A New Tool to Assess Quality of Life in Patients with Idiopathic Pulmonary Fibrosis or Non-specific Interstitial Pneumonia.

BACKGROUND: Quality of life (QoL) is significantly impaired in patients with pulmonary fibrosis, however reliable tools to assess QoL issues specific for this group of patients are still missing. We thus aimed to develop a new questionnaire called "Quality of life in patients with idiopathic pulmonary fibrosis" (QPF) to measure QoL in patients with fibrotic idiopathic interstitial pneumonias (IIP). METHODS: An item pool was created on the basis of a German expert group with support of patients suffering from pulmonary fibrosis. In a 1st step, this version of the questionnaire was completed by 52 patients with idiopathic pulmonary fibrosis (IPF) or non-specific interstitial pneumonia (NSIP). Following this, an item- and an exploratory factor analysis was carried out and a 2nd version created. In a multicenter validation study in a one-group pre-post design, the questionnaire was filled in by 200 patients with IIP (IPF = 190, iNSIP = 10) at 2 time points with an interval of 6 months. Cross-validation was carried out with the St. Georges Respiratory Questionnaire (SGRQ). RESULTS: The mean age of the patients was 71.0 years (50-90 years), 82.5 % were male. Item analysis revealed that most of Cronbach alpha and selectivity values of QPF-scales could be considered as sufficient (e. g. QPF-scale "condition" [alpha = 0.827], "impairment" [alpha = 0.882]). At scale level, there were significant differences in terms of a deterioration or improvement in the QPF-condition and QPF-breathlessness scales and also in the SGRQ-activity scale. Analysis of construct validation of QPF and SGRQ showed moderate correlations between both questionnaires. A deterioration in health status from the patient's and doctor's perspective was seen in the scales "impairment", "shortness of breath" and "health status" of the QPF. The QPF was able to detect a change in the patient's mood ("condition" scale) in the course of treatment. CONCLUSION: This newly developed questionnaire maps the special needs of the patients well. The QPF is suitable for screening of quality of life as well as for supplementing the medical history and for monitoring the course of disease in fibrotic IIPs.

A Comparison of Existing Questionnaires for Identifying the Causes of Interstitial and Rare Lung Diseases.

BACKGROUND: A thorough diagnostic process is essential with regard to prognosis and treatment of the more than 200 different types of interstitial lung diseases (ILD). Key to this complex process is a comprehensive medical history. For this, a template is recommended and questionnaires are increasingly used. Yet, the optimal questionnaire has not been established. OBJECTIVES: We aimed to compare well-established questionnaires that are used in the diagnostic process of interstitial and rare lung diseases. METHODS: Via a structured internet search and ILD expert interviews, we identified 6 different questionnaires for the diagnosis of ILDs: the questionnaires developed by the German Respiratory Society (DGP), American College of Chest Physicians (ACCP), National Jewish Health (NJH), Österreichische Röntgengesellschaft/Gesellschaft für Medizinische Radiologie und Nuklearmedizin (OERG), University of California, Los Angeles Health (UCLA), and University of California, San Francisco Medical Center (UCSF). We compared the forms, lengths, and contents of the 6 questionnaires regarding symptoms, comorbidities, drug history, previous ILD therapies, family history, smoking habits, occupational history, exposures, travel history, and former diagnostic procedures. RESULTS: The questionnaires differed in length and content. The UCLA questionnaire focuses on connective tissue diseases extensively, while the NJH questionnaire captures previous diagnostics in detail. The OERG questionnaire is condensed, while the other 5 questionnaires are very detailed. The UCSF questionnaire contains a personal assessment part for the patient. For the majority of the questions, the patient can choose options from a preselected list of possible answers. The DGP questionnaire offers the patient the opportunity to add additional information in the form of free text to some of the key questions. CONCLUSIONS: Questionnaires are an important tool in the diagnostic process of ILDs. Further validation and adjustment to clinical guidelines will help to improve existing questionnaires. Future work must aim to develop an internationally accepted template.

Physical Activity and Fatigue in Patients with Sarcoidosis.

BACKGROUND: Little is known about physical activity in daily life among patients with sarcoidosis. Fatigue is a frequent and disabling symptom that might negatively affect physical activity levels. METHODS: In patients with sarcoidosis, we measured physical activity (steps per day) by accelerometry (SenseWear Armband) for 1 week. We assessed lung function (DLCO, FVC), exercise capacity (6-min walking distance [6MWD]), health-related quality of life (St George's Respiratory Questionnaire [SGRQ]), generic quality of life (12-Item Short-Form Health Survey [SF-12]), and fatigue (Multidimensional Fatigue Inventory [MFI-20]). RESULTS: We investigated 57 patients with sarcoidosis (mean age 50 years, 56% male, mean DLCO 73% predicted, mean FVC 91% predicted, mean 6MWD 525 m, mean steps per day 7,490), of whom n = 14 (25%) had severe fatigue. The MFI-20 subscales "reduced activity" and "physical fatigue" were weakly associated with steps per day on a bivariate level (Spearman ρ = -0.274 and ρ = -0.277, respectively; p < 0.05), while the other subscales and the total score were not. 6MWD, SGRQ score, and SF-12 (physical health) score showed stronger associations with steps per day in bivariate analyses (Pearson r = 0.499, r = -0.386, and r = 0.467, respectively; p < 0.01), and were independent predictors of steps per day in multivariate linear regression analyses adjusting for confounders (p < 0.05). In ROC curve analyses, 6MWD, SGRQ score, and SF-12 (physical health) score properly identified sedentary patients (steps per day <5,000; AUROC 0.90, 0.81, and 0.80, respectively; p < 0.01). Fatigue was less predictive (MFI-20 subscale "general fatigue," AUROC 0.70; p = 0.03). CONCLUSION: While exercise capacity and quality of life measurements were robust predictors of physical activity in patients with sarcoidosis, associations of objectively measured physical activity with fatigue were surprisingly weak. In sarcoidosis, fatigue might not preclude affected patients from being physically active, although this symptom is subjectively perceived as highly disabling.

Prognosis and longitudinal changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Physical activity (PA) is associated with disease severity in idiopathic pulmonary fibrosis (IPF), but longitudinal studies evaluating its prognostic value and changes over time are lacking. METHODS: We measured PA (steps per day, SPD) in a cohort of 46 IPF-patients (mean age, 67 years; mean FVC, 76.1%pred.) by accelerometry at baseline, recorded survival status during 3 years follow-up and repeated measurements in survivors. We compared the prognostic value of PA to established mortality predictors including lung function (FVC, DLCO) and 6-min walking-distance (6MWD). RESULTS: During follow-up (median 34 months) 20 patients (43%) died. SPD and FVC best identified non-survivors (AUROC-curve 0.79, p < 0.01). After adjustment for confounders (sex, age, therapy), a standardized increase (i.e. one SD) in SPD, FVC%pred. or DLCO%pred. was associated with a more than halved risk of death (HR < 0.50; p < 0.01). Compared to baseline, SPD, FVC, and 6MWD annually declined in survivors by 973 SPD, 130 ml and 9 m, resulting in relative declines of 48.3% (p < 0.001), 13.3% (p < 0.001) and 7.8% (p = 0.055), respectively. CONCLUSION: While PA predicts mortality of IPF patients similar to established functional measures, longitudinal decline of PA seems to be disproportionally large. Our data suggest that the clinical impact of disease progression could be underestimated by established functional measures.

Reduced physical activity in lymphangioleiomyomatosis compared with COPD and healthy controls: disease-specific impact and clinical correlates.

RATIONALE: Sporadic lymphangioleiomyomatosis (LAM) is an orphan lung disease for which daily physical activity has not been studied so far and it is unclear whether a disease-specific impact beyond airflow limitation exists. Clinical correlates indicating reduced physical activity in addition to established parameters like airflow limitation and hypoxaemia are largely undetermined. METHOD: We measured physical activity (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) in 34 women with LAM, 32 FEV1-matched female patients with COPD and 15 age-matched healthy women for 1 week using an accelerometer. In addition, we assessed lung function measurements, questionnaires for generic and respiratory health status (12-Item Short Form Survey, SF-12; St. George's Respiratory Questionnaire, SGRQ), dyspnoea (modified Medical Research Council dyspnoea scale, mMRC) and fatigue (Multidimensional Fatigue Inventory, MFI-20). RESULTS: Patients with LAM (mean age 52.7 years, mean FEV1 62.7% predicted) showed reduced SPD, PAL and MMA (p<0.01) compared with healthy controls and reduced MMA (p=0.032) compared with female patients with COPD (mean age 65.2 years, mean FEV1 62.6% predicted). In multivariate regression analyses, adjusting for FEV1 and long-term oxygen therapy, either generic health status (SF-12 physical health) or fatigue (MFI-20) were the strongest independent predictors for SPD in patients with LAM (p=0.006 and p=0.004, respectively). CONCLUSIONS: Physical activity in daily life is substatially reduced in LAM, when compared with healthy controls and COPD - indicating a disease specific impact. The regular assessment of fatigue and generic health status may improve disease management in LAM by taking daily physical activity of patients with LAM more adequately into account.

Clinical Correlates of Reduced Physical Activity in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Little is known about the consequences of idiopathic pulmonary fibrosis (IPF) for physical activity (PA). OBJECTIVES: We aimed to investigate levels of PA in IPF and to study associations of PA with lung function, exercise capacity, symptoms, and quality of life. METHODS: In stable patients with IPF we measured PA (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) by accelerometry (SenseWear Armband) for 1 week. We also assessed lung function (forced vital capacity, FVC; diffusing capacity for carbon monoxide, DLCO); exercise capacity (6-minute walking distance, 6MWD); dyspnea (modified Medical Research Council, mMRC); fatigue (Multidimensional Fatigue Inventory, MFI-20), and generic (12-Item Short Form Survey, SF-12) and health-related quality of life (St. George's Respiratory Questionnaire) as further clinical variables. RESULTS: We investigated 48 patients with IPF in two centers (mean age, 67 years; 75% male; 23% on long-term oxygen therapy; mean FVC 75%pred.; mean DLCO 43%pred.; mean 6MWD 355 ± 140 m; mean SPD 5,017 ± 3,360). On a bivariate level, all clinical variables were significantly associated with SPD (p < 0.05). The associations of mMRC, MFI-20, SF-12 (physical health), and 6MWD with SPD were independent of impaired lung function (p < 0.05). At multivariate analyses, either 6MWD (total explained variance of the model, total R2: 42%) or MFI-20 (total R2: 39%) were the strongest independent predictors of SPD. CONCLUSION: Fatigue and exercise capacity are strong and independent predictors of PA in patients with IPF, which suggests that both measures should be assessed when the consequences of IPF for PA in daily life are studied.

Screening for Helicobacter pylori in Idiopathic Pulmonary Fibrosis Lung Biopsies.

BACKGROUND: Increasing evidence suggests a role of gastro-oesophageal reflux (GER) in idiopathic pulmonary fibrosis (IPF) pathogenesis. Recently, an association between serum Helicobacter pylori (HP) antibody positivity and more severe disease was described, but HP has not been directly analysed in lung tissue so far. OBJECTIVE: To investigate the presence of HP in the lung tissue of IPF patients. METHODS: Two tertiary interstitial lung disease care centre databases were screened for available lung biopsy material from IPF patients. Clinical and radiological data, including presence of GER and antiacid medication, were evaluated. HP-specific PCR was carried out on the IPF lung biopsy specimens. RESULTS: A total of 39 IPF patients were included, of whom 85% were male. The patients' median age was 66 years, their vital capacity was 79% predicted, and their diffusing capacity for carbon monoxide was 53% predicted. In all, 82% of the lung biopsies were surgical and 18% transbronchial. Comorbidities were GER disease in 23% (n = 9), sleep apnoea in 13% (n = 5) and hiatal hernia in 38% of the cases (n = 15). Proton pump inhibitors were prescribed at the time of biopsy in 21% of the cases (n = 9). After a median follow-up of 25 months (range 6-69), there were 1 death, 1 lung transplantation and 8 acute exacerbations without relevant differences between the GER and non-GER subgroups. HP DNA was not detected in any of the lung tissue samples. CONCLUSION: The fact that no HP DNA was detected in the lung tissues calls into question the proposed relevance of HP to the direct pathogenesis of IPF.

Sarcoidosis with involvement of the paranasal sinuses - a retrospective analysis of 12 biopsy-proven cases.

BACKGROUND: Extrapulmonary involvement by sarcoidosis is observed in about 30-40% of patients with sarcoidosis. Little is known about the frequency and clinical characteristics of sinonasal sarcoidosis. METHODS: We retrospectively analyzed 12 cases of biopsy-proven sinonasal sarcoidosis. Patients were identified from a patient population of 1360 patients with sarcoidosis at the Outpatient Clinic for Sarcoidosis and Rare Lung Diseases at LungClinic Grosshansdorf, a tertiary care hospital for respiratory medicine. RESULTS: The most frequent signs and symptoms were nasal polyps (4 cases), epistaxis (3 cases), nasal crusts (8 cases) and anosmia (5 cases). Pulmonary sarcoidosis of the patients was staged as stage I (n = 1) and stage II (n = 11) on chest radiographs. Spirometry was normal in 11 patients. 7 patients had a diffusion capacity of the lung for carbon monoxide of less than 90% of predicted. Other organs were affected in 8 patients. All patients received systemic corticosteroid treatment and most patients received topical steroids. 5 patients received steroid sparing agents. Repeated sinus surgery had to be performed in 4 patients. CONCLUSIONS: Sinonasal involvement is a rare disease manifestation of sarcoidosis with a frequency slightly lower than 1% in our patient population. The clinical course of sinonasal sarcoidosis can be complicated by relapse despite systemic immunosuppressive treatment and repeated sinus surgery.

Bronchoalveolar lavage enzyme-linked immunospot for a rapid diagnosis of tuberculosis: a Tuberculosis Network European Trialsgroup study.

RATIONALE: The rapid diagnosis of pulmonary tuberculosis (TB) is difficult when acid fast bacilli (AFB) cannot be detected in sputum smears. OBJECTIVES: Following a proof of principle study, we examined in routine clinical practice whether individuals with sputum AFB smear-negative TB can be discriminated from those with latent TB infection by local immunodiagnosis with a Mycobacterium tuberculosis-specific enzyme-linked immunospot (ELISpot) assay. METHODS: Subjects suspected of having active TB who were unable to produce sputum or with AFB-negative sputum smears were prospectively enrolled at Tuberculosis Network European Trialsgroup centers in Europe. ELISpot with early-secretory-antigenic-target-6 and culture-filtrate-protein-10 peptides was performed on peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage mononuclear cells (BALMCs). M. tuberculosis-specific nucleic acid amplification (NAAT) was performed on bronchoalveolar lavage fluid. MEASUREMENTS AND MAIN RESULTS: Seventy-one of 347 (20.4%) patients had active TB. Out of 276 patients who had an alternative diagnosis, 127 (46.0%) were considered to be latently infected with M. tuberculosis by a positive PBMC ELISpot result. The sensitivity and specificity of BALMC ELISpot for the diagnosis of active pulmonary TB were 91 and 80%, respectively. The BALMC ELISpot (diagnostic odds ratio [OR], 40.4) was superior to PBMC ELISpot (OR, 10.0), tuberculin skin test (OR, 7.8), and M. tuberculosis specific NAAT (OR, 12.4) to diagnose sputum AFB smear-negative TB. In contrast to PBMC ELISpot and tuberculin skin test, the BALMC ELISpot was not influenced by previous history of TB. CONCLUSIONS: Bronchoalveolar lavage ELISpot is an important advancement to rapidly distinguish sputum AFB smear-negative TB from latent TB infection in routine clinical practice.

Multidrug- and extensively drug-resistant tuberculosis, Germany.

We evaluated risk factors and treatment outcomes associated with multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) in Germany in 2004-2006. In 177 (4%) of 4,557 culture-positive TB cases, Mycobacterium tuberculosis isolates were identified as MDR TB; an additional 7 (0.15%) met criteria for XDR TB. Of these 184 patients, 148 (80%) were born in countries of the former Soviet Union. In patients with XDR TB, hospitalization was longer (mean +/- SD 202 +/- 130 vs. 123 +/- 81 days; p = 0.015) and resistance to all first-line drugs was more frequent (36% vs. 86%; p = 0.013) than in patients with MDR TB. Seventy-four (40%) of these 184 patients received treatment with linezolid. Treatment success rates ranged from 59% for the entire cohort (59% for MDR TB and 57% for XDR TB) to 87% for those with a definitive outcome (n = 125; 89% for MDR TB and 80% for XDR TB). Extensive drug susceptibility testing and availability of second- and third-line drugs under inpatient management conditions permit relatively high treatment success rates in MDR- and XDR TB.

Effect of beclomethasone dipropionate (BDP) as extrafine aerosol on bronchoalveolar lavage (BAL) lymphocytes in chronic sarcoidosis.

BACKGROUND AND AIM OF THE STUDY: Patients with pulmonary sarcoidosis can benefit from inhaled corticosteroids. In this study we assessed the effect of beclomethasone dipropionate (BDP), administered as extrafine, HFA(hydrofluoroalkane)-driven aerosol with high peripheral deposition, on bronchoalveolar lavage (BAL) lymphocyte numbers, as a marker of the disease. METHODS: Fifteen patients with newly-diagnosed pulmonary sarcoidosis (Stages I-III) received either BDP 800 microg daily (n = 6) or placebo (n = 9) for 6 months in a parallel-group design. Before and after treatment, clinical and radiological states were assessed, bronchoalveolar lavage (BAL) performed, and the cellular composition of BAL fluid as well as cytokine production by BAL lymphocytes determined. RESULTS: BDP caused a decrease in the percentage of BAL lymphocytes in the BDP (p < 0.05) but not the placebo group. HLA-DR expression on lymphocytes was diminished after BDP (p < 0.05), while intracellular cytokine production by lymphocytes was not altered. Chest radiography suggested an improvement in the BDP group. There was also a rise (p < 0.05) in the diffusing capacity for carbon monoxide. CONCLUSIONS: Though based on a small group of patients, the present findings suggest that in patients with pulmonary sarcoidosis of stage II and minor functional impairment, inhalation of high doses of BDP as extrafine, peripherally deposited aerosol is associated with a reduction in the number of BAL lymphocytes, in parallel with improvements in other markers of the disease.

Exercise training raises daily activity stronger than predicted from exercise capacity in patients with COPD.

The 6-min walking (6MWD) and 6-min treadmill distance (6MTD) are often used as measures of exercise performance in patients with COPD. The aim of our study was to assess their relationship to daily activity in the course of an exercise training program. Eighty-eight patients with stable COPD (71m/17f; mean +/- SD age, 60 +/-8 year; FEV1, 43+/-14% pred) were recruited, 66 of whom performed a hospital-based 10-day walking training, whereas 22 were treated as control. On day 16MTD, and on days 8 and 10, 6MTD and 6MWD were determined. In addition, patients used an accelerometer (TriTrac-R3D) to record 24 h-activity, whereby training sessions were excluded. In both groups there was a linear relationship (r > or = 0.84 and P < 0.0001) between 6MTD and 24 h-activity, the slope of which was 2.5-fold greater in the training group (P < 0.01). Similar relationships emerged for 6MWD. There was no association between baseline 6MTD, FEV1 or BMI and any of the other measures. These data suggest that daily activity did not markedly vary with exercise capacity under baseline conditions. Participation in a training program increased activity significantly stronger than predicted from the gain in exercise capacity. This underlines the importance of non-physiological, patient-centered factors associated with training in COPD.

Assessment of lymph node tuberculosis in northern Germany: a clinical review.

AIM OF STUDY: To evaluate patient profiles, diagnostic approaches, and treatment strategies in patients with lymph node tuberculosis. METHODS: Demographic data, diagnostic findings, and therapies were retrospectively analyzed in 60 patients with lymph node tuberculosis who were hospitalized between 1992 and 1999. RESULTS: Thirty percent (n = 18) of patients were natives, and 70% were immigrants (n = 42). The cervical lymph nodes were most frequently involved (63.3%), followed by the mediastinal lymph nodes (26.7%) and the axillary lymph nodes (8.3%). All patients (except one patient who was HIV-positive) showed a positive response to tuberculin skin testing. Lymph node excision and fine-needle aspiration (FNA) were similarly effective in obtaining sufficient material for histologic and microbiological analysis. Mycobacterium tuberculosis was identified in 43.3% of patients by microbiological testing, and culture methods showed the highest sensitivity. Despite standard treatment, the initial enlargement of the lymph nodes occurred in 20% of patients and local complications occurred in 10%. CONCLUSION: Lymph node tuberculosis is still an important issue in developed countries and has to be considered in differential diagnosis. The best approach appears to be a combination of skin testing and FNA. Negative results in the identification of M tuberculosis do not exclude the diagnosis of lymph node tuberculosis.

Susceptibility to tuberculosis is associated with TLR1 polymorphisms resulting in a lack of TLR1 cell surface expression.

Human TLR1 plays an important role in host defense against Mycobacterium tuberculosis. Our aim was to analyze the association of the loss of TLR1 surface expression and TLR1 SNPs with susceptibility to TB. TLR1neg and TLR1pos cells from healthy individuals were identified by flow cytometry and compared by sequencing. TLR1 expression was measured using quantitative real-time PCR and immunoblotting. TLR1 SNP analyses of healthy individuals and TB patients from EU-C and Ghana were performed, and association of the TLR1 genotypes with increased risk of developing TB was statistically evaluated. Lack of TLR1 surface expression accompanied by impaired function was strongly associated with TLR1 SNP G743A. Genotyping of EU-C controls and TB patients revealed an association of TLR1 743A/1805G alleles [OR 2.37 (95% CI 1.13, 4.93), P=0.0219; OR 2.74 (95% CI 1.26, 6.05), P=0.0059] as well as TLR1neg 743AA/1805GG versus TLR1pos genotypes 743AG/1805TG [OR 4.98 (95% CI 1.64, 15.15), P=0.0034; OR 5.70 (95% CI 1.69, 20.35), P=0.0015] and 743AG + GG/1805TG + TT [OR 3.54 (95% CI 1.29, 9.90), P=0.0086; OR 4.17 (95% CI 1.52, 11.67), P=0.0025] with increased susceptibility to TB. No association of G743A with TB was found in Ghana as a result of a low frequency of genotype 743AA. Our data gain new insights in the role of TLR1 in M. tuberculosis defense and provide the first evidence that TLR1 variants are associated with susceptibility to TB in a low-incidence country.

Antimycobacterial immune responses in patients with pulmonary sarcoidosis.

INTRODUCTION: Sarcoidosis is a multisystem granulomatous disease of unknown origin. Pathogenetic involvement of Mycobacterium tuberculosis has frequently been discussed in the aetiology of sarcoidosis; however, studies still remain contradictory. OBJECTIVE: We addressed the question of mycobacterial involvement in the pathogenesis of sarcoidosis by analysing cellular immune responses to mycobacterial antigens. METHODS: We examined the interferon (IFN)-gamma production by enzyme-linked immunospot in response to purified protein derivate (PPD) mycobacterial-specific antigen early secretory antigenic target (ESAT)-6 and culture filtrate protein (CFP)-10 by peripheral blood mononuclear cells (PBMCs) and bronchoalveolar-lavage mononuclear cells (BALMCs) of patients with pulmonary sarcoidosis, smear-negative tuberculosis and controls. RESULTS: Release of IFN-gamma in response to ex vivo contact with PPD, ESAT-6 or CFP-10 by BALMC and PBMC were comparable among patients with sarcoidosis and controls (PBMC P = 0.2326; BALMC P = 0.1767) and were less frequently observed in both groups compared to patients with tuberculosis (BALMC P < 0.05; PBMC P < 0.0001). Within PBMC, the immunophenotype of sarcoidosis patients differed from that of patients with tuberculosis, as well as from that of controls, while within BALMC it resembled that of patients with tuberculosis. CONCLUSION: In contrast to patients with tuberculosis, the frequency of mycobacteria-specific local and systemic immune responses is not elevated in patients with sarcoidosis when compared to controls. The immunophenotype represents the local resemblance of the granulomatous reaction underlying tuberculosis and sarcoidosis while showing systemical difference. These observations do not support a role of an infection with M. tuberculosis in the pathogenesis of sarcoidosis.

Rapid diagnosis of smear-negative tuberculosis by bronchoalveolar lavage enzyme-linked immunospot.

RATIONALE: In a large proportion of patients with active pulmonary tuberculosis (pTB), acid-fast bacilli smear results for sputum and bronchial secretions are negative. Detectable growth of Mycobacterium tuberculosis (MTB) in cultures takes several weeks and MTB-specific DNA amplification results on sputum and bronchial secretions are variable in these patients. OBJECTIVE: We investigated whether a rapid diagnosis of pTB can be established by enumeration of MTB-specific mononuclear cells from bronchoalveolar lavage (BAL) fluid in routine clinical practice. METHODS: Patients presenting to a tertiary hospital with medical histories and pulmonary infiltrates compatible with tuberculosis, and negative acid-fast bacilli smear results (three) from sputum, were prospectively enrolled in this study. An MTB-specific enzyme-linked immunospot assay (ELISPOT [T-SPOT.TB; Oxford Immunotec, Abingdon, UK]) with early antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) peptides was performed on peripheral blood mononuclear cells (PBMCs) and mononuclear cells from the BAL fluid (BALMCs). MEASUREMENTS AND MAIN RESULTS: Of 37 patients, 12 were found to have smear-negative pTB and 25 were found to have an alternative diagnosis. Patients with tuberculosis had a median number of 17 ESAT-6-specific cells and 24.5 CFP-10-specific cells per 200,000 PBMCs and 37.5 ESAT-6-specific cells and 49.5 CFP-10-specific cells per 200,000 cells in the BAL fluid. Control patients had a median of 1 ESAT-6-specific cell and 1 CFP-10-specific cell per 200,000 PBMCs and no ESAT-6- and CFP-10-specific cells per 200,000 cells in the BAL fluid (p < 0.0001). All patients with TB but none of the control subjects had more than 5 spot-forming cells per 200,000 BALMCs with either peptide in the BAL fluid ELISPOT. CONCLUSION: Smear-negative pulmonary tuberculosis can be diagnosed rapidly by identification of MTB-specific cells in the BAL fluid.