Elevated serum Activin A in chronic obstructive pulmonary disease with skeletal muscle wasting

OBJECTIVE: Muscle wasting contributes to the reduced quality of life and increased mortality in chronic obstructive pulmonary disease (COPD). Muscle atrophy in mice with cachexia was caused by Activin A binding to ActRIIB. The role of circulating Activin A leading to muscle atrophy in COPD remains elusive. METHODS: In the present study, we evaluated the relationship between serum levels of Activin A and skeletal muscle wasting in COPD patients. The expression levels of serum Activin A were measured in 78 stable COPD patients and in 60 healthy controls via ELISA, which was also used to determine the expression of circulating TNF-α levels. Total skeletal muscle mass (SMM) was calculated according to a validated formula by age and anthropometric measurements. The fat-free mass index (FFMI) was determined as the fat-free mass (FFM) corrected for body surface area. RESULTS: Compared to the healthy controls, COPD patients had upregulated Activin A expression. The elevated levels of Activin A were correlated with TNF-α expression, while total SMM and FFMI were significantly decreased in COPD patients. Furthermore, serum Activin A expression in COPD patients was negatively associated with both FFMI and BMI. CONCLUSION: The above results showed an association between increased circulating Activin A in COPD patients and the presence of muscle atrophy. Given our previous knowledge, we speculate that Activin A contributes to skeletal muscle wasting in COPD.

Variables clínicas y funcionales asociadas al riesgo de muerte en el seguimiento a largo plazo en pacientes con enfermedad pulmonar obstructiva crónica / Clinical and functional variables associated to long-term mortality in COPD patients

Background: Identifying risk factors for long-term mortality in patients with chronic obstructive pulmonary disease (COPD) could improve their clinical management. Aim: To examine the clinical variables associated to long-term mortality in a cohort of COPD patients. Patients and Methods: A clinical and respiratory functional assessment, chest computed tomography and clinical follow up for five years was carried out in 202 COPD patients aged 66 ± 9 years (59% males), active or former smokers of 10 or more pack-years. Results: Thirty four percent of patients were active smokers, consuming 46 ± 23 packs/year, 86% had comorbidities, especially chronic cardiovascular and metabolic diseases. Forty-six patients died in the five years follow-up (5-year mortality was therefore 22.8%). In the univariate analysis, the main risk factors associated to long-term mortality were an older age, male sex, dyspnea severity, severe exacerbation risk, chronic respiratory failure, magnitude of lung emphysema, airflow obstruction and lung hyperinflation, reduction of thigh muscle cross-sectional area and physical activity limitation. In the multivariate analysis, the three independent risk factors for long-term mortality were dyspnea severity, chronic hypoxemia and exercise limitation measured with the six minutes' walk test. Conclusions: Systematic clinical assessment allowed to identify the main risk factors associated with long-term mortality in patients with COPD, which could be used in planning preventive and management programs aimed at the high-risk population.

Soluble urokinase-type plasminogen activator receptor as a measure of treatment response in acute exacerbation of COPD / Receptor do ativador de plasminogênio tipo uroquinase solúvel como medida da resposta ao tratamento da exacerbação aguda da DPOC

ABSTRACT Objective: To evaluate the value of soluble urokinase-type plasminogen activator receptor (suPAR) in the diagnosis of acute exacerbation of COPD (AECOPD) and in monitoring treatment response, analyzing the relationship between suPAR and fibrinogen in AECOPD. AECOPD leads to increased airway inflammation, contributing to an exaggerated release of inflammatory mediators. Methods: We recruited 45 patients with AECOPD and 20 healthy control subjects. Medical histories were taken, and all subjects underwent clinical examination, chest X-ray, pulmonary function tests, and blood gas analysis. On day 1 (treatment initiation for the AECOPD patients) and day 14 (end of treatment), blood samples were collected for the determination of serum suPAR and plasma fibrinogen. Results: Serum levels of suPAR were significantly higher in the AECOPD group than in the control group. In the AECOPD patients, there was a significant post-treatment decrease in the mean serum suPAR level. The sensitivity, specificity, and accuracy of suPAR were 95.6%, 80.0%, and 93.0%, respectively. The Global Initiative for Chronic Obstructive Lung Disease stage (i.e., COPD severity) correlated positively and significantly with serum levels of suPAR and plasma levels of fibrinogen. Conclusions: Monitoring the serum suPAR level can be helpful in the evaluation of the COPD treatment response and might be a valuable biomarker for determining the prognosis of AECOPD. Because serum suPAR correlated with plasma fibrinogen, both markers could be predictive of AECOPD.

RESUMO Objetivo: Avaliar o valor do soluble urokinase-type plasminogen activator receptor (suPAR, receptor do ativador de plasminogênio tipo uroquinase solúvel) no diagnóstico de exacerbação aguda da DPOC (EADPOC) e no monitoramento da resposta ao tratamento, analisando-se a relação entre o suPAR e o fibrinogênio na EADPOC. A EADPOC leva ao aumento da inflamação das vias aéreas, contribuindo para a liberação exagerada de mediadores inflamatórios. Métodos: Foram recrutados 45 pacientes com EADPOC e 20 controles saudáveis. Realizou-se anamnese, e todos os indivíduos foram submetidos a exame clínico, radiografia de tórax, provas de função pulmonar e gasometria arterial. No dia 1 (início do tratamento para os pacientes com EADPOC) e no dia 14 (final do tratamento), foram coletadas amostras de sangue para dosagem de suPAR sérico e de fibrinogênio plasmático. Resultados: Os níveis séricos de suPAR foram significativamente maiores no grupo EADPOC do que no grupo controle. Nos pacientes com EADPOC, houve diminuição significativa da média de suPAR sérico após o tratamento. A sensibilidade, a especificidade e a acurácia do suPAR foram, respectivamente, de 95,6%, 80,0% e 93,0%. O estágio da doença segundo a Global Initiative for Chronic Obstructive Lung Disease (isto é, a gravidade da DPOC) apresentou correlação positiva e significativa com os níveis séricos de suPAR e os níveis plasmáticos de fibrinogênio. Conclusões: O monitoramento do suPAR sérico pode ser útil na avaliação da resposta ao tratamento da DPOC e seria um biomarcador valioso para a determinação do prognóstico da EADPOC. Como o suPAR sérico apresentou correlação com o fibrinogênio plasmático, ambos os marcadores poderiam ser preditores da EADPOC.

Prevalence of alpha-1 antitrypsin deficiency and allele frequency in patients with COPD in Brazil / Prevalência da deficiência de alfa-1 antitripsina e frequência alélica em pacientes com DPOC no Brasil

ABSTRACT Objective: To determine the prevalence of alpha 1-antitrypsin (AAT) deficiency (AATD), as well as allele frequency, in COPD patients in Brazil. Methods: This was a cross-sectional study involving 926 COPD patients 40 years of age or older, from five Brazilian states. All patients underwent determination of AAT levels in dried blood spot (DBS) samples by nephelometry. Those with DBS AAT levels ≤ 2.64 mg/dL underwent determination of serum AAT levels. Those with serum AAT levels of < 113 mg/dL underwent genotyping. In case of conflicting results, SERPINA1 gene sequencing was performed. Results: Of the 926 COPD patients studied, 85 had DBS AAT levels ≤ 2.64 mg/dL, and 24 (2.6% of the study sample) had serum AAT levels of < 113 mg/dL. Genotype distribution in this subset of 24 patients was as follows: PI*MS, in 3 (12.5%); PI*MZ, in 13 (54.2%); PI*SZ, in 1 (4.2%); PI*SS, in 1 (4.2%); and PI*ZZ, in 6 (25.0%). In the sample as a whole, the overall prevalence of AATD was 2.8% and the prevalence of the PI*ZZ genotype (severe AATD) was 0.8% Conclusions: The prevalence of AATD in COPD patients in Brazil is similar to that found in most countries and reinforces the recommendation that AAT levels be measured in all COPD patients.

RESUMO Objetivo: Determinar a prevalência da deficiência de alfa 1-antitripsina (AAT), bem como a frequência alélica, em pacientes com DPOC no Brasil. Métodos: Estudo transversal com 926 pacientes com DPOC, com 40 anos ou mais, oriundos de cinco estados brasileiros. Todos os pacientes foram submetidos a dosagem de AAT em amostras de sangue seco por meio de nefelometria. Aqueles em que a concentração de AAT no sangue seco foi ≤ 2,64 mg/dl foram submetidos a dosagem sérica de AAT. Aqueles em que a concentração sérica de AAT foi < 113 mg/dl foram submetidos a genotipagem. Quando os resultados foram discrepantes, foi realizado o sequenciamento do gene SERPINA1. Dos 926 pacientes com DPOC estudados, 85 apresentaram concentração de AAT em sangue seco ≤ 2,64 mg/dl, e 24 (2,6% da amostra) apresentaram concentração sérica de AAT < 113 mg/dl. A distribuição genotípica nesse subgrupo de 24 pacientes foi a seguinte: PI*MS, em 3 (12,5%); PI*MZ, em 13 (54,2%); PI*SZ, em 1 (4,2%); PI*SS, em 1 (4,2%); e PI*ZZ, em 6 (25,0%). Na amostra estudada, a prevalência global da deficiência de AAT foi de 2,8% e a prevalência do genótipo PI*ZZ (deficiência grave de AAT) foi de 0,8%. Conclusões: A prevalência da deficiência de AAT em pacientes com DPOC no Brasil é semelhante àquela encontrada na maioria dos países e reforça a recomendação de que se deve medir a concentração de AAT em todos pacientes com DPOC.

Increased ultrasensitive C-reactive protein is not associated with obesity in hospitalized heart failure patients / Proteína C-reativa ultrassensível não se associa com obesidade em pacientes hospitalizados por insuficiência cardíaca

ABSTRACT Objective: To evaluate the association between obesity and levels of high-sensitivity C-reactive protein (hs-CRP) in patients with heart failure admitted to a tertiary hospital. Methods: Cross-sectional study with a consecutive sampling of hospitalized patients with heart failure. Sociodemographic and clinical data were collected, and the nutritional status was assessed through indicators such as body mass index (in kg/m2), waist circumference (in cm), waist-hip ratio, triceps skinfold (in mm) and subscapularis skinfold (in mm). Neck circumference (in cm) was measured as well as serum levels of hs-CRP, in mg/L. Results: Among 123 patients, the mean age was 61.9±12.3 years and 60.2% were male. The median of hs-CRP was 8.87mg/L (3.34 to 20.01). A tendency to an inverse correlation between neck circumference and hs-CRP was detected (r=-0.167; p=0.069). In the multiple linear regression analysis, after adjustment for age, disease severity (NYHA classification III and IV, low ejection fraction, left ventricular dysfunction during diastole), and infectious conditions there was an inverse association between hs-CRP and neck circumference (ß=-0.196; p=0.03) and subscapularis skinfold (ß=-0.005; p=0.01) in the total sample, which was not maintained after the stratification by sex. Conclusion: Increased levels of hs-CRP in patients hospitalized for heart failure were not associated with obesity.

RESUMO Objetivo: Avaliar a associação entre obesidade e níveis de proteína c-reativa ultrassensível (PCR-us) em pacientes com insuficiência cardiac admitidos em um hospital terciário. Métodos: Estudo transversal com amostragem consecutiva de pacientes com insuficiência cardíaca hospitalizados. Foram coletados dados sociodemográficos e clínicos, e o estado nutricional foi avaliado por meio de indicadores como índice de massa corporal (em kg/m2), circunferência da cintura (em cm), razão cintura-quadril, dobra cutânea tricipital (em mm) e dobra cutânea subescapular (em mm). Circunferência do pescoço (em cm) foi aferida bem como níveis séricos de PCR-us, em mg/L. Resultados: Em 123 pacientes, a média da idade foi 61,9±12,3 anos, e 60,2% eram do sexo masculino. A mediana de PCR-us foi de 8,87mg/L (3,34 a 20,01). Detectou-se tendência à correlação inversa entre circunferência do pescoço e PCR-us (r=-0,167; p=0,069). Na análise por regressão linear múltipla, após ajustes para idade, gravidade da doença (classificação NYHA III e IV, fração de ejeção baixa, disfunção ventricular esquerda durante a diástole) e quadros infecciosos, houve associação inversa entre PCR-us e circunferência do pescoço (ß=-0,196; p=0,03) e dobra cutânea subescapular (ß=-0,005; p=0,01) na amostra total, que não se manteve após estratificação para sexo. Conclusão: O aumento dos níveis de PCR-us em pacientes hospitalizados por insuficiência cardíaca não se associou à obesidade.

MFG-E8, a clearance glycoprotein of apoptotic cells, as a new marker of disease severity in chronic obstructive pulmonary disease

Milk fat globule epidermal growth factor 8 (MFG-E8) is an opsonin involved in the phagocytosis of apoptotic cells. In patients with chronic obstructive pulmonary disease (COPD), apoptotic cell clearance is defective. However, whether aberrant MFG-E8 expression is involved in this defect is unknown. In this study, we examined the expression of MFG-E8 in COPD patients. MFG-E8, interleukin (IL)-1β and transforming growth factor (TGF)-β levels were measured in the plasma of 96 COPD patients (93 males, 3 females; age range: 62.12±10.39) and 87 age-matched healthy controls (85 males, 2 females; age range: 64.81±10.11 years) using an enzyme-linked immunosorbent assay. Compared with controls, COPD patients had a significantly lower plasma MFG-E8 levels (P<0.01) and significantly higher plasma TGF-β levels (P=0.002), whereas there was no difference in plasma IL-1β levels between the two groups. Moreover, plasma MFG-E8 levels decreased progressively between Global Initiative for Chronic Obstructive Lung Disease (GOLD) I and GOLD IV stage COPD. Multiple regression analysis showed that the forced expiratory volume in 1 s (FEV1 % predicted) and smoking habit were powerful predictors of MFG-E8 in COPD (P<0.01 and P=0.026, respectively). MFG-E8 was positively associated with the FEV1 % predicted and negatively associated with smoking habit. The area under the receiver operating characteristic curve was 0.874 (95% confidence interval: 0.798-0.95; P<0.01). Our findings demonstrated the utility of MFG-E8 as a marker of disease severity in COPD and that cigarette smoke impaired MFG-E8 expression in these patients.

Relationship between vitamin D and lung function, physical performance and balance on patients with stage I-III chronic obstructive pulmonary disease / Relação entre vitamina D e função pulmonar, desempenho físico e equilíbrio em pacientes em estágio I a III de doença pulmonar obstrutiva crônica

Summary Objectives: vitamin D is important for muscle function and it affects different aspects of muscle metabolism. This study aim to determine whether serum 25(OH) D levels are related to lung functions, physical performance and balance in patients with chronic obstructive pulmonary disease (COPD). Methods: in 90 patients with COPD and 57 healthy controls lung function tests, physical performance tests (time up and go, gait velocity test, sit-to-stand test, isometric strength, isokinetic strength), static (functional reach test) and dynamic (time up and go) balance tests and the association of 25(OH)D levels with lung functions, physical performance and balance were evaluated. Results: the COPD patients had significantly more deficit in physical function and balance parameters, and in dynamic balance test (p<0.005). Isokinetic knee muscle strength (flexor and extensor) in COPD patients was significantly lower than in the controls (p<0.05); FEV1 (p=0.008), FVC (p=0.02), FEV1/FVC (p=0.04), TLC (p=0.01) were lower in COPD patients with vitamin D deficiency [25(OH) D less than 15ng/mL] than in COPD patients without vitamin D deficiency. Hand grip test (p=0.000) and isokinetic knee muscle strength (flexor and extensor) (p<0.05) were also lower in COPD patients with vitamin D deficiency. Vitamin D deficiency was more pronounced in patients with stage III COPD (p<0.05). Conclusion: patients with COPD had worst physical functioning, poor balance and less muscle strength. Severe disturbed lung and peripheral muscle functions are more pronounced in COPD patients with vitamin D deficiency. .

Resumo Objetivos: a vitamina D é importante para a função muscular e afeta diferentes aspectos do metabolismo muscular. O objetivo é determinar se os níveis séricos de 25 (OH) D estão relacionados com as funções pulmonares, desempenho físico e equilíbrio em pacientes com doença pulmonar obstrutiva crônica (DPOC). Métodos: em 90 pacientes com DPOC e 57 controles saudáveis, testes de espirometria, testes de desempenho (tempo de levantar e ir, teste de velocidade da marcha, teste sitto-stand, força isométrica, força isocinética) e testes de estática (teste de alcance funcional) e dinâmica (tempo de levantar e ir) de equilíbrio foram realizados; e foram avaliados a associação de níveis de 25 (OH) D com as funções pulmonares, desempenho físico e equilíbrio. Resultados: os pacientes com DPOC apresentaram significativamente mais déficit nos parâmetros de função e equilíbrio físico, e no teste de equilíbrio dinâmico (p<0,005). Força muscular isocinética do joelho (flexores e extensores) em pacientes com DPOC foi significativamente menor do que nos controles (p<0,05); VEF1 (p=0,008), CVF (p=0,02), VEF1/CVF (p=0,04), CPT (p=0,01) foram mais baixos em pacientes com DPOC e com deficiência de vitamina D [25 (OH) D menor do que 15 ng/ml] do que em pacientes com DPOC sem deficiência de vitamina D. Os resultados do teste da força de preensão manual (p=0,000) e força muscular isocinética do joelho (flexor e extensor) (p<0,05) também foram menores nos pacientes com DPOC e com deficiência de vitamina D. A deficiência de vitamina D foi mais pronunciada em pacientes em estágio III da DPOC (p<0,05). Conclusão: pacientes com DPOC tiveram pior desempenho físico, falta de equilíbrio e menor força muscular. Perturbações graves das funções pulmonares e musculares periféricas são mais pronunciadas em pacientes com DPOC e com deficiência de vitamina D. .

Utility of the combination of serum highly-sensitive C-reactive protein level at discharge and a risk index in predicting readmission for acute exacerbation of COPD, / Utilidade de se combinar o nível sérico de proteína C reativa de alta sensibilidade no momento da alta com um índice de risco para prever a reinternação por exacerbação aguda da DPOC

OBJECTIVE: Frequent readmissions for acute exacerbations of COPD (AECOPD) are an independent risk factor for increased mortality and use of health-care resources. Disease severity and C-reactive protein (CRP) level are validated predictors of long-term prognosis in such patients. This study investigated the utility of combining serum CRP level with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) exacerbation risk classification for predicting readmission for AECOPD. METHODS: This was a prospective observational study of consecutive patients hospitalized for AECOPD at Peking University Third Hospital, in Beijing, China. We assessed patient age; gender; smoking status and history (pack-years); lung function; AECOPD frequency during the last year; quality of life; GOLD risk category (A-D; D indicating the greatest risk); and serum level of high-sensitivity CRP at discharge (hsCRP-D). RESULTS: The final sample comprised 135 patients. Of those, 71 (52.6%) were readmitted at least once during the 12-month follow-up period. The median (interquartile) time to readmission was 78 days (42-178 days). Multivariate analysis revealed that serum hsCRP-D ≥ 3 mg/L and GOLD category D were independent predictors of readmission (hazard ratio = 3.486; 95% CI: 1.968-6.175; p < 0.001 and hazard ratio = 2.201; 95% CI: 1.342-3.610; p = 0.002, respectively). The ordering of the factor combinations by cumulative readmission risk, from highest to lowest, was as follows: hsCRP-D ≥ 3 mg/L and GOLD category D; hsCRP-D ≥ 3 mg/L and GOLD categories A-C; hsCRP-D < 3 mg/L and GOLD category D; hsCRP-D < 3 mg/L and GOLD categories A-C. CONCLUSIONS: Serum hsCRP-D and GOLD classification are independent predictors of readmission for AECOPD, and their predictive value increases when they are used in combination. .

OBJETIVO: Reinternações frequentes por exacerbações agudas da DPOC (EADPOC) são um fator de risco independente para maior mortalidade e uso de recursos de saúde. A gravidade da doença e o nível de proteína C reativa (PCR) são preditores validados do prognóstico em longo prazo para tais pacientes. Investigamos a utilidade da combinação do nível sérico de PCR com a classificação de risco de exacerbação da Global Initiative for Chronic Obstructive Lung Disease (GOLD) para predizer a reinternação por EADPOC. MÉTODOS: Estudo observacional prospectivo de pacientes consecutivos hospitalizados por EADPOC no Peking University Third Hospital, in Pequim, China. Avaliamos a idade; gênero, história e carga tabágicas (anos-maço), função pulmonar, frequência de EADPOC no último ano; qualidade de vida; categoria de risco GOLD (A-D, D indicando maior risco); e nível sérico de PCR de alta sensibilidade na alta (PCRas-A). RESULTADOS: A amostra final consistiu em 135 pacientes. Desses, 71 (52,6%) foram reinternados ao menos uma vez durante o período de seguimento de 12 meses. A mediana (intervalo interquartílico) do tempo de reinternação foi de 78 dias (42-178 dias). A análise multivariada revelou que PCRas-A sérico ≥ 3 mg/L e categoria GOLD D foram preditores independentes de reinternação (razão de risco = 3,486; IC95%: 1,968-6,175; p < 0,001 e razão de risco = 2,201; IC95%: 1,342-3,610; p = 0,002, respectivamente). A ordem das combinações dos fatores por risco cumulativo de readmissão, da maior para a menor foi a seguinte: PCRas-A ≥ 3 mg/L e categoria GOLD D; PCRas-A ≥ 3 mg/L e categorias GOLD A-C; PCRas-A < 3 mg/L e categoria GOLD D; e PCRas-A < 3 mg/L e categorias GOLD A-C. CONCLUSÕES: ...

Evaluation of von Willebrand factor in COPD patients / Avaliação do fator de von Willebrand em pacientes com DPOC

OBJECTIVE: To compare the absolute serum von Willebrand factor (vWF) levels and relative serum vWF activity in patients with clinically stable COPD, smokers without airway obstruction, and healthy never-smokers. METHODS: The study included 57 subjects, in three groups: COPD (n = 36); smoker (n = 12); and control (n = 9). During the selection phase, all participants underwent chest X-rays, spirometry, and blood testing. Absolute serum vWF levels and relative serum vWF activity were obtained by turbidimetry and ELISA, respectively. The modified Medical Research Council scale (cut-off score = 2) was used in order to classify COPD patients as symptomatic or mildly symptomatic/asymptomatic. RESULTS: Absolute vWF levels were significantly lower in the control group than in the smoker and COPD groups: 989 ± 436 pg/mL vs. 2,220 ± 746 pg/mL (p < 0.001) and 1,865 ± 592 pg/mL (p < 0.01). Relative serum vWF activity was significantly higher in the COPD group than in the smoker group (136.7 ± 46.0% vs. 92.8 ± 34.0%; p < 0.05), as well as being significantly higher in the symptomatic COPD subgroup than in the mildly symptomatic/asymptomatic COPD subgroup (154 ± 48% vs. 119 ± 8%; p < 0.05). In all three groups, there was a negative correlation between FEV1 (% of predicted) and relative serum vWF activity (r2 = −0.13; p = 0.009). CONCLUSIONS: Our results suggest that increases in vWF levels and activity contribute to the persistence of systemic inflammation, as well as increasing cardiovascular risk, in COPD patients. .

OBJETIVO: Comparar os níveis séricos absolutos e a atividade sérica em percentual do fator de von Willebrand (FvW) em pacientes com DPOC clinicamente estáveis, tabagistas sem obstrução das vias aéreas e em indivíduos saudáveis que nunca fumaram. MÉTODOS: Foram incluídos no estudo 57 indivíduos, em três grupos: DPOC (n = 36), tabagista (n = 12) e controle (n = 9). Todos os participantes realizaram radiografia do tórax, espirometria e exame de sangue durante a fase de seleção. Os níveis séricos absolutos e a atividade sérica em percentual do FvW foram obtidos por turbidimetria e ELISA, respectivamente. A escala Medical Research Council modificada foi utilizada para classificar pacientes como sintomáticos ou assintomáticos/pouco sintomáticos no grupo DPOC (ponto de corte = 2). RESULTADOS: Os níveis absolutos do FvW no grupo controle foram significativamente menores que os nos grupos tabagista e DPOC: 989 ± 436 pg/mL vs. 2.220 ± 746 pg/mL (p < 0,001) e 1.865 ± 592 pg/mL (p < 0,01). Os valores em percentual de atividade do FvW no grupo DPOC foram significativamente maiores que no grupo tabagista (136,7 ± 46,0% vs. 92,8 ± 34,0%; p < 0,05), assim como foram significativamente maiores no subgrupo DPOC sintomático que no subgrupo DPOC assintomático/pouco sintomático (154 ± 48% vs. 119 ± 8%; p < 0,05). Houve uma correlação negativa entre o VEF1 (% do previsto) e os níveis em percentual de atividade do FvW nos três grupos (r2 = −0,13; p = 0,009). CONCLUSÕES: Nossos resultados sugerem que aumentos nos níveis de FvW e de sua atividade contribuem para a manutenção da inflamação sistêmica e o aumento do risco cardiovascular em pacientes com DPOC. .

Oxygen desaturation during the six-minute walk test in COPD patients / Análise da dessaturação de oxigênio durante o teste de caminhada de seis minutos em pacientes com DPOC

Objective: To evaluate the behavior of oxygen saturation curves throughout the six-minute walk test (6MWT) in patients with COPD. Methods: We included 85 patients, all of whom underwent spirometry and were classified as having moderate COPD (modCOPD, n = 30) or severe COPD (sevCOPD, n = 55). All of the patients performed a 6MWT, in a 27-m corridor with continuous SpO2 and HR monitoring by telemetry. We studied the SpO2 curves in order to determine the time to a 4% decrease in SpO2, the time to the minimum SpO2 (Tmin), and the post-6MWT time to return to the initial SpO2, the last designated recovery time (RT). For each of those curves, we calculated the slope. Results: The mean age in the modCOPD and sevCOPD groups was 66 ± 10 years and 62 ± 11 years, respectively. At baseline, SpO2 was > 94% in all of the patients; none received supplemental oxygen during the 6MWT; and none of the tests were interrupted. The six-minute walk distance did not differ significantly between the groups. The SpO2 values were lowest in the sevCOPD group. There was no difference between the groups regarding RT. In 71% and 63% of the sevCOPD and modCOPD group patients, respectively, a ≥ 4% decrease in SpO2 occurred within the first minute. We found that FEV1% correlated significantly with the ΔSpO2 (r = −0.398; p < 0.001), Tmin (r = −0.449; p < 0.001), and minimum SpO2 (r = 0.356; p < 0.005). Conclusions: In the sevCOPD group, in comparison with the modCOPD group, SpO2 was lower and the Tmin was greater, suggesting a worse prognosis in the former. .

Objetivo: Avaliar o comportamento da curva de saturação de oxigênio durante o teste de caminhada de seis minutos (TC6) em pacientes com DPOC. Métodos: Incluímos 85 pacientes e todos realizaram espirometria, sendo classificados como portadores de DPOC moderada (DPOCm, n = 30) ou grave (DPOCg, n = 55). Todos os pacientes realizaram TC6 em um corredor de 27 m com monitoramento contínuo da SpO2 e FC por telemetria. A partir das curvas de SpO2, foram analisados os tempos para atingir a queda de 4% da SpO2, para atingir a SpO2 mínima (Tmin) e para a recuperação da SpO2 após o TC6 (TR). Foram calculadas as inclinações dessas curvas. Resultados: A média de idade nos grupos DPOCm e DPOCg foi de 62 ± 11 anos e 66 ± 10 anos, respectivamente. Todos os pacientes iniciaram o teste com SpO2 > 94%, nenhum recebeu suplementação de oxigênio durante o TC6, e não houve interrupções. A distância percorrida no TC6 não apresentou diferença significativa entre os grupos. Os menores valores da SpO2 ocorreram no grupo DPOCg. Não houve diferença no TR entre os grupos, e 71% e 63% dos pacientes nos grupos DPOCg e DPOCm, respectivamente, apresentaram queda de SpO2 ≥ 4% até o primeiro minuto. O VEF1% apresentou correlações significativas com ΔSpO2 (r = −0,398; p < 0,001), Tmin (r = −0,449; p < 0,001) e SpO2 mínima (r = 0,356; p < 0,005). Conclusões: As curvas dos pacientes do grupo DPOCg em relação às do grupo DPOCm apresentaram valores menores de SpO2 e maior Tmin, sugerindo um pior prognóstico nos primeiros. .

Proteína C Reactiva en la EPOC y su relación con la gravedad de la enfermedad, las exacerbaciones y las comorbilidades / C-Reactive protein levels in patients with chronic obstructive pulmonary disease

Background: Patients with chronic obstructive pulmonary disease (COPD) have elevated serum levels of ultrasensitive C reactive protein (CRPus). This raise may be related directly to COPD and its associated systemic inflammation or secondary to other factors such as smoking status, disease severity, acute exacerbations, or associated complications. Aim: To evaluate the potential causes of raised levels of CRPus in stable COPD patients. Patients and Methods: Cohorts of 133 mild-to-very severe COPD patients (41 current smokers), 31 never-smokers, and 33 current smoker controls were compared. Clinical assessments included body mass index (BMI), fat (FM) and fat-free mass (FFM) measurement by DEXA, forced expiratory volume in one second (FEV1), arterial oxygen tension (PaO2), six-minute walking test (SMWT), emphysema (EMPH) and right thigh muscle cross-sectional area (TMCSA), both quantified by high resolution computed tomography. Results: Serum CRPus levels were significantly higher in COPD patients than in controls (7 ± 4.2 and 3.7 ± 2.7 mg/L respectively; p < 0.0001). Being smoker did not influence CRPus levels. These levels were significantly correlated with FM (r = 0.30), BMI (r = 0.21), FEV1 (r = -0.21), number of acute exacerbations of the disease in the last year (r = 0.28), and PaO2 (r = -0.27). Using multivariate analysis FM, PaO2, and number of acute exacerbations of the disease in the last year had the strongest association with CRPus levels. Conclusions: CRPus is elevated in COPD patients, independent of smoking status. It is weakly associated with fat mass, arterial oxygen tension and frequency of exacerbations.

Etiología y biomarcadores de inflamación sistémica en las exacerbaciones leves a moderadas de la enfermedad pulmonar obstructiva crónica / Etiology and biomarkers of systemic inflammation in mild to moderate COPD exacerbations

Background: The etiology of acute exacerbations of chronic obstructive pulmonary disease (COPD) is heterogeneous and still under discussion. Inflammation increases during exacerbation of COPD. The identification of inflammatory changes will increase our knowledge and potentially guide therapy. Aim: To identify which inflammatory parameters increase during COPD exacerbations compared to stable disease, and to compare bacterial and viral exacerbations. Material and Methods: In 85 COPD patients (45 males, mean age 68 ± 8 years, FEV1 46 ± 17% of predicted) sputum, nasopharyngeal swabs and blood samples were collected to identify the causative organism, during a mild to moderate exacerbation. Serum ultrasensitive C reactive protein (CRP), fibrinogen and interleukin 6 (IL 6), neutrophil and leukocyte counts were measured in stable conditions, during a COPD exacerbation, 15 and 30 days post exacerbation. Results: A total of 120 mild to moderate COPD exacerbations were included. In 74 (61.7%), a microbial etiology could be identified, most commonly Mycoplasma pneumoniae (15.8%), Rhinovirus (15%), Haemophilus influenzae (14.2%), Chlamydia pneumoniae (11.7%), Streptococcus pneumoniae (5.8%) and Gram negative bacilli (5.8%). Serum CRP, fibrinogen and IL 6, and neutrophil and leukocyte counts significantly increased during exacerbation and recovered at 30 days post exacerbation. Compared to viral exacerbations, bacterial aggravations were associated with a systemic inflammation of higher magnitude. Conclusions: Biomarkers of systemic inflammation increase during mild to moderate COPD exacerbations. The increase in systemic inflammation seems to be limited to exacerbations caused by bacterial infections.

Comparison between continuous positive airway pressure and bilevel positive pressure ventilation in treatment of acute exacerbation of chronic obstructive pulmonary disease

In the management of COPD with respiratory failure two types of non invasive ventilation, continuous positive airway pressure and bilevel positive airway pressure [CPAP and BIPAP] were emerged with the aim of correcting gas exchange abnormalities and avoiding endotracheal intubation. To evaluate and compare the effectiveness of 2 types of noninvasive respiratory support systems, continuous positive airway pressure, and bilevel positive pressure ventilation in treatment of acute exacerbation of chronic obstructive pulmonary disease: This study included 60 patients with acute exacerbation of chronic obstructive pulmonary disease [COPD] [48 males and 12 females] with age ranged from [51 to 69 years] admitted in Chest Department and Respiratory Care Unit in Chest Department Sayed Galal University Hospital, Al Azhar University during the period between May 2011 and February 2012. These patients fulfilled the diagnostic criteria for COPD patients with acute respiratory failure with exclusion of patients presenting with any of exclusive criteria for non invasive ventilation. Patients were classified randomly into 3 groups. 1. Group 1 [CPAP group]: included 20 patients treated with standard therapy plus respiratory support with CPAP using the apparatus [VPAP III ST-A with QuickNav] and use a Res Med mask. 2. Group 2 [BIPAP group]: included 20 patients treated with standard therapy plus respiratory support with CPAP using the apparatus [VPAP III ST-A with QuickNav] and use a Res Med mask. 3. Group 3 [standard group]: Included 20 patients treated with controlled oxygen therapy, antibiotics, bronchodilators, corticosteroids, anticoagulant and other medications needed for the patient. All patients were subjected to history taking, clinical examination, routine laboratory investigations, chest X-ray, ECG and blood gasses analysis. This study revealed the following: Clinical assessment at time of admission revealed non significant difference between the three groups as regard respiratory rate, pulse, systolic and diastolic blood pressure [SBP and DBP] and consciousness level at time of admission with p value 0.767, 0.252, 0.350, 0.441and 0.817 respectively and there was no statistically significant difference between the three groups as regard Pa0[2], PaC0[2], 0[2] saturation and pH with -p-value 0.127, 0.077, 0.098 and 0.998 respectively. In group 2 [BIPAP group]: - There was improvement in the arterial Pa0[2] in comparison to group 1 and 3 after 1, 6, 12 h and on second day with significant improvement especially after 6, 12 h and in second day with p value 0.013 < 0.001 and 0.012 respectively. - There was significant improvement in the arterial PaCO[2] in comparison to group 1 and 3 after 1, 6, 12 h and on second day with p value 0.000, 0.000, 0.012 and 0.002 respectively. - There was improvement in 02 saturation in comparison to group 1 and 3 after 1, 6, 12 h and on second day with significant improvement especially after 12 h and on second day with p value 0.0492 and 0.041 respectively. - There was mild improvement in arterial pH in comparison to group 1 and 3 with significant improvement especially after 12 h with p value [0.001]. As regard duration of stay in ICU, there was less duration of stay in both groups 1 and 2 in comparison to group 3 with decrease, but non significant, in duration of stay in ICU in group 2 in comparison to group 1. Finally group 2 [BIPAP group] had significant statistical difference in avoiding endotracheal intubation ETI in comparison to group 1 and 3 withp value [0.033]. BIPAP has a superior efficacy in correcting gas exchange abnormalities and avoiding endotracheal intubation than CPAP

Hepcidin: a useful marker in chronic obstructive pulmonary disease

This study was designed to evaluate the levels of hepcidin in the serum of patients with chronic obstructive pulmonary disease [COPD]. In the study, 74 male patients [ages 45-75] in a stable period for COPD were grouped as Group I: Mild COPD [n:25], Group II: Moderate COPD [n:24], and Group III: Severe COPD [n:25]. Healthy non-smoker males were included in Group IV [n:35] as a control group. The differences of hepcidin level among all the groups were examined. Also, in the patient groups with COPD, hepcidin level was compared with age, body mass index, cigarette [package/year], blood parameters [iron, total iron binding capacity, ferritin, hemoglobin, hematocrit [hct]], respiratory function tests, and arterial blood gas results. Although there was no difference between the healthy control group and the mild COPD patient group [P=0.781] in terms of hepcidin level, there was a difference between the moderate [P=0.004] and the severe COPD patient groups [P=0.002]. The hepcidin level of the control group was found to be higher than the moderate and severe COPD patient groups. In the severe COPD patients, hepcidin level increased with the increase in serum iron [P=0.000], hct [P=0.009], ferritin levels [P=0.012], and arterial oxygen saturation [SaO[2], P=0.000]. The serum hepcidin level that is decreased in severe COPD brings into mind that it may play a role in the mechanism to prevent hypoxemia. The results suggest that serum hepcidin level may be a useful marker in COPD. Larger prospective studies are needed to confirm our findings between hepcidin and COPD

Apoptosis of T Lymphocytes Isolated from Peripheral Blood of Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease

PURPOSE: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways and progressive destruction of lung parenchyma. Apoptosis is critical for the maintenance of normal tissue homeostasis and is in equilibrium with proliferation and differentiation. This study was undertaken to investigate relationship between apoptosis of peripheral blood lymphocytes during exacerbation of COPD and inflammatory response that characterizes this condition. MATERIALS AND METHODS: Seventeen patients with COPD exacerbation, 21 stable COPD, and 12 control subjects were included. T lymphocytes were isolated from peripheral blood using MACS. Apoptosis of T lymphocytes was assessed with FACS using annexin V and 7-aminoactinomycin. Serum levels of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha were determined by an immunoassay technique. RESULTS: There was significantly increased percentage of apoptotic lymphocytes, CD 4+, and CD 8+ T cells in the peripheral blood of patients with exacerbation of COPD compared with stable COPD. Serum levels of IL-6, IL-8, and TNF-alpha were significantly increased in patients with exacerbation of COPD compared with stable COPD. Only TNF-alpha presented a positive correlation with apoptotic lymphocytes in patients with exacerbation of COPD. CONCLUSION: Increased apoptotic lymphocytes may be associated with upregulation of TNF-alpha in the peripheral blood of patients with acute exacerbation of COPD.

Marcadores de inflamación sistémica en pacientes ex fumadores con enfermedad pulmonar obstructiva crónica en etapa estable / Systemic inflammation among stable ex smokers with chronic obstructive pulmonary disease

Background: Low grade systemic inflammation is commonly observed in chronic obstructive pulmonary disease (COPD). Aim: To evaluate the extent of systemic inflammation in a group of ex-smokers with COPD in stable condition and its relation with pulmonary function and clinical manifestations. Patients and Methods: We studied 104 ex-smokers aged 69 ± 8 years (62 males) with mild to very severe COPD and 52 healthy non-smoker subjects aged 66 ± 11 years (13 males) as control group. High sensitivity serum C reactive protein (CRP), interleukin 6 (IL6), fibrinogen (F) and neutrophil count (Nc) were measured. Forced expiratory volume in the first minute (FEV1), inspiratory capacity (IC), arterial blood gases, six minutes walking test, dyspnea and body mass index (BMI) were measured, calculating the BODE index. Health status was assessed using the Saint George Respiratory Questionnaire (SGRQ), the chronic respiratory questionnaire (CRQ), registering the number of acute exacerbations (AE) during the previous year and inhaled steroids’s use. Systemic inflammation was considered present when levels of CRP or IL6 were above the percentile 95 of controls (7.98 mg/L and 3.42 pg/ml, respectively). Results: COPD patients had significantly higher CRP and IL6 levels than controls. Their F and Nc levels were within normal limits. Systemic inflammation was present in 56 patients, which had similar disease severity and frequency of inhaled steroid use, compared with patients without inflammation. Patients with systemic inflammation had more AE in the previous year; lower inspiratory capacity, greater dyspnea during the six minutes walk test and worse SGRQ and CRQ scores. Conclusions: Low-grade systemic inflammation was found in 56 of 104 ex-smokers with COPD. This group showed a greater degree of lung hyperinflation, dyspnea on exercise and poor quality of life.

Plasma C-Reactive Protein and Endothelin-1 Level in Patients with Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension

Pulmonary hypertension is a frequent complication of chronic obstructive pulmonary disease (COPD) and associated with a worse survival and increased risk of hospitalization for exacerbation of COPD. However, little information exists regarding the potential role of systemic inflammation in pulmonary hypertension of COPD. The purpose of the present study was to investigate the degree of C-reactive protein (CRP) and endothelin-1 (ET-1) levels in COPD patient with and without pulmonary hypertension. The levels of CRP and ET-1 were investigated in 58 COPD patient with pulmonary hypertension and 50 patients without pulmonary hypertension. Pulmonary hypertension was defined as a systolic pulmonary artery pressure (Ppa) > or =35 mmHg assessed by Doppler echocardiography. Plasma CRP and ET-1 levels were significantly higher in patients with pulmonary hypertension than in patients without hypertension. There were significant positive correlations between the plasma ET-1 level and CRP level in the whole study groups. For COPD patients, systolic Ppa correlated significantly with plasma CRP levels and plasma ET-1 levels. These findings support a possibility that CRP and ET-1 correlate to pulmonary hypertension in COPD patients.

MAPA em portadores de DPOC com dessaturação no sono / MAPA en portadores de EPOC con desaturación durante el sueño / ABPM in COPD patients with sleep desaturation

FUNDAMENTO: A hipoxemia no período de sono pode, por mecanismo de ativação simpática, alterar a pressão arterial. Poucos estudos demonstram os parâmetros pressóricos em portadores de DPOC, que não têm apnéia do sono, mas que dessaturam nesse período. OBJETIVOS: Analisar os parâmetros pressóricos em pacientes com DPOC e dessaturação no sono, não causada por apnéia. MÉTODOS: Treze pacientes com DPOC foram submetidos à espirometria, gasometria arterial, polissonografia e MAPA para avaliação pressórica. Quatorze pacientes sem DPOC foram submetidos à espirometria, oximetria e MAPA. As análises pressóricas foram feitas tanto na vigília quanto no sono. Os dois grupos foram constituídos por pacientes sem antecedentes hipertensivos. RESULTADOS: Os dois grupos eram semelhantes em relação à idade, altura, peso e índice de massa corporal. Houve diferença significativa (p < 0,05) entre os parâmetros pressóricos nos períodos de vigília, sono, 24 horas e descenso do sono. Observou-se valores pressóricos maiores nos portadores de DPOC, exceto em níveis diastólicos em vigília, máximos valores ao sono e nas 24 horas. O descenso do sono no grupo DPOC foi atenuado, enquanto no grupo controle foi fisiológico, com menores valores pressóricos. CONCLUSÕES: Os resultados da pressão arterial sistólica e diastólica se mostraram maiores no grupo DPOC do que no grupo controle. A significância dessa afirmação ocorreu em todos os períodos aferidos, exceto em vigília e nas 24 horas para níveis de pressão diastólica. Pode-se concluir que, o grupo portador de DPOC com dessaturação no sono possui níveis de pressão arterial significativamente maiores do que o grupo controle.

BACKGROUND: Sleep hypoxemia may change blood pressure by sympathetic activation. Few studies have analyzed blood pressure parameters in COPD patients who do not present sleep apnea, but do present sleep desaturation. OBJECTIVES: To analyze blood pressure parameters in COPD patients with sleep desaturation not caused by apnea. METHODS: Thirteen patients with COPD underwent spirometry, blood gas, polysomnography and ABPM for blood pressure evaluation. Fourteen patients without COPD underwent spirometry, oximetry and ABPM. Blood pressure analyses were carried out both during wakefulness and sleep. Both groups were comprised of patients with no history of hypertension. RESULTS: The two groups were similar as regards age, height, weight, and body mass index. A significant difference (p<0.05) was found between blood pressure levels during the wakefulness, sleep, 24-hour and sleep dip periods. Higher blood pressure levels were observed in patients with COPD, except for diastolic levels during wakefulness and maximum values during sleep and in the 24 hours. Sleep dip in the COPD group was attenuated, whereas physiological dip was observed in the control group, with lower blood pressure levels. CONCLUSIONS: Systolic and diastolic blood pressure levels in the COPD group were higher than those of the control group, with a significant difference found for all periods studied, except for diastolic levels during wakefulness and in the 24 hours. We can conclude that the group of COPD patients with sleep desaturation has significantly higher blood pressure levels than the control group.

FUNDAMENTO: La hipoxemia en el período de sueño puede, por mecanismo de activación simpática, alterar la presión arterial. Pocos estudios demuestran los parámetros de presión en portadores de EPOC, que no tiene apnea del sueño, y que desaturan en ese período. OBJETIVO: Analizar los parámetros de presión en pacientes con EPOC y desaturación en el sueño, no causada por apnea. MÉTODOS: Trece pacientes con EPOC se sometieron a la espirometría, la gasometría arterial, la polisonografía y al MAPA para la evaluación de presión. Un total de 14 pacientes sin EPOC se sometieron a la espirometría, la oximetría y MAPA. Los análisis de presión se hicieron tanto en la vigilia como en el sueño. Los dos grupos estaban conformados por pacientes sin antecedentes hipertensivos. RESULTADOS: Los dos grupos se asemejaban respecto a la edad, la altura, el peso e el índice de masa corporal. Hubo diferencia significativa (p < 0,05) entre los parámetros de presión en los períodos de vigilia, sueño, 24 horas y descenso del sueño. Se observaron valores de presión arterial mayores en los portadores de EPOC, a excepción de los niveles diastólicos en vigilia, máximos valores al sueño y en las 24 horas. El descenso del sueño en el grupo EPOC se halló atenuado, mientras que en el grupo control fue fisiológico, con menores valores de presión arterial. CONCLUSIÓN: Los resultados de la presión arterial sistólica y diastólica se hallaron mayores en el grupo EPOC que en el grupo control. La significancia de esa afirmación ocurrió en todos los períodos medidos, a excepción de la vigilia y en las 24 horas para niveles de presión diastólica. Se puede concluir que, el grupo portador de EPOC con desaturación en el sueño posee niveles de presión arterial significativamente mayores que en el grupo control.