Nós investigamos o perfil inflamatório do lavado broncoalveolar (LBA) em crianças portadoras de asma de difícil controle apesar do tratamento com corticóide oral e sua relação com parâmetros clínicos e funcionais. O LBA foi realizado em 24 crianças com asma de difícil controle (13M/11F; idade média de 13 anos) e 5 controles. Houve aumento do número de neutrófilos em 15 das 24 crianças (60%) portadoras de asma de difícil controle (mediana 15%, 5-43%) e aumento de eosinófilos em 5 pacientes (mediana 9%, 6.5%-18.5%). Observou-se uma correlação entre a necessidade de corticóide oral e o número de internações e o percentual de eosinófilos no LBA. Ocorreu uma tendência de maiores números de neutrófilos no lavado e uma pior função pulmonar. Nós identificamos dois subgrupos de crianças portadoras de asma de difícil controle com características clínicas e funcionais distintas. Pacientes com aumento do percentual de neutrófilos tendem a apresentar uma pior função pulmonar. Um pequeno número de pacientes apresentou um padrão eosinofílico no lavado broncoalveolar com função pulmonar normal, porém sinais de instabilidade clínica. / Therapy resistant asthma is a major clinical problem in childhood. We investigated the inflammatory cell profile in the airways of children with severe asthma despite systemic steroid treatment and the relationship with clinical and functional severity. Bronchoalveolar lavage (BAL) was performed in 24 children with severe asthma (13M/11F; mean age 12.5 yrs, range 5-l4 yrs), and 5 controls. All received prednisolone prior to BAL. Neutrophils were the predominant inflammatory cell type in BAL in 15/24 (60%) children with asthma (median 15%, 5-43%).and only 5 patients had increases in eosinophils (median 9%, 6.5%-18,5%). There was a correlation between higher BAL eosinophils and more admissions Patients with higher BAL neutrophils showed a trend for lower pre-BAL lung function. We identified subgroups of children with severe asthma presenting different clinical and functional characteristics. Patients with increased percentages in BAL neutrophils showed a trend for lower lung function. A small number of patients presented eosinophilic airway inflammation in BAL with virtually normal lung function but showing signs of clinical instability.

Estudos para a avaliação da resistência das vias aéreas de pré-escolares com fibrose cística através da técnica do interruptor (Rint) são escassos. Foi realizado um estudo tranversal, com 38 pacientes acompanhados no ambulatório de Fibrose Cística do Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul. Foram realizadas medida da Rint, seguida da avaliação espirométrica em todos os pacientes, repetindo os testes após o uso de salbutamol para a aferição da resposta ao broncodilatador. Nos resultados, foram encontradas forte correlação entre o inverso da Rint e o volume expiratório forçado no 1º segundo (VEF1), (r=0,8 p<0,001) e moderadas correlações entre o inverso da Rint e o fluxo expiratório forçado entre 25% e 75% da capacidade vital (FEF 25-75), (r=0,74 p<0,001) e entre o inverso da Rint e o índice de massa corporal (IMC), (r=0,62 p<0,001). A acurácia da avaliação da resposta ao broncodilatador pela Rint, foi testada através da curva ROC (Receiver Operator Characteristic Curve),comparando-se com resposta ao broncodilatador na espirometria. Foi obtida uma área de 0,75 para o ponto de corte de -28%, correspondendo a uma sensibilidade de 66% e uma especificidade de 82%. Os achados indicam que a Rint apresenta boa correlação com a espirometria, no entanto a técnica não possui uma acurácia suficiente para substituir a Espirometria na avaliação da resposta ao broncodilatador. / Few studies have been published on airway resistance measurements using the interrupter technique (IT). We performed a cross-sectional study, evaluating 38 children and adolescents with Cystic Fibrosis (CF), followed at the outpatient CF clinic of Hospital São Lucas from Pontifícia Universidade Católica do Rio Grande do Sul. Airway resistance (Rint) was measured by the IT, followed by spirometry in all patients. Measurements were repeated after inhalation of salbutamol in order to evaluate bronchodilator response. There was a strong corelation between inverse Rint and forced expiratory volume in one second (FEV1) (r=0.8, p<0.001) and fair correlations between the inverse Rint and mid expiratory flow (MEF) (r=0.74 p<0.001) and between inverse Rint and body mass index (BMI) (r=0.62 p<0.001). The accuracy of bronchodilator response by the IT was tested through the ROC (reciever operating curve), comparing results with spirometry bronchodilator response. An area of 0.75 under the curve was obtained, for the cutoff point of -28% of Rint, achieving a sensitivity of 66% and a specificity of 82%. The findings suggest that Rint shows good correlation with spirometry parameters, although the IT is not sufficiently acurate to replace spirometry in the evaluation of bronchodilator response.

Nós investigamos o perfil inflamatório do lavado broncoalveolar (LBA) em crianças portadoras de asma de difícil controle apesar do tratamento com corticóide oral e sua relação com parâmetros clínicos e funcionais. O LBA foi realizado em 24 crianças com asma de difícil controle (13M/11F; idade média de 13 anos) e 5 controles. Houve aumento do número de neutrófilos em 15 das 24 crianças (60%) portadoras de asma de difícil controle (mediana 15%, 5-43%) e aumento de eosinófilos em 5 pacientes (mediana 9%, 6.5%-18.5%). Observou-se uma correlação entre a necessidade de corticóide oral e o número de internações e o percentual de eosinófilos no LBA. Ocorreu uma tendência de maiores números de neutrófilos no lavado e uma pior função pulmonar. Nós identificamos dois subgrupos de crianças portadoras de asma de difícil controle com características clínicas e funcionais distintas. Pacientes com aumento do percentual de neutrófilos tendem a apresentar uma pior função pulmonar. Um pequeno número de pacientes apresentou um padrão eosinofílico no lavado broncoalveolar com função pulmonar normal, porém sinais de instabilidade clínica. / Therapy resistant asthma is a major clinical problem in childhood. We investigated the inflammatory cell profile in the airways of children with severe asthma despite systemic steroid treatment and the relationship with clinical and functional severity. Bronchoalveolar lavage (BAL) was performed in 24 children with severe asthma (13M/11F; mean age 12.5 yrs, range 5-l4 yrs), and 5 controls. All received prednisolone prior to BAL. Neutrophils were the predominant inflammatory cell type in BAL in 15/24 (60%) children with asthma (median 15%, 5-43%).and only 5 patients had increases in eosinophils (median 9%, 6.5%-18,5%). There was a correlation between higher BAL eosinophils and more admissions Patients with higher BAL neutrophils showed a trend for lower pre-BAL lung function. We identified subgroups of children with severe asthma presenting different clinical and functional characteristics. Patients with increased percentages in BAL neutrophils showed a trend for lower lung function. A small number of patients presented eosinophilic airway inflammation in BAL with virtually normal lung function but showing signs of clinical instability.

Introdução: A capacidade de exercício tem sido pouco estudadaem pacientes combronquiolite obliterante pós-infecciosa (BOPI). Além disso, há poucos estudos avaliando indivíduos após a infância. Objetivos: Avaliar a capacidade aeróbia máxima em pacientes adolescentes e adultos com diagnóstico prévio de BOPI e identificar os mecanismos de limitação ao exercício. Métodos: Estudo transversal com recuperação retrospectiva de testes espirométricos de 4-6 anos antes dos atuais. Foram estudados 16 pacientes com BOPI (10-23 anos), acompanhados em um ambulatório de atendimento terciário. Todos os indivíduos realizaram teste de função pulmonar em repouso e teste de exercício cardiopulmonar com pesquisa de broncoespasmo induzido pelo exercício (BIE). Um grupo composto de 10 indivíduos saudáveis, pareado por sexo, idade e altura, foi usado como controle. Resultados: Quando comparados ao grupo controle, os pacientes com BOPI apresentaram pior função pulmonar em repouso, com moderada a grave obstrução ao fluxo de ar e aprisionamento aéreo. Capacidade aeróbica de pico foi significativamente menor nos pacientes ( O2 pico: 87±22 vs 110±21% previsto; p=0,01), com uma maior proporção de pacientes com capacidade aeróbica abaixo do normal [ O2 pico<84% previsto: 7/16(44%) vs 1/10(10%); p= 0,09]. A capacidade aeróbica máxima (expressa tanto em valores absolutos como em % previsto) dos pacientes foi significativamente associada com idade (r=0,59, p=0,02), índice de massa corpórea (IMC) (r=0,55, p=0,03), capacidade difusiva pulmonar (DLCO% previsto) (r=0,66, p=0,01), capacidade inspiratória (CI) / capacidade pulmonar total (CPT) (r=0,52, p=0,04) e volume residual (RV) / CPT (r=-0,56, p=0,03). Nenhuma associação foi encontrada, no entanto, entre a O2 de pico e os valores finais de exercícios e variação da oximetria de pulso (SpO2), relação ventilação de pico/ventilação voluntária máxima( E/VVM) e outros valores da função pulmonar em repouso quando expresso em % do previsto. Por outro lado, o volume expiratório forçado no 1ºs (VEF1) foi moderadamente correlacionado com DLCO (r=0,59, p=0,03) e fortemente com CI/CPT (r=0,90, p=0,00) e VR/CPT (r=-0,89, p=0,00). Valores espirométricos atuais não foram diferentes dos de 4-6 anos atrás, quando expresso em % do previsto [VEF1: 60±30 vs 60±22; capacidade vital forçada (CVF): 73±22 vs 69±14], embora, quando expresso em litros, valores atuais foram maiores (VEF1: 1,94±0,93 vs 1,14±0,50; CVF: 2,79±0,89 vs 1,52±0,45, p<0,01). Conclusão: Pacientes adolescentes e adultos com BOPI apresentaram uma capacidade aeróbia de pico reduzida em comparação comcontroles saudáveis, sendo que aproximadamente metade dos pacientes tiveram redução da capacidade aeróbica quando expresso em porcentagem do previsto. A capacidade aeróbica de pico foi diretamente relacionada com a idade, a capacidade de difusão pulmonar e os parâmetros de hiperinflação pulmonar e aprisionamento aéreo. Quanto maior a limitação do fluxo de ar (menor VEF1) maior foi a hiperinsuflação e aprisionamento aéreo. / Introduction: Repercussion in exercise capacity has been poorly studied in patients with post-infectious bronchiolitis obliterans (PBO). Additionally, studies have mainly evaluated children and a follow-up in older subjects is lacking. Aims: Evaluate with maximal incremental cardiopulmonary exercise tests older adolescents and adults with previous diagnosis of PBO and indentify the mechanisms of exercise limitation. Methods: The study has a cross-sectional design with retrospective retrieval of the available spirometric data of 4-6 years ago. We studied 16 patients with POB (10 to 23 yrs old), followed up inan outpatient tertiary care clinic. All subjects underwent resting lung function testingand exercise testing. A control group, composedbysex, age and height, was usedcontaining 10subjects. Results: When compared PBO patients with control group, patients presented worse resting lung function, with moderate-to-severe air flow obstruction and air trapping. Peak exercise capacity was significantly lower in patients (peak O2: 87±22 vs 110±21% pred; P=0.01) with a greater proportion than in patients presenting reduced aerobic capacity [peak O2<84% pred: 7/16(44%) vs 1/10(10%); p= 0.09]. In correlations analyses, peak aerobic capacity (expressed both as absolute values and %pred) was significantly correlated with age in patients (r= 0.59, p= 0.02), body mass index (BMI) (r= 0.55, p= 0.03), lung diffusion capacity (DLCO% pred) (r= 0.66, p= 0.01), rest inspiratory capacity(IC)/total lung capacity(TLC) (r= 0.52, p=0.04) and residual volume (RV)/TLC (r= -0.56, p= 0.03). No association was found, however, between peak O2 and final exercise values and change from rest of SpO2 (p=0.79 and 0.76, respectively) peak ventilation/maximal ventilatory ventilation ratio ( E/MVV) (p=0.82) and other resting lung function values [forced expiratory volume in 1s (FEV1), forced vital capacity (FVC), FEV1/FVC, IC, TLC and RV) when expressed as %pred. On the other hand, FEV1 were moderately correlated with DLCO (r= 0.59, p= 0.03), and strongly with IC/TLC (r= 0.90, p= 0.00) and RV/TLC (r= -0.89, p= 0.00). Current spirometric values were not different from those of 4-6 years ago when expressed as % of pred (FEV1: 60±30 vs 60±22; FVC: 73±22 vs 69±14), although when expressed in liters, current values are greater (FEV1: 1.94±0.93 vs 1.14±0.50; FVC: 2.79±0.89 vs 1.52±0.45; p= 0.00 and 0.00, respectively). Conclusion: We have shown in a sample of adolescent and adult patients with PBO that peak aerobic capacity is reduced compared to healthy controls and almost half of the patients had reduced aerobic capacity when expressed as percent of predict. Peak aerobic capacity was directly correlated with age, lung diffusion capacity and parameters of rest hyperinflation and air trapping. The greater the air flow limitation (lower FEV1), the greater the hyperinflation and air trapping were.

Introdução: A característica clínica principal da DPOC é a intolerância ao exercício físico. O mecanismo dessa limitação é complexo e multifatorial. Os principais mecanismos considerados responsáveis são a hiperinsuflação pulmonar dinâmica (HD) e disfunção muscular periférica. A hipótese principal do presente estudo é que a diminuição da massa livre de gordura (MLG) nesses pacientes, além de diretamente contribuir para redução da capacidade aeróbia, poderia contribuir indiretamente causando acentuação da HD durante o exercício. Objetivo: Investigar se a quantidade de MLG tem efeitos diretos na hiperinsuflação pulmonar dinâmica, durante o exercício em pacientes com DPOC. Métodos: 38 pacientes em estádio moderado a grave realizaram teste de exercício cardiopulmonar incremental até o limite da tolerância com medidas seriadas de capacidade inspiratória (CI). A MLG foi medida pelo teste de bioimpedância elétrica de corpo inteiro. Foram coletados também dados de função pulmonar (espirometria). Resultados: A média de idade dos pacientes foi de 66,5 ± 7,3 anos de idade, com média de VEF1 de 0,98 ± 0.05L (42 ± 15% do previsto). Valores de CI no pico do exercício (uma variável inversamente relacionada com os volumes pulmonares operacionais, ou seja, quanto maior a CI menor é hiperinflação pulmonar) foram significativamente (p <0,05) correlacionados com a CI de repouso (r = 0,78), VEF1 (r = 0,66), CVF (r = 0,56), MLG (r = 0,46) e com o índice de massa livre de gordura (IMLG) (r = 0,39). No entanto, na análise multivariada apenas o VEF1 e a CI em repouso permaneceram preditivos da CI de pico de exercício. A CI de pico foi um preditor significativo da capacidade aeróbia máxima. Conclusão: A MLG apresentou relação direta com as medidas de hiperinsuflação dinâmica durante o exercício. Contudo, a associação não se manteve quando foram feitos ajustes para indicadores de limitação do fluxo aéreo expiratório (VEF1) e hiperinflação pulmonar em repouso (CI de repouso). / Purposes: Investigate if the amount of fat free mass (FFM) has direct effects in dynamic hyperinflation during exercise in COPD patients. Methods: 38 patients with moderate to severe COPD performed treadmill incremental cardiopulmonary exercise test to the limit of tolerance with serial measurements of inspiratory capacity (IC). FFM was measured by whole-body bioelectrical impedance. Results: Patients were 66.5±7.3 years-old with mean FEV1 of 0.98±0.05L (42±15% of predicted). Peak exercise values of IC (a variable inversely related with operational lung volumes, i.e. the greater IC lower is pulmonary hyperinflation) was significantly (p<0.05) correlated with IC at rest (r=0.78), FEV1 (r=0.66), FVC (r=0.56), FFM (r=0.46) and FFM index (r=0.39). However, in multivariable analyzes only FEV1 and IC at rest remained predictive of peak IC. Peak IC was a significant predictor of peak aerobic capacity. Conclusion: FFM was directly related with measurements of dynamic hyperinflation. Nonetheless, this association disappeared when adjustments were made for indicators of expiratory airflow limitation (FEV1) and lung hyperinflation at rest (rest IC).

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome in Europe. After inhalation of virus shed by bank voles, the virus systemically targets the vascular endothelium leading to vascular dysfunction and leakage. Many patients with PUUV infection experience cardiopulmonary manifestations but the underlying mechanisms have not been determined. The aims of the studies presented were to describe cardiopulmonary manifestations, investigate pathogenetic mechanisms including presence of virus in the lungs and the local immune response in PUUV infection. The results showed cardiopulmonary involvement of varying severity in almost all studied patients. High-resolution computed tomography frequently revealed vascular leakage into the lungs or pleural cavities. Pulmonary function tests generally showed reduced gas diffusing capacity, evidenced in patients as dyspnea, poor oxygenation and frequent need of oxygen treatment. Among patients who were not fully recovered at 3 months follow-up, remaining decreased gas diffusing capacity was highly common. Echocardiography revealed mainly right heart dysfunction which was related to manifestations within the lungs, in terms of increased estimated pulmonary vascular resistance, mild to moderate pulmonary hypertension, and reduced right ventricular systolic function in patients with more pronounced lung involvement, as indicated by need of oxygen treatment. Analyses on bronchoalveolar lavage (BAL) and bronchial biopsies revealed a highly activated cytotoxic T cell (CTL) response in the lungs. The CTL response was not balanced by the expansion of regulatory T cells and high numbers of CTLs were associated with more severe disease. PUUV RNA was detected in almost all patients’ BAL samples and the viral load was inversely correlated to the number of CTLs. Three patients presenting with severe and fatal cardiopulmonary distress were also described. Autopsies revealed PUUV protein in vascular endothelium in all investigated organs, including the heart and lungs, along with a massive CTL response mainly in the lungs. In conclusion, cardiopulmonary involvement of varying severity was present in almost all patients with PUUV infection. Cytotoxic immune responses could contribute to disease development but also help in clearing the infection. Long lasting fatigue after hantavirus infection may be explained by remaining manifestations within the lungs.

[Truncated abstract] Respiratory system impedance (Zrs) is commonly measured at low to medium frequencies (0.5 - 40 Hz) to infer structural and physiological information about the respiratory system. Coupled with the use of mathematical models of the lungs, Zrs has been used to partition the behaviour of the conductive airways and the respiratory tissues. High-frequency (HF) Zrs beyond 100 Hz has been comparatively less studied and understood. Past work has revealed spectral features at high frequencies termed antiresonances, marked by peaks in the real part of Zrs, often coinciding with zero-crossings in the imaginary part. It has been shown that the first occurrence of antiresonance in humans primarily reflects the contribution of the airways, and is a property of sound wave propagation in the airways. Also, the first antiresonance is altered in diseases such as chronic airflow obstruction, and wheeze in infants. The main aim of this project is to shed further understanding about the first antiresonance, via the behaviour of two parameters characterising this feature of the HF spectrum: the frequency at which the first antiresonance occurs, far,1, and the magnitude of the real part of Zrs at this frequency, Rrs(far,1). In our studies, Zrs is measured as an input impedance using the forced oscillation technique with a loudspeaker-in-box and wavetube setup, and employing pseudorandom frequency signals. We studied the effects of altered lung conditions, first in an animal model, then progressed on to humans. v vi In the rat, we found that both far,1 and Rrs(far,1) tended to decrease together with increasing lung volume. With methacholine(MCh)-induced bronchoconstriction, rats showed increases in far,1 and Rrs(far,1) with increasing MCh dose, but these occurred at higher doses compared to increases in airway resistance. The changes in these HF parameters were independent of the changes in tissue properties. ... It was found that in a group of patients with emphysema, VDRrs(far,1) was significantly more negative, potentially due to alterations to airway dimensions and wall properties. Furthermore, VDRrs(far,1) was correlated with extent of obstruction and hyperinflation, suggesting a relationship with severity of emphysema. These results show that the first antiresonance reflect changes in the airways, and its measurement shows promise as a clinical tool, in its potential as an easy-to-perform assessor of conditions in which the airways are altered. Keywords: antiresonance, respiratory input impedance, high frequencies, emphysema

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Estudos para a avaliação da resistência das vias aéreas de pré-escolares com fibrose cística através da técnica do interruptor (Rint) são escassos. Foi realizado um estudo tranversal, com 38 pacientes acompanhados no ambulatório de Fibrose Cística do Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul. Foram realizadas medida da Rint, seguida da avaliação espirométrica em todos os pacientes, repetindo os testes após o uso de salbutamol para a aferição da resposta ao broncodilatador. Nos resultados, foram encontradas forte correlação entre o inverso da Rint e o volume expiratório forçado no 1º segundo (VEF1), (r=0,8 p<0,001) e moderadas correlações entre o inverso da Rint e o fluxo expiratório forçado entre 25% e 75% da capacidade vital (FEF 25-75), (r=0,74 p<0,001) e entre o inverso da Rint e o índice de massa corporal (IMC), (r=0,62 p<0,001). A acurácia da avaliação da resposta ao broncodilatador pela Rint, foi testada através da curva ROC (Receiver Operator Characteristic Curve),comparando-se com resposta ao broncodilatador na espirometria. Foi obtida uma área de 0,75 para o ponto de corte de -28%, correspondendo a uma sensibilidade de 66% e uma especificidade de 82%. Os achados indicam que a Rint apresenta boa correlação com a espirometria, no entanto a técnica não possui uma acurácia suficiente para substituir a Espirometria na avaliação da resposta ao broncodilatador. / Few studies have been published on airway resistance measurements using the interrupter technique (IT). We performed a cross-sectional study, evaluating 38 children and adolescents with Cystic Fibrosis (CF), followed at the outpatient CF clinic of Hospital São Lucas from Pontifícia Universidade Católica do Rio Grande do Sul. Airway resistance (Rint) was measured by the IT, followed by spirometry in all patients. Measurements were repeated after inhalation of salbutamol in order to evaluate bronchodilator response. There was a strong corelation between inverse Rint and forced expiratory volume in one second (FEV1) (r=0.8, p<0.001) and fair correlations between the inverse Rint and mid expiratory flow (MEF) (r=0.74 p<0.001) and between inverse Rint and body mass index (BMI) (r=0.62 p<0.001). The accuracy of bronchodilator response by the IT was tested through the ROC (reciever operating curve), comparing results with spirometry bronchodilator response. An area of 0.75 under the curve was obtained, for the cutoff point of -28% of Rint, achieving a sensitivity of 66% and a specificity of 82%. The findings suggest that Rint shows good correlation with spirometry parameters, although the IT is not sufficiently acurate to replace spirometry in the evaluation of bronchodilator response.