantation or treatment with immunosuppressive drugs (n=118) had a low in-hospital mortality (4.3%) and were classified as low risk. IP with hematological malignancies, chemotherapy, chest radiation or marrow transplantation (n=166) had a high mortality (20%) and were classified as high risk. Compared with non-IP, low-risk IP had similar PSI-controlled mortality (OR=0.9, P=0.80), whereas high-risk IP had significantly greater mortality (OR=2.8, P<0.0001). The concordance index revealed similar discrimination for the PSI in low-risk IP (0.77) and in non-IP (0.7), but inferior discrimination in high-risk patients (0.6). CONCLUSIONS Patients with CAP and immunosuppression can be divided into low-risk and high-risk groups. The low-risk IP have mortality similar to non-IP and can be risk stratified by using the PSI.

Impaired health-related quality of life in pulmonary nontuberculous mycobacterial disease

INTRODUCTION The impact of pulmonary nontuberculous mycobacterial (pNTM) disease on health-related quality of life (HRQL) has not been quantified. METHODS We performed a prospective observational study of HRQL in 51 patients with pNTM disease. One generic (Short-form 36, version 2 -SF-36), and one pulmonary disease-specific instrument (St. Georges Respiratory Questionnaire--SGRQ) were administered to each subject. RESULTS Fifty-one patients with pNTM disease from one ambulatory clinic were enrolled. The mean (sd) age was 67 (10) years and 80% (41/51) were female. The most common causative NTM was MAC in 84% (43/51) followed by Mycobacterium abscessus in 8% (4/51). Radiographic disease type was nodular bronchiectasis in 71% (36/51) and fibrocavitary in 22% (11/51). For SF-36, most raw scores were at least 10 points below Canadian population-based normals, and all normbased scores were below the expected normal value of 50. For SGRQ, all scores were worse by ≥ 25 points compared with published normals. In multivariable analyses, only FVC and DLCO were significantly associated with SF-36, and only FVC and emphysema were significantly associated with SGRQ. CONCLUSION Patients with pNTM disease have significantly impaired HRQL that is most closely associated with lung function and not readily explained by age, sex or extra-pulmonary comorbidity.

Detailed Analysis of the Radiographic Presentation of Mycobacterium kansasii Lung Disease in Patients With HIV Infection

BACKGROUND Published criteria for the diagnosis of Mycobacterium kansasii lung disease require the presence of clinical symptoms, positive microbiologic results, and radiographic abnormalities. In patients with HIV infection, the radiographic findings of M kansasii lung disease are not well described. METHODS Medical records and chest radiographs of all patients with HIV infection and at least one respiratory specimen culture positive for M kansasii at San Francisco General Hospital between December 1989 and July 2002 were reviewed. RESULTS Chest radiographic results were abnormal in 75 of 83 patients (90%) included in the study. Radiographic abnormalities were diverse, with consolidation (66%) and nodules (42%) as the most frequent findings. The mid or lower lung zones were involved in 89% of patients. The pattern of radiographic abnormalities did not differ based on acid-fast bacilli smear status, the presence or absence of coexisting pulmonary infections, or CD4+ T-lymphocyte count. In multivariate Cox regression analysis, cavitation was the only radiographic abnormality independently associated with mortality (hazard ratio, 4.8; 95% confidence interval, 1.2 to 19.6). CONCLUSION Patients with HIV infection and M kansasii lung disease present with diverse radiographic patterns, most commonly consolidation and nodules predominantly located in the mid and lower lung zones. This finding is in contrast to the upper-lobe cavitary presentation described in patients without HIV infection. Although rare, the presence of cavitary disease in patients with HIV infection and M kansasii independently predicts worse outcome. The diversity in the radiographic presentation of M kansasii lung disease implies that clinicians should obtain sputum mycobacterial culture samples from any patient with HIV infection and an abnormal chest radiograph finding.