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Abstract
Rationale: We evaluated whether treatment outcomes for patients with multidrug-resistant and extensively drug-resistant tuberculosis can be substantially improved when sufficient resources for personalizing medical care are available.
Objectives: To describe the characteristics and outcomes of patients with pulmonary multidrug-resistant tuberculosis at the Otto Wagner Hospital in Vienna, Austria.
Methods: We conducted a retrospective single-center study of patients initiated on treatment for multi-drug resistant tuberculosis between January 2003 and December 2012 at the Otto Wagner Hospital, Vienna, Austria. The records of patients with multidrug-resistant tuberculosis were reviewed for epidemiological, clinical, laboratory, treatment, and outcome data.
Measurements and Main Results: Ninety patients with pulmonary multidrug-resistant tuberculosis were identified. The median age was 30 years (interquartile range, 26–37). All patients were of non-Austrian origin, and 70 (78%) came from former states of the Soviet Union. Thirty-nine (43%) patients had multidrug-resistant tuberculosis; 28 (31%) had additional bacillary resistance to at least one second-line injectable drug and 9 (10%) to a fluoroquinolone. Fourteen (16%) patients had extensively drug-resistant tuberculosis. Eighty-eight different drug combinations were used for the treatment of the 90 patients. Surgery was performed on 10 (11.1%) of the patients. Sixty-five (72.2%) patients had a successful treatment outcome, 8 (8.9%) defaulted, 3 (3.3%) died, 8 (8.9%) continued treatment in another country and their outcome was unknown, and 6 (6.7%) were still on therapy. None of the patients experienced treatment failure. Treatment outcomes for patients with extensively drug-resistant tuberculosis were similar to those of patients with multidrug-resistant tuberculosis.
Conclusions: High rates of treatment success can be achieved in patients with multidrug-resistant and extensively drug-resistant tuberculosis when individually tailored treatment regimens can be provided in a high-resource setting.
Despite global efforts, tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide (1). Although the incidence of TB has declined in recent years, the emergence and increase in multidrug-resistant (MDR)-TB is a cause of great concern. According to the World Health Organization (WHO), an estimated 480,000 cases of MDR-TB occurred in 2013, resulting in 210,000 deaths (2).
MDR-TB is defined as bacillary resistance to isoniazid and rifampicin, while extensively drug-resistant (XDR)-TB is defined by additional resistance to at least one second-line injectable drug (amikacin, kanamycin, capreomycin) and at least one fluoroquinolone (3). The WHO recommends that patients with MDR-TB receive antimicrobial treatment of at least 20 months’ duration (4), with a regimen that includes a minimum of four second-line drugs, in addition to pyrazinamide, that are likely to be effective in the therapy.
MDR-TB treatment is frequently associated with adverse drug events (5), as well as with high costs (6) and high rates of loss to follow-up and treatment failure (7–11). Additionally, owing to limited possibilities to test for drug resistance and to optimize regimens in many settings where the global burden of MDR-TB is highest, treatment for MDR-TB is often standardized, regardless of the severity of disease and the resistance pattern of the associated strain.
Poor treatment outcomes were reported in a metaanalysis of over 6,700 patients, where MDR-TB treatment success ranged from 64% in patients with MDR-TB and no additional resistance to injectable drugs or fluoroquinolones to 40% in patients with XDR-TB (8). Additionally, according to data published by the European Centre for Disease Prevention and Control (ECDC) in an analysis of treatment outcomes, treatment success was registered in only 46% of MDR-TB cases and only 23.2% of XDR-TB cases (10). Furthermore, access to MDR-TB treatment is often difficult, with only one-third of the estimated patients being started on a treatment regimen in 2013 (2).
While the European region of the WHO has the highest proportion of all patients with MDR-TB identified worldwide, the vast majority of these patients live in the eastern part of the European region, especially in countries of the former Soviet Union. Compared with the European Union/European Economic Area countries, where a total of only 1,255 patients with laboratory-confirmed MDR-TB were identified in 2013, there were 33,679 patients with MDR-TB identified in Eastern Europe during the same time period (10). Furthermore, an estimated 100,000 MDR-TB cases occurred in India and China (2).
Poor treatment outcomes that have been reported for MDR-TB may not be applicable when resources for diagnosis and treatment are readily available and MDR-TB management can be optimized. Austria has a low incidence of TB, where only 16 patients with multidrug-resistant/extensively drug-resistant (M/XDR)-TB were registered in 2013 (12).
More than half (57%) of the patients diagnosed with MDR-TB in Austria were treated at the Otto Wagner Hospital in Vienna. This hospital has a dedicated unit for the treatment of patients with M/XDR-TB, where highly specialized care can be provided under optimal circumstances. In addition to continuous and unrestricted drug availability as well as rigorous monitoring during the course of therapy (clinical, laboratory, microbiological, and radiological), the management of all patients includes regular physiotherapy and psychological counseling sessions supporting treatment adherence and coping skills for dealing with the adverse events of therapy. Interpreters are present when required in order to assist patients with communication issues. Furthermore, social workers from the department of public health, as well as an on-site, fully dedicated social worker, provide assistance with administrative and insurance-related issues and organize further care after discharge from the hospital.
We evaluated treatment outcomes for patients with M/XDR-TB under personalized medical care. Some of the results of this study have been reported previously in the form of an abstract (13).
Patients with microbiologically confirmed pulmonary MDR-TB and positive cultures for Mycobacterium tuberculosis from respiratory samples who were admitted to the Otto Wagner Hospital, Vienna, for treatment between January 2003 and December 2012 were included in the study. Otto Wagner Hospital is a referral center with extensive expertise in the treatment of patients with TB in Austria.
Patients were identified using the department patient register, which included all patients with M/XDR-TB hospitalized at the site. Entries were cross-referenced with the microbiological registries to identify M. tuberculosis strains with rifampicin and isoniazid resistance. Patient records were reviewed for epidemiological, clinical, laboratory, treatment, and outcome data, and information was recorded in an anonymized database, which was further analyzed.
Drug susceptibility testing was performed in a specialized laboratory at the Institute for Medical Microbiology and Hygiene, Austrian Agency of Health and Food Safety, and confirmed at the National Reference Center for Mycobacteriology, Borstel, Germany, one of the WHO supranational reference laboratories for TB evaluation. All patients included in the study had a positive M. tuberculosis culture available for drug susceptibility testing. Susceptibility testing was performed for the following drugs: isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin, amikacin, capreomycin, fluoroquinolones, prothionamide, cycloserine, para-aminosalicylic acid, and linezolid.
Patients were considered to have received an appropriate MDR-TB treatment regimen once they had received at least four drugs in combination therapy that were thought to be effective according to the results of drug susceptibility testing, including a second-line injectable drug for the intensive phase of treatment (14). TB treatment was directly observed during the entire course of therapy. To ascertain the microbiological response to treatment, sputum cultures were collected on a monthly basis during hospitalization and every 1–2 months afterward until the end of therapy.
Outcome was ascertained using the revised WHO definitions (3). Patients were considered to have a favorable outcome if they were cured or if they had completed the treatment or had an unfavorable outcome in the case of default, treatment failure, or death.
Data processing and analysis were performed using SPSS version 17.0 software (SPSS Inc., Chicago, IL). The Mann-Whitney U test was used to test for differences between continuous variables, and the chi-square test or Fisher’s exact test was used for categorical variables. The level of significance was set at α = 0.05. Multivariate analysis with backward stepwise logistic regression was then used to predict treatment outcome when the P value from the univariate analysis was less than 0.20.
The study was approved by the ethics committee of the City of Vienna (Ethikkommission der Stadt Wien EK 14-240-VK).
We identified 94 patients with M/XDR-TB who were admitted during the study period. Four patients had extrapulmonary M/XDR-TB and were excluded from the analysis. The median patient age at diagnosis was 30 years (interquartile range [IQR], 26–37). The male-to-female ratio was 1.5:1.
All patients were of non-Austrian origin and came from the Russian Federation (n = 55 [61.1%]), Georgia (n = 11 [12.2%]), Romania (n = 11 [12.2%]), or other countries (n = 13 [14.4%]). Fifty of the patients from the Russian Federation were from Chechnya. Seventeen patients were intravenous drug users, and 52 (58%) were active smokers. All patients were tested for HIV infection, but none were HIV seropositive. The characteristics of the patients included in the study are presented in Table 1.
| Variable | MDR-TB (n = 76) | XDR-TB (n = 14) | P Value |
|---|---|---|---|
| Male sex, n (%) | 45/76 (59.2) | 9/14 (64.3) | 0.722 |
| Age, yr, median (IQR) | 30 (25.3–35.3) | 33.5 (28.8–42.3) | 0.101 |
| Country of birth, n (%) | |||
| Former Soviet Union | 60/76 (78.9) | 10/14 (71.4) | 0.503 |
| Other | 16/76 (21.1) | 4/14 (28.6) | |
| Previous TB treatment, n (%) | 38/69 (55.1) | 10/13 (76.9) | 0.142 |
| Cavitary disease, n (%) | 50/76 (65.8) | 12/14 (85.7) | 0.211 |
| Smear positive at diagnosis, n (%) | 50/75 (66.7) | 11/14 (78.6) | 0.535 |
| Resistance to all first-line drugs, n (%) | 31/76 (40.8) | 9/14 (64.3) | 0.104 |
| Resistance to fluoroquinolones, n (%) | 9/75 (12) | 14/14 (100) | NA |
| Resistance to second-line injectable drugs, n (%) | 28/76 (36.8) | 14/14 (100) | NA |
| Number of drugs in the intensive phase, median (IQR) | 5 (5–6) | 6 (6–6.3) | 0.021 |
| Number of drugs in the continuation phase, median (IQR) | 3 (3–4) | 4 (3–4) | 0.051 |
| Linezolid treatment, n (%) | 49/76 (64.5) | 12/14 (85.7) | 0.177 |
| Bedaquiline treatment, n (%) | 3/76 (3.9) | 4/14 (28.6) | 0.010 |
| Days in hospital, median (IQR) | 128 (89.8–212.5) | 335 (190.5–436.5) | <0.001 |
| Duration of treatment, mo, median (IQR) | 19.5 (17.8–24) | 24 (22.3–24.8) | 0.012 |
| Culture conversion, n (%) | 71/65 (95.9) | 14/14 (100) | 1.00 |
| Time to smear conversion, d, median (IQR) | 56.5 (21–119.5) | 128 (56–269.5) | 0.024 |
| Time to culture conversion, d, n (%) | 61 (30.8–96) | 110 (54.8–288.8) | 0.010 |
Thirty-nine (43%) patients had MDR-TB only; 28 (31%) had additional resistance to at least one second-line injectable drug and 9 (10%) to a fluoroquinolone; and 14 (16%) of the patients had XDR-TB. The patients with XDR-TB were originally from Chechnya (n = 9), Romania (n = 3), Georgia (n = 1), and China (n = 1). Resistance to at all first-line drugs was recorded in 40 (44%) of the patients. The results of the drug susceptibility testing are shown in Figure 1. Of note is that eight (8.9%) M. tuberculosis strains were susceptible to rifabutin.
Figure 1. Spectrum of first- and second-line antituberculosis drug resistance in 90 strains of Mycobacterium tuberculosis from patients with multidrug-resistant/extensively drug-resistant tuberculosis at Otto Wagner Hospital, Vienna, Austria, admitted between 2003 and 2012. PAS = para-aminosalicylic acid.
[More] [Minimize]The median time from hospital admission to the start of an appropriate M/XDR-TB treatment was 23.5 days (IQR, 0.8–45). Eighty-eight different drug combinations were used for treatment of 90 (97.8%) of the patients. The drug regimens according to their composition are represented in Figure 2. The intensive phase consisted of a median of five drugs (IQR, 5–6). During the continuation phase, a median of three drugs (IQR, 3–4) were used. For facilitating the administration of parenteral therapy, 48 (53.3%) of the patients received treatment with a totally implantable central venous access system (port-a-cath; Smiths Medical, Dublin, OH). Surgery was performed in 10 (11.1%) of the patients.
Figure 2. Drug regimens for the treatment of multidrug-resistant/extensively drug-resistant tuberculosis (M/XDR-TB). Regimens are represented according to their composition. The box at center shows how many patients received fluoroquinolones, aminoglycosides, both, or none. Arrows point to drugs added to the regimen. The numbers in the circles represent the number of patients who went through that particular node. The black dots represent the number of patients ending the regimen in that node. AMC = amoxicillin/clavulanic acid; BDQ = bedaquiline; CFZ = clofazimine; CLA = clarithromycin; CS = cycloserine; DDS = dapsone; EMB = ethambutol; FQ = fluoroquinolones; FUS = fusidic acid; IMP = imipenem; INJ = second-line injectable drugs; LZD = linezolid; PAS = para-aminosalicylic acid; PTO = prothionamide; PZA = pyrazinamide; RFB = rifabutin; SXT = trimethoprim/sulfamethoxazole.
[More] [Minimize]Smear conversion occurred after a median 61 days (IQR, 22–135) following the initiation of adequate treatment, while culture conversion occurred after a median of 62 days (IQR, 34–112.8 d). Only three (3.3%) patients did not experience a culture conversion. Figure 3 shows smear and culture conversion during anti-TB treatment. Culture conversion occurred in 40 (46%) patients within the first 2 months of effective M/XDR-TB therapy and in 72 (82.8%) patients within 6 months.
Figure 3. (A) Smear conversion and (B) culture conversion during antituberculosis treatment. Smear conversion is shown only for patients with a positive smear at treatment initiation.
[More] [Minimize]The median duration of the intensive phase was 123 days (IQR, 82–228 d) and that of the continuation phase was 494 days (IQR, 388–599 d). The overall median duration of therapy was 21 months (IQR, 18–24 mo); in patients with a favorable outcome, the median duration of therapy was 23 months (IQR, 19–24 mo). For patients who experienced an unfavorable outcome, the median duration of therapy was 4 months (IQR, 3–18 mo; P < 0.001). One patient defaulted before therapy could be initiated.
The median duration of inpatient stay was 141 days (IQR, 96.5–230.3 d). The median duration of treatment in the outpatient setting was 15 months (IQR, 12–23 mo). Patients with smear-positive TB had a significantly longer hospital stay, with a median duration of 191 days (IQR, 108.5–243 d), than smear-negative patients, with a median duration 102.5 days (IQR, 67.5–134.8 d; P < 0.001). Additionally, the median length of hospital stay was longer in patients with XDR-TB than in patients with non-XDR-TB (335 vs. 128 d; P < 0.001). Of the nine patients with a known outcome, six (66.7%) had a favorable outcome.
As shown in Table 2, 65 (72.2%) patients had a favorable treatment outcome (56 fulfilled the criteria for cure, and 9 completed treatment), 8 (8.9%) defaulted, 3 (3.3%) died, 8 (8.9%) continued the treatment in their home country after hospital discharge and their outcome was therefore unknown, and 6 (6.7%) were still on therapy. One of the patients who died had concomitant central nervous system TB. If only the cases with a known outcome are considered, then 85.5% of patients had a successful outcome. Of 14 patients with XDR-TB, 9 (64%) were cured, 1 (7%) died, and 4 (29%) were still on treatment. None of the patients included in the study experienced treatment failure.
| MDR-TB (n = 76) | XDR-TB (n = 14) | |
|---|---|---|
| Favorable outcome (cured + completed) | 56 (73.7) | 9 (64.3) |
| Cured | 47 (61.8) | 9 (64.3) |
| Completed | 9 (11.8) | 0 (0) |
| Unfavorable outcome (died + failure) | 2 (2.6) | 1 (7.1) |
| Died | 2 (2.6) | 1 (7.1) |
| Failure | 0 (0) | 0 (0) |
| Unknown outcome (default + transferred out) | 16 (21) | 0 (0) |
| Default | 8 (10.5) | 0 (0) |
| Transferred out | 8 (10.5) | 0 (0) |
| Still on treatment | 2 (2.6) | 4 (28.6) |
Of the seven patients who were treated with bedaquiline, five were still on treatment when the data were analyzed, one had been transferred to another treatment facility, and one had died. All patients treated with bedaquiline, who had prolonged culture positivity, achieved culture conversion. Of the 14 patients who received fusidic acid, 13 had a favorable outcome, while 1 died (P = 0.68). In the univariate analysis the duration of therapy (P < 0.01), treatment with cycloserine (P < 0.01), not receiving treatment with pyrazinamide (P = 0.04), and a negative culture status at 6 months (P = 0.04) were associated with a favorable treatment outcome. In the multivariate analysis, the duration of therapy (odds ratio, 0.66; 95% confidence interval, 0.51–0.86; P = 0.002) and culture status at 6 months (odds ratio, 0.04; 95% confidence interval, 0.02–0.70; P = 0.03) were associated with a favorable outcome.
Adverse gastrointestinal events occurred in 74 (82.2%) patients, polyneuropathy in 48 (53.3%), ototoxicity in 31 (34.4%), psychiatric adverse effects in 44 (48.9%), and elevated liver enzymes during therapy in 44 (48.9%). Treatment with linezolid was more frequently associated with polyneuropathy (62.3% vs. 34.5%; P = 0.023), while ototoxicity was associated with amikacin therapy (52.2% vs. 28.4%; P = 0.046). Ototoxicity was present in 25% of patients who received capreomycin, as compared with 42% of patients without capreomycin treatment (P = 0.92).
While treatment outcomes for patients with M/XDR-TB in Europe are frequently reported to be poor (15), we are able to show in the present study that treatment outcomes for pulmonary M/XDR-TB can be substantially improved in a highly resourced setting where patient management is individualized. By using tailored drug regimens, treatment success rates close to the target proposed by the WHO (13) can be achieved. In this study performed at a single referral center in Austria, treatment success rates were over 72% (and over 85% in patients with a definite outcome), in contrast to the ECDC data, which demonstrated a successful treatment outcome in only 46% of patients from Europe (10).
One explanation for this large difference might be the incomplete reporting of treatment outcomes to the ECDC and a larger proportion of patients lost to follow-up due to migration, as well as an offsetting contribution by countries with a large number of patients with MDR-TB and low treatment success rates, such as Romania and Lithuania (10). Furthermore, individualized therapy is also likely to have played an important role in the achievement of high rates of treatment success, considering that in this study 88 different drug combinations were used.
With the advent of two new drugs for the treatment of MDR-TB and XDR-TB, treatment outcomes may improve substantially. As six of the seven patients receiving a bedaquiline-based treatment regimen experienced sustained culture conversion, it is hoped that treatment outcomes may improve in general in the European region when these drugs become universally available. Recently, it has been reported that 28 (97%) of 29 patients with culture-positive pulmonary M/XDR-TB who were treated with a bedaquiline-containing regimen experienced culture conversion at 6 months of treatment (16). Furthermore, the 6-month culture status provides a very good approximation of whether a successful outcome has been achieved in patients treated for MDR-TB (17).
While analyses of large patient cohorts describe unfavorable outcomes in more than half of patients with MDR-TB, researchers in studies from individual countries or specialized centers have reported significantly higher rates of treatment success. For example, researchers in studies of selected patient cohorts from other European countries have described treatment success rates of 59% (Germany) (18), 68% (Belgium) (19), 71% (United Kingdom) (20), 76% (Switzerland) (21), and 79% (the Netherlands) (22). Interestingly, the overall and MDR-TB treatment success rates in Austria were lower than the ones from this study, of 66% and 65%, respectively, emphasizing the importance of highly specialized management (10).
All patients with M/XDR-TB in this study were not of Austrian origin. The ECDC TB report also suggests that over half of patients with TB in the countries of Western Europe are of foreign origin (10). This underscores the importance of migration in the epidemiology of MDR-TB. While in the countries of Western Europe most patients with MDR-TB have access to appropriate treatment, in other countries fewer patients do, such as in Russia, where less than half of the estimated 44,000 patients with MDR-TB were started on treatment in 2011 (23). In Ukraine, a country with a high burden of MDR-TB due to conflict and population displacement, many patients have difficulties in accessing treatment (24). More than half of the patients with M/XDR-TB in the present study were from Chechnya. This might be because Austria has the second largest Chechen diaspora in Europe, including a large proportion of refugees (25), and in Chechnya about half of TB cases are MDR (26).
Another factor that contributes to treatment accessibility and success is the cost of MDR-TB therapy. A full course of MDR-TB treatment costs 70 times more than treatment for pan-susceptible TB. Costs for XDR-TB might be as much as 280-fold higher, making it a considerable burden on countries where M/XDR-TB is prevalent (6).
Interestingly, almost one-tenth of the M. tuberculosis strains isolated were still susceptible to rifabutin. This underscores the importance of drug susceptibility testing for rifabutin and, if susceptible, of including rifabutin in the therapeutic regimen, which, due to its effectiveness, could potentially lead to a shorter duration of therapy and improved treatment outcome.
A number of drugs of unclear efficacy against M. tuberculosis were used for the treatment of MDR-TB. Fusidic acid, an antibiotic that works via protein synthesis inhibition and is active on gram-positive bacteria, was used as part of the drug regimen in almost one-fifth of the patients in the study. There was a trend showing a higher rate of favorable outcome in patients receiving fusidic acid, but the difference was not significant. In vitro studies have shown that fusidic acid has an inhibitory effect on M. tuberculosis growth (27, 28). As fusidic acid has not been evaluated in early bactericidal activity studies or in clinical trials, it should be explored as a repurposed drug for the treatment of MDR-TB.
Over two-thirds of patients in this study were treated with linezolid, which has been shown to be effective in patients with M/XDR-TB (18, 29). The authors of a recently published meta-analysis on linezolid-containing regimens reported favorable outcomes in 83% of patients treated with linezolid (30); however, most of the studies were retrospective and had no control arm. Unfortunately, linezolid therapy is associated with frequent and sometimes severe adverse events requiring treatment discontinuation (30, 31). In the present study, linezolid therapy was also significantly associated with polyneuropathy in over 60% of patients. The multivariate analysis showed that a longer total duration of therapy and the status of sputum culture at 6 months were associated with a favorable outcome.
The M. tuberculosis strains from the patients included in the study had high rates of additional resistance to anti-TB drugs other than rifampicin and isoniazid. Over 44% of strains had resistance to all first-line drugs, 49% had resistance to prothionamide, 46% had resistance to at least one second-line injectable drug, and over one-fourth had resistance to fluoroquinolones. These findings are in line with other recent observations on the level of bacillary drug resistance of MDR M. tuberculosis in the region (32, 33). This represents higher rates of resistance than reported in studies using standardized treatment regimens for MDR-TB (34) and suggests that a standardized treatment approach should not be followed in the European region, as patients may be treated with second-line anti-TB drugs that are not effective. Standardized treatment could lead to further acceleration of drug resistance development. It is important to note that, with an individualized treatment approach, high treatment success rates could be achieved despite the “MDR-TB plus” scenario in patients treated for M/XDR-TB in Vienna.
MDR-TB requires a prolonged duration of therapy and is associated with an increased length of hospital stay, frequent and sometimes irreversible adverse events, and extremely high costs. Due to the physical and psychological difficulties experienced by patients during the course of treatment, specialized support is of great value. It is very likely that the regular psychological counseling and social support given to the patients in this study setting played an important contribution in improving treatment adherence and attaining high rates of treatment success. Although this study is retrospective and lacks a direct comparison to other management strategies, it provides unique information on a large number of patients with pulmonary M/XDR-TB at a single center in a Western European country with a low TB incidence.
This study shows that high rates of successful treatment outcomes can be achieved in patients with M/XDR-TB in Europe when (1) the drug regimen is individualized to the results of second-line drug susceptibility testing and (2) second-line drugs are available for treatment without restrictions. Also playing an important role in the high rates of treatment success were adequate funding to provide medications, appropriate testing, and supportive care; treatment adherence due to prolonged hospitalization; and effective management of adverse events.
The results also underscore the importance of a multidisciplinary treatment approach comprising individualized patient care, psychological and social support to improve adherence to therapy, and early detection and management of treatment-related adverse events (35). With these combined efforts, treatment outcomes for patients with M/XDR-TB can be substantially improved.
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This work was supported by the German Center for Infection Research (DZIF).
Author Contributions: I.D.O.: contributed to the concept and design of the article, the analysis and interpretation of the data, and the drafting and revising of the manuscript; C.L.: contributed to the idea, concept, and design of the article; the analysis and interpretation of the data; and the drafting and revising of the manuscript; A.I., L.M., and S.H.: contributed to the collection and analysis of data as well as revision of the manuscript; and R.R.: contributed to the idea, concept, and design of the article; the collection, analysis, and interpretation of the data; and the drafting and revising of the manuscript. All authors approved the final version of the manuscript for publication.
Author disclosures are available with the text of this article at www.atsjournals.org.
