Fabry disease during the COVID-19 pandemic. Why and how treatment should be continued.

Fabry disease is an X-linked disease due to a deficiency of the lysosomal enzyme alpha-galactosidase A. Clinical symptoms in classically affected males include acroparesthesia, anhydrosis and angiokeratoma, which may present during childhood followed by cardiac, cerebral and renal complications. Even though pulmonary involvement is not widely appreciated by clinicians, an obstructive lung disease is another recognized component of Fabry disease. Coronavirus Disease-19 (COVID-19), caused by the SARS-CoV-2 virus was labeled as a global pandemic and patients with Fabry disease can be considered at high risk of developing severe complications. The impact of COVID-19 on patients with Fabry disease receiving enzyme replacement therapy is still unknown. Many patients who receive treatment in the hospital experienced infusion disruptions due to fear of infection. Effects of temporary treatment interruption was described in more detail in other lysosomal storage diseases, but the recommencement of therapy does not fully reverse clinical decline due to the temporary discontinuation. When possible, home-therapy seems to be the most efficient way to maintain enzyme replacement therapy access during pandemic. Sentence take-home message: Home-therapy, when possible, seems to be the most efficient way to maintain enzyme replacement therapy access during pandemic in patients with Fabry disease.

Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease.

BACKGROUND: Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume or purulence of sputum, or both. Personal and healthcare costs associated with exacerbations indicate that any therapy that reduces the occurrence of exacerbations is useful. A marked difference among countries in terms of prescribing of mucolytics reflects variation in perceptions of their effectiveness. OBJECTIVES: Primary objective• To determine whether treatment with mucolytics reduces frequency of exacerbations and/or days of disability in patients with chronic bronchitis or chronic obstructive pulmonary disease. Secondary objectives• To assess whether mucolytics lead to improvement in lung function or quality of life.• To determine frequency of adverse effects associated with use of mucolytics. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register and reference lists of articles on 10 separate occasions, most recently in July 2014. SELECTION CRITERIA: We included randomised studies that compared oral mucolytic therapy versus placebo for at least two months in adults with chronic bronchitis or COPD. We excluded studies of people with asthma and cystic fibrosis. DATA COLLECTION AND ANALYSIS: This review analysed summary data only, most derived from published studies. For earlier versions, one review author extracted data, which were rechecked in subsequent updates. In later versions, review authors double-checked extracted data and then entered data into RevMan for analysis. MAIN RESULTS: We added four studies for the 2014 update. The review now includes 34 trials, recruiting a total of 9367 participants. Many studies did not clearly describe allocation concealment; hence selection bias may have inflated the results, which reduces our confidence in the findings.Results of 26 studies with 6233 participants show that the likelihood that a patient could be exacerbation-free during the study period was greater among mucolytic groups (Peto odds ratio (OR) 1.75, 95% confidence interval (CI) 1.57 to 1.94). However, more recent studies show less benefit of treatment than was reported in earlier studies in this review. The overall number needed to treat with mucolytics for an additional beneficial outcome for an average of 10 months - to keep an additional participant free from exacerbations - was eight (NNTB 8, 95% CI 7 to 10). Use of mucolytics was associated with a reduction of 0.03 exacerbations per participant per month (mean difference (MD) -0.03, 95% CI -0.04 to -0.03; participants = 7164; studies = 28; I(2) = 85%) compared with placebo, that is, about 0.36 per year, or one exacerbation every three years. Very high heterogeneity was noted for this outcome, so results need to be interpreted with caution. The type or dose of mucolytic did not seem to alter the effect size, nor did the severity of COPD, including exacerbation history. Longer studies showed smaller effects of mucolytics than were reported in shorter studies.Mucolytic use was associated with a reduction of 0.43 days of disability per participant per month compared with placebo (95% CI -0.56 to -0.30; studies = 13; I(2) = 61%). With mucolytics, the number of people with one or more hospitalisations was reduced, but study results were not consistent (Peto OR 0.68, 95% CI 0.52 to 0.89; participants = 1788; studies = 4; I(2) = 58%). Investigators reported improved quality of life with mucolytics (MD -2.64, 95% CI -5.21 to -0.08; participants = 2231; studies = 5; I(2) = 51%). Although this mean difference did not reach the minimal clinically important difference of -4 units, we cannot assess the population impact, as we do not have the data needed to carry out a responder analysis. Mucolytic treatment was not associated with any significant increase in the total number of adverse effects, including mortality (Peto OR 1.03, 95% CI 0.52 to 2.03; participants = 2931; studies = 8; I(2) = 0%), but the confidence interval is too wide to confirm that the treatment has no effect on mortality. AUTHORS' CONCLUSIONS: In participants with chronic bronchitis or COPD, we are moderately confident that treatment with mucolytics may produce a small reduction in acute exacerbations and a small effect on overall quality of life. Our confidence in the results is reduced by the fact that effects on exacerbations shown in early trials were larger than those reported by more recent studies, possibly because the earlier smaller trials were at greater risk of selection or publication bias, thus benefits of treatment may not be as great as was suggested by previous evidence.

Relationship between insulin-like growth factor I levels, early insulin treatment, and clinical outcomes of very low birth weight infants.

OBJECTIVES: Insulin regulates the secretion of insulin-like growth factor I (IGF-I) in the newborn, and low levels of IGF-I have been linked to neonatal morbidity. As part of the Neonatal Insulin Replacement Therapy in Europe Trial, we investigated the impact of early insulin treatment on IGF-I levels and their relationship with morbidity and growth. STUDY DESIGN: Prospective cohort analyses of data collected as part of an international randomized controlled trial. Blood samples (days 1, 3, 7, and 28), were taken for IGF-I bioassay from 283 very low birth weight infants (<1500 g). RESULTS: Early insulin treatment led to a late increase in IGF-I levels between day 7 and 28 (P = .028). In the first week of life IGF-I levels were lower in infants with early hyperglycemia; mean difference -0.10 µg/L (95% CI -0.19, -0.02, P = .02). Lower levels of IGF-I at day 28 were independently associated with an increased risk of chronic lung disease, OR 3.23 (95% CI, 1.09-9.10), and greater IGF-I levels were independently associated with better weight gain, 0.10 kg (95% CI, 0.03-0.33, P = .02). CONCLUSIONS: Early intervention with insulin is related to increased IGF-I levels at 28 days. Low IGF-I levels are associated with hyperglycemia, increased morbidity, and reduced growth. Increasing IGF-I levels may improve outcomes of very low birth weight infants.

Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease.

BACKGROUND: Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume or purulence of sputum, or both. Because of the personal and healthcare costs associated with exacerbations, any therapy that reduces the number of exacerbations is useful. There is a marked difference among countries in terms of prescribing of mucolytics depending on whether or not they are perceived to be effective. PRIMARY OBJECTIVE: to determine if treatment with mucolytics reduces the frequency of exacerbations, days of disability, or both, in participants with chronic bronchitis or chronic obstructive pulmonary disease, or both. SECONDARY OBJECTIVES: to determine if mucolytics lead to an improvement in lung function or quality of life and to determine the frequency of adverse effects associated with mucolytics. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register and reference lists of articles on ten separate occasions, the most recent being in July 2012. SELECTION CRITERIA: We included randomised studies that compared oral mucolytic therapy with placebo for at least two months in adults with chronic bronchitis or COPD. We excluded studies of people with asthma and cystic fibrosis. DATA COLLECTION AND ANALYSIS: The review analysed summary data only, the majority from published studies. For earlier versions, one author extracted data, which was rechecked in subsequent updates. In later versions, we double-checked data extraction. We then entered data into RevMan for analysis. MAIN RESULTS: Two further trials have been added to the review for the 2012 update. There are now 30 trials in the review, recruiting a total of 7436 participants. Allocation concealment was not clearly described in the early trials, and selection bias may have inflated the results, which reduces our confidence in the findings of these trials.The likelihood of being exacerbation-free during the study period (22 trials in 4886 participants with a mean duration of 10 months) was greater in the mucolytic group for the double-blind trials (Peto odds ratio (OR) 1.84; 95% confidence interval (CI) 1.63 to 2.07). However, the more recent trials show less benefit of treatment than the earlier trials included in this review. The overall number needed to treat with mucolytics to keep an additional participant free from exacerbations over 10 months was seven (NNTB 7; 95% CI 6 to 9). The use of mucolytics was associated with a reduction of 0.04 exacerbations per participant per month (95% CI -0.04 to -0.03) compared with placebo; that is about 0.48 per year, or one exacerbation every two years. There was very high heterogeneity in this outcome (I(2) = 87%) so results need to be interpreted with caution.The number of days of disability per month also fell (mean difference (MD) -0.48; 95% CI -0.65 to -0.30) in 12 trials on 2305 participants. There was no clinically important improvement in lung function or consistent impact on quality of life with mucolytics. Mucolytic treatment was not associated with any significant increase in adverse effects, including mortality (Peto OR 0.75; 95% CI 0.35 to 1.64) in six trials on 1821 participants. AUTHORS' CONCLUSIONS: In participants with chronic bronchitis or COPD, treatment with a mucolytic may produce a small reduction in acute exacerbations, but may have little or no effect on the overall quality of life. The effects on exacerbations shown in early trials were larger than those found in the more recent studies. This may be because the earlier smaller trials were at higher risk of selection or publication bias, so the benefits of treatment may not be as large as suggested by the previous evidence.

Cigarette smoking, cadmium exposure, and zinc intake on obstructive lung disorder.

BACKGROUND AND OBJECTIVE: This study examined whether zinc intake was associated with lower risk of smoking-induced obstructive lung disorder through interplay with cadmium, one of major toxicants in cigarette smoke. METHODS: Data were obtained from a sample of 6,726 subjects aged 40+ from the Third National Health and Nutrition Examination Survey. The forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured using spirometry. Gender-, ethnicity-, and age-specific equations were used to calculate the lower limit of normal (LLN) to define obstructive lung disorder as: observed FEV1/FVC ratio and FEV1 below respective LLN. Zinc intake was assessed by questionnaire. Logistic regression analysis was applied to investigate the associations of interest. RESULTS: The analyses showed that an increased prevalence of obstructive lung disorder was observed among individuals with low zinc intake regardless of smoking status. The adjusted odds of lung disorder are approximately 1.9 times greater for subjects in the lowest zinc-intake tertile than those in the highest tertile (odds ratio = 1.89, 95% confidence interval = 1.22-2.93). The effect of smoking on lung function decreased considerably after adjusting for urinary cadmium. Protective association between the zinc-to-cadmium ratio (log-transformed) and respiratory risk suggests that zinc may play a role in smoking-associated lung disorder by modifying the influence of cadmium. CONCLUSIONS: While zinc intake is associated with lower risk of obstructive lung disorder, the role of smoking cession and/or prevention are likely to be more important given their far greater effect on respiratory risk. Future research is warranted to explore the mechanisms by which zinc could modify smoking-associated lung disease.

Environmental pollutants damage airway epithelial cell cilia: Implications for the prevention of obstructive lung diseases.

Mucociliary epithelium lining the upper and lower respiratory tract constitutes the first line of defense of the airway and lungs against inhaled pollutants and pathogens. The concerted beating of multiciliated cells drives mucociliary clearance. Abnormalities in both the structure and function of airway cilia have been implicated in obstructive lung diseases. Emerging evidence reveals a close correlation between lung diseases and environmental stimuli such as sulfur dioxide and tobacco particles. However, the underlying mechanism remains to be described. In this review, we emphasize the importance of airway cilia in mucociliary clearance and discuss how environmental pollutants affect the structure and function of airway cilia, thus shedding light on the function of airway cilia in preventing obstructive lung diseases and revealing the negative effects of environmental pollutants on human health.

Elevated pulmonary dead space and coagulation abnormalities suggest lung microvascular thrombosis in patients undergoing cardiac surgery.

OBJECTIVE: Inflammation has been shown to trigger microvascular thrombosis. Patients undergoing cardiac surgery sustain significant inflammatory insults to the lungs and in addition are routinely given anti-fibrinolytic agents to promote thrombosis. In view of these risk factors we investigated if evidence of pulmonary microvascular thrombosis occurs following cardiac surgery and, if so, whether a pre-operative heparin infusion may limit this. DESIGN: Double-blind randomised controlled trial. SETTING: Tertiary university affiliated hospital. PATIENTS: Twenty patients undergoing elective cardiac surgery. INTERVENTIONS: Patients were randomised to receive a pre-operative heparin infusion or placebo. All patients were administered aprotinin. MEASUREMENTS AND RESULTS: Pulmonary microvascular obstruction was estimated by measuring the alveolar dead-space fraction. Pulmonary coagulation activation was estimated by measuring the ratio of prothrombin fragment levels in radial and pulmonary arterial blood. Systemic tissue plasminogen activator (t-PA) levels were also assessed. In the placebo group cardiac surgery triggered increased alveolar dead-space fraction levels and the onset of prothrombin fragment production in the pulmonary circulation. Administration of pre-operative heparin was associated with a lower alveolar dead-space fraction (p < 0.05) and reduced prothrombin fragment production in the pulmonary circulation (p < 0.05). Pre-operative heparin also increased baseline t-PA levels (p < 0.05). CONCLUSION: The changes in the alveolar dead-space fraction and pulmonary coagulation activation suggest that pulmonary microvascular thrombosis develops during cardiac surgery and this may be limited by a pre-operative heparin infusion.

Predictors of persistent airway stenosis in patients with endobronchial tuberculosis.

SETTING: The university and municipal hospitals in Seoul, Korea. OBJECTIVE: To evaluate the predictors of persistent airway stenosis following anti-tuberculosis chemotherapy in patients with endobronchial tuberculosis (TB). DESIGN: Diagnosis of TB was confirmed by microbiology or histopathology. Bronchoscopic examinations revealed that patients had endobronchial lesions compatible with endobronchial TB. Study subjects had at least one follow-up bronchoscopy to evaluate their treatment response. Treatment response was determined by changes in the degree or extent of airway stenosis between the first and last bronchoscopic examinations. RESULTS: Sixty-seven subjects were recruited retrospectively from Seoul National University Hospital and Seoul National University Boramae Hospital. Persistent bronchostenosis occurred in 41.8% of the patients. In multivariate regression analysis, age >45 years (OR 3.65), pure or combined fibrostenotic subtype (OR 5.54) and duration from onset of chief complaint to the initiation of anti-tuberculosis chemotherapy >90 days (OR 5.98) were identified as independent predictors of persistent airway stenosis. Oral corticosteroids (prednisolone equivalent >or=30 mg/d) did not reduce the frequency of persistent airway stenosis. CONCLUSION: Early diagnosis and early administration of anti-tuberculosis chemotherapy before involvement of the deeper airways is important to prevent the development of unwanted sequelae of bronchostenosis.

Effects of a MAPK p38 inhibitor on lung function and airway inflammation in equine recurrent airway obstruction.

REASONS FOR PERFORMING STUDY: It has been suggested that many of the beneficial effects of corticosteroids are mediated through mitogen-activated protein kinase (MAPK) p38 inhibition. OBJECTIVE: To investigate the efficacy of the MAPK p38 inhibitor compound MRL-EQ1 to either prevent (Phase 1) or treat (Phase 2) recurrent airway obstruction (RAO) in horses. METHODS: MRL-EQ1 was administered i.v. at a dosage of 0.75-1.5 mg/kg bwt q. 12 h. In Phase 1, susceptible horses in clinical remission were divided into 2 groups (n = 5/group), based on historical values of respiratory mechanics. All horses were entered in the study in pairs (one control, one treated horse) and exposed to the same environmental challenge (stabling, mouldy hay and dusty conditions). The treatment group received MRL-EQ1 for 14 days while the control horses were untreated during the same period. In Phase 2, affected horses were ranked by severity of respiratory dysfunction and split randomly into either dexamethasone or MRL-EQ1 treatment groups (n = 5/group). Bronchoalveolar lavage fluid, respiratory mechanic measurements, MRL-EQ1 plasma concentration and tumour necrosis factor (TNF) whole blood activity were evaluated sequentially. RESULTS: In Phase 1, MRL-EQ1 did not prevent the occurrence of clinical signs and pulmonary inflammation. However, treatment was associated with a reduction in severity and a delay in the onset of signs and a reduction in pulmonary neutrophilia. In Phase 2, plasma concentrations achieved resulted in ex vivo suppression of lipopolysaccharide-induced TNF production in equine blood. MRL-EQ1 did not improve airway inflammation or lung function and was associated in a dose dependent manner with behavioural (depression, excitability) and blood changes (neutrophilia, increased serum muscle enzyme concentrations). CONCLUSIONS: Inhibition of p38 in the horse was partially effective in reducing clinical signs and airway inflammation when administered prior to, but not during clinical exacerbation in RAO. POTENTIAL RELEVANCE: Inhibitors of p38 MAPK with a better toxicity profile may be effective in the prevention or treatment of RAO.

Predictors of attendance and dropout at the Lung Health Study 11-year follow-up.

Participant attrition and attendance at follow-up were examined in a multicenter, randomized, clinical trial. The Lung Health Study (LHS) enrolled a total of 5887 adults to examine the impact of smoking cessation coupled with the use of an inhaled bronchodilator on chronic obstructive pulmonary disease (COPD). Of the initial LHS 1 volunteers still living at the time of enrolment in LHS 3 (5332), 4457 (84%) attended the LHS 3 clinic visit, a follow-up session to determine current smoking status and lung function. The average period between the beginning of LHS 1 and baseline interview for LHS 3 was 11 years. In univariate analyses, attenders were older, more likely female, more likely to be married, smoked fewer cigarettes per day, and were more likely to have children who smoked at the start of LHS 1 than non-attenders. Attenders were also less likely to experience respiratory symptoms, such as cough, but had decreased baseline lung function compared with non-attenders. Volunteers recruited via mass mailing were more likely to attend the long-term follow-up visit. Those recruited by public site, worksite, or referral methods were less likely to attend. In multivariate models, age, gender, cigarettes smoked per day, married status, and whether participants' children smoked were identified as significant predictors of attendance versus non-attendance at LHS 3 using stepwise logistic regression. Treatment condition (smoking intervention or usual care) was not a significant predictor of attendance at LHS 3. Older females who smoked less heavily were most likely to participate. These findings may be applied to improve participant recruitment and retention in future clinical trials.

Pilot study investigating the ability of an herbal composite to alleviate clinical signs of respiratory dysfunction in horses with recurrent airway obstruction.

Recurrent airway obstruction (RAO), known previously as chronic obstructive pulmonary disease (COPD), is a debilitating respiratory condition that significantly contributes to lost training days and illness in racehorses. Herbs are becoming increasingly popular for the prophylaxis or treatment of the clinical signs of RAO despite a paucity of research on efficacy and safety. We evaluated the ability of an herbal composite containing garlic, white horehound, boneset, aniseed, fennel, licorice, thyme, and hyssop to reduce the clinical signs of RAO, hypothesizing that the product would safely reduce signs and would improve the inflammatory cell profile within the lungs. The composite was fed to 6 horses with symptomatic RAO for 21 d in a crossover manner. Ventigraphs were used to record respiratory rate and intrapleural pressure; the proportion of inflammatory cells in fluid aspirated from the trachea was determined. Blood biochemical and hematologic screening was conducted to identify possible adverse effects. Treatment with the composite did not result in statistically significant changes in any of the parameters evaluated. A trend to a decrease in respiratory rate (P = 0.1) and an increase in the proportion of macrophages (P = 0.1) was observed in the horses receiving the herbal composite compared with placebo. These data indicate a potential for the herbal composite to safely reduce the elevated respiratory rate in horses with RAO. Future research with a greater number of horses is warranted to further characterize the effect of this product on horses with RAO.

Tiotropium bromide exerts anti-inflammatory effects during resistive breathing, an experimental model of severe airway obstruction.

INTRODUCTION: Resistive breathing (RB), a hallmark of obstructive airway diseases, is characterized by strenuous contractions of the inspiratory muscles that impose increased mechanical stress on the lung. RB is shown to induce pulmonary inflammation in previous healthy animals. Tiotropium bromide, an anticholinergic bronchodilator, is also shown to exert anti-inflammatory effects. The effect of tiotropium on RB-induced pulmonary inflammation is unknown. METHODS: Adult rats were anesthetized, tracheostomized and breathed spontaneously through a two-way non-rebreathing valve. Resistances were connected to the inspiratory and/or expiratory port, to produce inspiratory resistive breathing (IRB) of 40% or 50% Pi/Pi,max (40% and 50% IRB), expiratory resistive breathing (ERB) of 60% Pe/Pe,max (60% ERB) or combined resistive breathing (CRB) of both 40% Pi/Pi,max and 60% Pe/Pe,max (40%/60% CRB). Tiotropium aerosol was inhaled prior to RB. After 6 h of RB, mechanical parameters of the respiratory system were measured and bronchoalveolar lavage (BAL) was performed. IL-1ß and IL-6 protein levels were measured in lung tissue. Lung injury was estimated histologically. RESULTS: In all, 40% and 50% IRB increased macrophage and neutrophil counts in BAL and raised IL-1ß and IL-6 lung levels, tissue elasticity, BAL total protein levels and lung injury score. Tiotropium attenuated BAL neutrophil number, IL-1ß, IL-6 levels and lung injury score increase at both 40% and 50% IRB. The increase in macrophage count and protein in BAL was only reversed at 40% IRB, while tissue elasticity was not affected. In all, 60% ERB raised BAL neutrophil count and total protein and reduced macrophage count. IL-1ß and IL-6 levels and lung injury score were increased. Tiotropium attenuated these alterations, except for the decrease in macrophage count and the increase in total protein level. In all, 40%/60% CRB increased macrophage and neutrophil count in BAL, IL-1ß and IL-6 levels, tissue elasticity, total protein in BAL and histological injury score. Tiotropium attenuated the aforementioned alterations. CONCLUSION: Tiotropium inhalation attenuates RB-induced pulmonary inflammation.

Evaluation of flavorings-related lung disease risk at six microwave popcorn plants.

OBJECTIVE: After investigating fixed airways obstruction in butter flavoring-exposed workers at a microwave popcorn plant, we sought to further characterize lung disease risk from airborne butter-flavoring chemicals. METHODS: We analyzed data from medical and environmental surveys at six microwave popcorn plants (including the index plant). RESULTS: Respiratory symptom and airways obstruction prevalences were higher in oil and flavorings mixers with longer work histories and in packaging-area workers near nonisolated tanks of oil and flavorings. Workers were affected at five plants, one with mixing-area exposure to diacetyl (a butter-flavoring chemical with known respiratory toxicity potential) as low as 0.02 ppm. CONCLUSIONS: Microwave popcorn workers at many plants are at risk for flavoring-related lung disease. Peak exposures may be hazardous even when ventilation maintains low average exposures. Respiratory protection and engineering controls are necessary to protect workers.

Is there a rationale for pulmonary rehabilitation following successful chemotherapy for tuberculosis?

The role of tuberculosis as a public health care priority and the availability of diagnostic tools to evaluate functional status (spirometry, plethysmography, and DLCO determination), arterial blood gases, capacity to perform exercise, lesions (chest X-ray and CT), and quality of life justify the effort to consider what needs to be done when patients have completed their treatment. To our knowledge, no review has ever evaluated this topic in a comprehensive manner. Our objective was to review the available evidence on this topic and draw conclusions regarding the future role of the "post-tuberculosis treatment" phase, which will potentially affect several million cases every year. We carried out a non-systematic literature review based on a PubMed search using specific keywords (various combinations of the terms "tuberculosis", "rehabilitation", "multidrug-resistant tuberculosis", "pulmonary disease", "obstructive lung disease", and "lung volume measurements"). The reference lists of the most important studies were retrieved in order to improve the sensitivity of the search. Manuscripts written in English, Spanish, and Russian were selected. The main areas of interest were tuberculosis sequelae following tuberculosis diagnosis and treatment; "destroyed lung"; functional evaluation of sequelae; pulmonary rehabilitation interventions (physiotherapy, long-term oxygen therapy, and ventilation); and multidrug-resistant tuberculosis.The evidence found suggests that tuberculosis is definitively responsible for functional sequelae, primarily causing an obstructive pattern on spirometry (but also restrictive and mixed patterns), and that there is a rationale for pulmonary rehabilitation. We also provide a list of variables that should be discussed in future studies on pulmonary rehabilitation in patients with post-tuberculosis sequelae. RESUMO O papel da tuberculose como uma prioridade de saúde pública e a disponibilidade de ferramentas diagnósticas para avaliar o estado funcional (espirometria, pletismografia e DLCO), a gasometria arterial, a capacidade de realizar exercícios, as lesões (radiografia de tórax e TC) e a qualidade de vida justificam o esforço de se considerar o que deve ser feito quando os pacientes completam seu tratamento. Até onde sabemos, nenhuma revisão avaliou esse tópico de forma abrangente. Nosso objetivo foi revisar as evidências disponíveis e obter algumas conclusões sobre o futuro papel da fase de "tratamento pós-tuberculose", que irá potencialmente impactar milhões de casos todos os anos. Realizou-se uma revisão não sistemática da literatura tendo como base uma pesquisa no PubMed usando palavras-chave específicas (várias combinações dos termos "tuberculose", "reabilitação", "tuberculose multirresistente", "doença pulmonar", "doença pulmonar obstrutiva", e "medidas de volume pulmonar"). As listas de referências dos artigos principais foram recuperadas para melhorar a sensibilidade da busca. Foram selecionados manuscritos escritos em inglês, espanhol e russo. As principais áreas de interesse foram sequelas de tuberculose após diagnóstico e tratamento; "pulmão destruído"; avaliação funcional das sequelas; intervenções de reabilitação pulmonar (fisioterapia, oxigenoterapia de longo prazo e ventilação); e tuberculose multirresistente. As evidências encontradas sugerem que a tuberculose é definitivamente responsável por sequelas funcionais, principalmente causando um padrão obstrutivo na espirometria (mas também padrões restritivos e mistos) e que há razão para a reabilitação pulmonar. Fornecemos também uma lista de variáveis a serem discutidas em futuros estudos sobre reabilitação pulmonar em pacientes com sequelas pós-tuberculose.

What lies ahead? Future research and treatment for chronic obstructive pulmonary disease.

The morphologic basis for airflow obstruction in chronic obstructive pulmonary disease is extremely complex and consists of heterogeneous lesions. Emphysema seems to be the single most important lesion in this disorder. Abnormalities of the peripheral conducting airways, including inflammation, fibrosis, smooth muscle hypertrophy, and hyperplasia of mucus-secreting elements, are also of functional importance. Low-grade inflammation involving both airways and parenchyma occurs after only short-term exposure to cigarette smoke. This chronic inflammatory reaction may initiate other, largely irreversible, tissue responses that are responsible for airflow function. In the case of emphysema, tissue obstruction is thought to be due to an elastase-antielastase imbalance, leading to accelerated destruction of elastic fibers in the alveolar walls. Logical strategies for controlling the development of emphysema might include measures to prevent the influx of phagocyte-borne elastases into the lung as well as efforts to supplement the antiprotease shield of the lower airways. Anti-inflammatory drugs might also be effective in suppressing cigarette-smoke-induced reactions in the conducting airways. Other agents might be effective by preventing bronchoconstriction and the proliferation of smooth muscle elements in airway walls.

Therapeutic algorithm for chronic obstructive pulmonary disease.

It would be foolhardy to offer an inflexible step-care protocol for the management of chronic obstructive pulmonary disease, given its heterogeneity and our uncertainty about its pathogenesis. Instead, the following outline might be regarded as a statement of principles to guide individual treatment plans. Smoking cessation is an essential, if difficult, first step, which is necessary to slow the accelerated rate of decline in pulmonary function that is characteristic of this disease. There is a compelling rationale for the use of influenza and pneumococcal vaccination, although proof of efficacy is lacking. If airways obstruction is present, inhaled quaternary anticholinergic bronchodilators seem to offer the greatest benefit with fewest side effects, making them the obvious first choice in bronchodilator therapy. In some patients, the addition of beta-agonists, theophylline, or both may augment bronchodilation. If significant airways obstruction persists despite the foregoing, an oral steroid trial is required. Some carefully selected patients whose exercise capacity has been limited despite optimal medical therapy may respond to a supervised exercise rehabilitation program. If hypoxemia is present, supplemental oxygen improves survival. Additional therapeutic modalities, ranging from preventive antioxidant administration to lung transplantation, remain investigational.

Public screening for lung disease: experience with the NIH Lung Health Study.

The Lung Health Study is the first major initiative of the National Heart, Lung, and Blood Institute in screening for and intervention in early lung disease. The objective of the study is to identify cigarette smokers who have early disease and determine whether an intervention program of smoking cessation and bronchodilator therapy will alter the course of their disease. After an extensive screening program, 5,887 participants have been randomized to one of three groups: usual care, intervention with smoking cessation and the use of a placebo inhaler, and intervention with smoking cessation and the use of ipratropium bromide. All participants will be followed for 5 years. Preliminary data from the screening indicate that chronic obstructive pulmonary disease is more prevalent than was previously recognized, that it is widespread in women as well as men, and that it is far more common in young individuals than was thought. Approximately two-thirds of the study participants have hyperreactive airways. Preliminary data from the Lung Health Study indicate that screening for lung function can be carried out in a cost-effective manner.

A nebulizer chronolog to monitor compliance with inhaler use.

The Lung Health Study is a 10-center 5-year clinical trial sponsored by the National Heart, Lung, and Blood Institute to evaluate the effectiveness of early intervention in chronic obstructive pulmonary disease (COPD). The specific objectives of the trial are to determine whether the accelerated decline in lung function characteristic of COPD and morbidity due to COPD can be reduced by special intervention at a relatively early stage in the evolution of the disease. Special intervention consists of a smoking-cessation program and the use of an inhaled bronchodilator to suppress airway hyperreactivity. The use of the inhaler canister is monitored every 4 months by canister weighing and, at two of the 10 centers, by an electronic recording device, the Nebulizer Chronolog. Among trial participants assigned the latter device, results from the first 4 months of the study indicate that only 52% of trial participants who were uninformed as to the nature of the chronolog used their inhaler at least twice daily as measured by the chronolog, compared with 87% as determined by self-report. Satisfactory or good compliance was achieved by 52% of these subjects as measured by the chronolog compared with 85% as assessed by canister weighing. Eighteen percent of uninformed participants "dumped" their inhalers within a 3-hour time period, contributing to the inaccuracy of canister weights as an indicator of compliance. Feedback of information to the participants from the chronolog improved the level of compliance and eliminated the "dumping" phenomenon. We conclude that, when accurate determinations of compliance are important, as in a drug trial, objective medication monitors should be considered. Electronic monitoring of inhaler use can provide valuable feedback, which encourages improved compliance.

Therapeutic approaches to chronic obstructive pulmonary disease: an emerging consensus.

In response to reports of rising asthma morbidity and mortality, several consensus statements have been drafted to guide the treatment of asthma. More recently, attempts have been made to develop similar guidelines for the management of chronic obstructive pulmonary disease (COPD). Just as the two diseases differ in their pathophysiology, their treatment algorithms have differed. For both disease groups, avoidance of further airway injury is the initial step in treatment. For asthmatics, this is often allergen avoidance, but for patients with COPD the usual inciting factor is cigarette smoking, thereby making smoking cessation the necessary first step. Whereas beta 2-agonist bronchodilators are used as needed in asthma management, regular bronchodilator therapy with anticholinergic drugs is the first-line approach in COPD. The role of anti-inflammatory drugs differs markedly between the two disease groups. Asthmatic patients benefit dramatically from inhaled anti-inflammatory drugs; little or no benefit can be demonstrated for the majority of patients with COPD. In COPD, the role of exercise rehabilitation programs can improve exercise tolerance. For selected patients with COPD with persistent hypoxemia, the use of supplemental oxygen can reduce mortality. For both patient groups, educational interventions can play a valuable role in making patients patients effective partners in their own care.

Early dexamethasone-attempting to prevent chronic lung disease.

BACKGROUND: We previously demonstrated improved survival and early outcomes in a pilot trial of 2 doses of intravenous dexamethasone for infants with surfactant-treated respiratory distress syndrome. (1) A multicenter, randomized, double-blind trial was undertaken to confirm these results. METHODS: Infants <30 weeks' gestation were eligible if they had respiratory distress syndrome, required mechanical ventilation at 12 to 18 hours of age, and had received at least 1 dose of exogenous surfactant. Infants were excluded if sepsis or pneumonia was suspected or if congenital heart disease or chromosomal abnormalities were present. A total of 384 infants were enrolled-189 randomized to dexamethasone (.5mg/kg birth weight at 12-18 hours of age and a second dose 12 hours later) and 195 to an equal volume of saline placebo. RESULTS: No differences were found in the dexamethasone versus placebo groups, respectively, regarding the primary outcomes of survival (79% vs 83%), survival without oxygen at 36 weeks' corrected gestational age (CGA; both 59%), and survival without oxygen at 36 weeks' CGA and without late glucocorticoid therapy (46% vs 44%). No significant differences between the groups in estimates from Kaplan-Meier survival analyses were found for median days on oxygen (50 vs 56 days), ventilation (20 vs 27 days), days to regain birth weight (15.5 vs 14 days), or length of stay (LOS; 88 vs 89 days). Infants given early dexamethasone were less likely to receive later glucocorticoid therapy for bronchopulmonary dysplasia during their hospitalization (27% vs 35%). No clinically significant side effects were noted in the dexamethasone group, although there were transient elevations in blood glucose and blood pressure followed by a return to baseline by study day 10. Among infants who died (40 vs 33), there were no differences in the median days on oxygen, ventilation, nor LOS. However, in survivors (149 vs 162), the following were observed: median days on oxygen 37 versus 45 days, ventilation 14 versus 19 days, and LOS 79 versus 81 days, for the dexamethasone versus placebo groups, respectively. CONCLUSIONS: This dose of early intravenous dexamethasone did not reduce the requirement for oxygen at 36 weeks' CGA and survival was not improved. However, early dexamethasone reduced the use of later prolonged dexamethasone therapy, and among survivors, reduced the median days on oxygen and ventilation. We conclude that this course of early dexamethasone probably represents a near minimum dose for instituting a prophylactic regimen against bronchopulmonary dysplasia.