Derivation and validation of clinical phenotypes for COPD: a systematic review.

BACKGROUND: The traditional classification of COPD, which relies solely on spirometry, fails to account for the complexity and heterogeneity of the disease. Phenotyping is a method that attempts to derive a single or combination of disease attributes that are associated with clinically meaningful outcomes. Deriving phenotypes entails the use of cluster analyses, and helps individualize patient management by identifying groups of individuals with similar characteristics. We aimed to systematically review the literature for studies that had derived such phenotypes using unsupervised methods. METHODS: Two independent reviewers systematically searched multiple databases for studies that performed validated statistical analyses, free of definitive pre-determined hypotheses, to derive phenotypes among patients with COPD. Data were extracted independently. RESULTS: 9156 citations were retrieved, of which, 8 studies were included. The number of subjects ranged from 213 to 1543. Most studies appeared to be biased: patients were more likely males, with severe disease, and recruited in tertiary care settings. Statistical methods used to derive phenotypes varied by study. The number of phenotypes identified ranged from 2 to 5. Two phenotypes, with poor longitudinal health outcomes, were common across multiple studies: young patients with severe respiratory disease, few cardiovascular co-morbidities, poor nutritional status and poor health status, and a phenotype of older patients with moderate respiratory disease, obesity, cardiovascular and metabolic co-morbidities. CONCLUSIONS: The recognition that two phenotypes of COPD were often reported may have clinical implications for altering the course of the disease. This review also provided important information on limitations of phenotype studies in COPD and the need for improvement in future studies.

The COPD assessment test: a systematic review.

The COPD assessment test (CAT) is a self-administered questionnaire that measures health-related quality of life. We aimed to systematically evaluate the literature for reliability, validity, responsiveness and minimum clinically important difference (MCID) of the CAT. Multiple databases were searched for studies analysing the psychometric properties of the CAT in adults with chronic obstructive pulmonary disease. Two reviewers independently screened, selected and extracted data, and assessed methodological quality of relevant studies using the COSMIN checklist. From 792 records identified, 36 studies were included. The number of participants ranged from 45 to 6469, mean age from 56 to 73 years, and mean forced expiratory volume in 1 s from 39% to 98% predicted. Internal consistency (reliability) was 0.85-0.98, and test-retest reliability was 0.80-0.96. Convergent and longitudinal validity using Pearson's correlation coefficient were: SGRQ-C 0.69-0.82 and 0.63, CCQ 0.68-0.78 and 0.60, and mMRC 0.29-0.61 and 0.20, respectively. Scores differed with GOLD stages, exacerbation and mMRC grades. Mean scores decreased with pulmonary rehabilitation (2.2-3 units) and increased at exacerbation onset (4.7 units). Only one study with adequate methodology reported an MCID of 2 units and 3.3-3.8 units using the anchor-based approach and distribution-based approach, respectively. Most studies had fair methodological quality. We conclude that the studies support the reliability and validity of the CAT and that the tool is responsive to interventions, although the MCID remains debatable.

Derivation of normative data for the COPD assessment test (CAT).

BACKGROUND: The tradition classification of the severity of COPD, based on spirometry, fails to encompass the heterogeneity of the disease. The COPD assessment test (CAT), a multi-dimensional, patient-filled questionnaire, assesses the overall health status of patients, and is recommended as part of the assessment of individuals with COPD. However, information regarding the range of values for the test in a non-COPD population (normative values) is limited, and consequently, knowledge regarding the optimal cut-off, and the minimum clinically important difference (MCID) for the test remain largely empirical. METHODS: CanCOLD is a population-based multi-center cohort study conducted across Canada, the methodology of which is based on the international BOLD initiative. The study includes subjects with COPD, at-risk individuals who smoke, and healthy control subjects. CAT questionnaires were administered at baseline to all subjects. Among non-COPD subjects, normative values for the CAT questionnaire, and psychometric properties of the test were characterized. Predictors of high CAT scores were identified using multivariable logistic regression. RESULTS: Of the 525 non-COPD subjects enrolled, 500 were included in the analysis. Mean FEV1/FVC ratio among the 500 included subjects was 0.77 (SD 0.49); the mean predicted FEV1 was 99.38% (SD 16.88%). The overall mean CAT score was 6 (SD 5.09); scores were higher among females (6.43, SD 5.59), and subjects over 80 years of age (mean 7.58, SD 6.82). Cronbach alpha for the CAT was 0.79, suggesting a high internal consistency for the test. A score of 16 was the 95th percentile for the population, and 27 subjects (5.4%) were found to have a CAT score > =16. Current smoking (aOR 3.41, 95% CI 1.05, 11.02), subject-reported physician-diagnosed asthma (aOR 7.59, 95% CI 2.71, 21.25) and musculoskeletal disease (aOR 4.09, 95% CI 1.72, 9.71) were found to be significantly associated with a score ≥16. CONCLUSIONS: The characterization of CAT scores in the general population will be useful for norm-based comparisons. Longitudinal follow-up of these subjects will help in the optimization of cut-offs for the test.

Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and metaanalysis.

OBJECTIVE: Symptoms of sleep-disordered breathing (SDB) are increased in pregnancy compared to the nongravid state. Maternal SDB may be associated with adverse pregnancy outcomes, but this is still under investigation. We performed a systematic literature review, and where feasible, a metaanalysis, to evaluate whether women with SDB in pregnancy have a higher risk of specific adverse pregnancy outcomes compared with women without SDB. STUDY DESIGN: Original studies published until June 2012 evaluating the association between gestational hypertension/preeclampsia, gestational diabetes, low birthweight infants, and maternal SDB, defined either by symptoms or the reference standard polysomnography, were identified from PubMed, EMBASE, and Web of Science. Data were extracted on study design and outcome estimates. When appropriate, effect estimates from each study were pooled using a random-effects model. RESULTS: Of the 4386 studies identified, 31 met the defined criteria. Twenty-one studies, all observational in design, reported dichotomous outcomes; 9 of these adjusted for potential confounders. Maternal SDB was significantly associated with gestational hypertension/preeclampsia (pooled adjusted odds ratio [aOR], 2.34; 95% confidence interval [CI], 1.60-3.09; 5 studies), and gestational diabetes (pooled aOR, 1.86; 95% CI, 1.30-2.42; 5 studies). CONCLUSION: Based on published observational studies to date, maternal SDB is associated with an increased risk of gestational hypertension and gestational diabetes after adjusting for potential confounders. However, large-scale, prospective cohort, and interventional studies are needed to further elucidate the relationship between maternal SDB and adverse pregnancy outcomes.

Scoring systems using chest radiographic features for the diagnosis of pulmonary tuberculosis in adults: a systematic review.

Chest radiography for the diagnosis of active pulmonary tuberculosis (PTB) is limited by poor specificity and reader inconsistency. Scoring systems have been employed successfully for improving the performance of chest radiography for various pulmonary diseases. We conducted a systematic review to assess the diagnostic accuracy and reproducibility of scoring systems for PTB. We searched multiple databases for studies that evaluated the accuracy and reproducibility of chest radiograph scoring systems for PTB. We summarised results for specific radiographic features and scoring systems associated with PTB. Where appropriate, we estimated pooled performance of similar studies using a random effects model. 13 studies were included in the review, nine of which were in low tuberculosis (TB) burden settings. No scoring system was based solely on radiographic findings. All studies used systems with various combinations of clinical and radiological features. 11 studies involved scoring systems that were used for making decisions concerning hospital respiratory isolation. None of the included studies reported data on intra- or inter-reporter reproducibility. Upper lobe infiltrates (pooled diagnostic OR 3.57, 95% CI 2.38-5.37, five studies) and cavities (diagnostic OR range 1.97-25.66, three studies) were significantly associated with PTB. Sensitivities of the scoring systems were high (median 96%, IQR 93-98%), but specificities were low (median 46%, IQR 35-50%). Chest radiograph scoring systems appear useful in ruling out PTB in hospitals, but their low specificity precludes ruling in PTB. There is a need to develop accurate scoring systems for people living with HIV and for outpatient settings, especially in high TB burden settings.

Diagnostic accuracy and reproducibility of WHO-endorsed phenotypic drug susceptibility testing methods for first-line and second-line antituberculosis drugs.

In an effort to update and clarify policies on tuberculosis drug susceptibility testing (DST), the World Health Organization (WHO) commissioned a systematic review evaluating WHO-endorsed diagnostic tests. We report the results of this systematic review and meta-analysis of the diagnostic accuracy and reproducibility of phenotypic DST for first-line and second-line antituberculosis drugs. This review provides support for recommended critical concentrations for isoniazid and rifampin in commercial broth-based systems. Further studies are needed to evaluate critical concentrations for ethambutol and streptomycin that accurately detect susceptibility to these drugs. Evidence is limited on the performance of DST for pyrazinamide and second-line drugs.

Immunodiagnosis of tuberculosis: state of the art.

Undiagnosed and mismanaged tuberculosis (TB) continues to fuel the global TB epidemic. Rapid, accurate and early diagnosis of TB is therefore a priority to improve TB case detection and interrupt transmission. Although considerable improvements have been made in TB diagnostics, there are two major gaps in the existing diagnostics pipeline: (1) lack of a simple accurate point-of-care test that can be used for rapid diagnosis at the primary care level; (2) lack of a biomarker (or combination of biomarkers) that can be used to identify latently infected individuals who will benefit most from preventive therapy. Currently available commercial serological (antibody detection) tests are inaccurate and do not improve patient outcomes. Despite this evidence, dozens of serological tests are sold and used in countries (e.g. India) with weak regulatory systems, especially in the private sector. Recognizing the threat posed by these suboptimal tests, a World Health Organization (WHO) Expert Group has strongly recommended against the use of serological tests for the diagnosis of pulmonary and extra-pulmonary TB. Another WHO Expert Group has discouraged the use of interferon-γ release assays for active pulmonary TB diagnosis in low- and middle-income countries. All existing tests for latent TB infection appear to have only modest predictive value and further research is needed to identify highly predictive biomarkers.

Increased Moxifloxacin Dosing Among Patients With Multidrug-Resistant Tuberculosis With Low-Level Resistance to Moxifloxacin Did Not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India.

BACKGROUND: Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available. METHODS: We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes. RESULTS: Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6-2.4]) or adjusted (HR, 0.8 [95% CI, .5-1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2-8.8]). CONCLUSIONS: In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test-based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.

Private patient perceptions about a public programme; what do private Indian tuberculosis patients really feel about directly observed treatment?

BACKGROUND: India accounts for one-fifth of the global incident cases of tuberculosis(TB). The country presently has the world's largest directly observed treatment, short course (DOTS) programme, that has shown impressive results and covers almost 100% of the billion-plus Indian population. Despite such a successful programme, the majority of Indian patients with tuberculosis prefer private healthcare, although repeated audits of this sector have shown the quality to be poor. We aimed to ascertain the level of awareness and knowledge of private patients with tuberculosis attending our clinic at a tertiary private healthcare institute with regards to the DOTS programme, understanding the reasons behind their preference for private healthcare, and evaluating their perceptions and reasons for accepting or failing to accept directly observed therapy as a treatment option. METHODS: A structured interview schedule was administered to private patients with tuberculosis at the P.D. Hinduja Hospital and Medical Research Centre, Mumbai, India between January 2006 to November 2007. RESULTS: Only 30 of 200 patients (15%) were aware of the DOTS programme. After being explained what directly observed therapy was, 136 patients (68%) found this form of treatment unacceptable.183 patients (91.5%) preferred buying the drugs themselves to visiting a DOTS centre. 90 patients (45%) were not prepared to be observed while swallowing their TB drugs, finding it an intrusion of privacy. CONCLUSIONS: Our study reveals a poor knowledge and awareness of the DOTS programme among the cohort of TB patients that we interviewed. The control of TB in India will undoubtedly benefit from more patients being attracted to and treated by the existing DOTS programmes. However, directly observed treatment, in its present form, is considered too rigid and intrusive and is unlikely to be accepted by a majority of patients seeking private healthcare. Novel strategies and more flexible options will have to be devised to ensure higher cure rates without compromising patient choice.

Central retinal vein occlusion in a patient after being commenced on sildenafil citrate for pulmonary arterial hypertension.

A 75-year-old female was commenced on sildenafil for the treatment of pulmonary arterial hypertension (PAH) secondary to chronic obstructive pulmonary disease (COPD). She reported blurring of vision within 72 hours after starting treatment and was found to have a central retinal vein occlusion (CRVO). Such an occurrence is the second case reported to date, and we review the possible mechanisms and literature on the subject.

Development of a simple reliable radiographic scoring system to aid the diagnosis of pulmonary tuberculosis.

RATIONALE: Chest radiography is sometimes the only method available for investigating patients with possible pulmonary tuberculosis (PTB) with negative sputum smears. However, interpretation of chest radiographs in this context lacks specificity for PTB, is subjective and is neither standardized nor reproducible. Efforts to improve the interpretation of chest radiography are warranted. OBJECTIVES: To develop a scoring system to aid the diagnosis of PTB, using features recorded with the Chest Radiograph Reading and Recording System (CRRS). METHODS: Chest radiographs of outpatients with possible PTB, recruited over 3 years at clinics in South Africa were read by two independent readers using the CRRS method. Multivariate analysis was used to identify features significantly associated with culture-positive PTB. These were weighted and used to generate a score. RESULTS: 473 patients were included in the analysis. Large upper lobe opacities, cavities, unilateral pleural effusion and adenopathy were significantly associated with PTB, had high inter-reader reliability, and received 2, 2, 1 and 2 points, respectively in the final score. Using a cut-off of 2, scores below this threshold had a high negative predictive value (91.5%, 95%CI 87.1,94.7), but low positive predictive value (49.4%, 95%CI 42.9,55.9). Among the 382 TB suspects with negative sputum smears, 229 patients had scores <2; the score correctly ruled out active PTB in 214 of these patients (NPV 93.4%; 95%CI 89.4,96.3). The score had a suboptimal negative predictive value in HIV-infected patients (NPV 86.4, 95% CI 75,94). CONCLUSIONS: The proposed scoring system is simple, and reliably ruled out active PTB in smear-negative HIV-uninfected patients, thus potentially reducing the need for further tests in high burden settings. Validation studies are now required.

Safety and efficacy of thioridazine as salvage therapy in Indian patients with XDR-TB.

New drugs are desperately needed to combat XDR-TB as effective treatment involves at least four drugs to which the patient is sensitive or has never received in the past. Most Indian patients have received almost all second line drugs and have amplified resistance to most of the available drugs. Thioridazine has proven anti tuberculous effects in vitro and in vivo mouse models and we used this drug as salvage therapy in 4 Indian patients with XDR (near total drug resistance) with advanced disease. We found this drug to be well tolerated, even in this malnourished and ill patient population. It also resulted in clinical improvement in 3 of the 4 patients. Larger studies are being planned with this drug being added on to standardized or individualized XDR-TB regimens at an earlier stage. Because thioridazine has been used successfully for therapy of XDR-TB when in combination with antibiotics to which the patients were nonresponsive, the suggestion has been made that Thioridazine is eligible for patent as "New Use".

Tuberculosis management by private practitioners in Mumbai, India: has anything changed in two decades?

SETTING: Mumbai, India. A study conducted in Mumbai two decades ago revealed the extent of inappropriate tuberculosis (TB) management practices of private practitioners. Over the years, India's national TB programme has made significant progress in TB control. Efforts to engage private practitioners have also been made with several successful documented public-private mix initiatives in place. OBJECTIVE: To study prescribing practices of private practitioners in the treatment of tuberculosis, two decades after a similar study conducted in the same geographical area revealed dismal results. METHODS: Survey questionnaire administered to practicing general practitioners attending a continuing medical education programme. RESULTS: The participating practitioners had never been approached or oriented by the local TB programme. Only 6 of the 106 respondents wrote a prescription with a correct drug regimen. 106 doctors prescribed 63 different drug regimens. There was tendency to over treat with more drugs for longer durations. Only 3 of the 106 respondents could write an appropriate prescription for treatment of multidrug-resistant TB. CONCLUSIONS: With a vast majority of private practitioners unable to provide a correct prescription for treating TB and not approached by the national TB programme, little seems to have changed over the years. Strategies to control TB through public sector health services will have little impact if inappropriate management of TB patients in private clinics continues unabated. Large scale implementation of public-private mix approaches should be a top priority for the programme. Ignoring the private sector could worsen the epidemic of multidrug-resistant and extensively drug-resistant forms of TB.