Research progress on the role and mechanism of 5-hydroxytryptamine and M2 macrophages in pulmonary interstitial fibrosis / 中华危重病急救医学

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease, the cause is not yet clear. Pathological manifestations are abnormal repair changes resulting from sustained lung injury. Macrophages have been identified as playing a key role in IPF pathogenesis. In different local microenvironments, macrophages can exhibit either classically activated (M1) or alternately activated (M2) phenotypes. M1 plays a key role in promoting inflammatory response and is involved in the process of causing alveolar tissue injury. M2 is involved in wound healing and stopping lung inflammation. Previous studies have shown that activation of 5-hydroxytryptamine (5-HT) signaling is enhanced in pulmonary fibrosis and that 5-HT receptors play an important role in the observed pro-fibrotic effects. As a multifunctional signaling molecule, 5-HT is closely related to lung macrophage polarization, early lung tissue injury, abnormal proliferation and repair, and late extracellular matrix (ECM) deposition. This article reviewed the role of 5-HT and M2 macrophages in the pathogenesis of IPF and the possible regulatory mechanism of 5-HT, in order to provide a reference for further research.

A case of interstitial lung and liver disease caused by MARS1 gene mutation / 中国当代儿科杂志

The patient is a female infant, 4 months and 9 days old, who was admitted to the hospital due to recurrent fever, cough, and hepatomegaly for over a month. The patient was a healthy full-term infant with a normal birth history. At 2 months and 22 days after birth, she developed recurrent fever, cough, and respiratory distress. Chest imaging revealed diffuse bilateral lung lesions, and fiberoptic bronchoscopy showed interstitial changes in both lungs. These suggested the presence of interstitial lung disease. The patient also presented with hepatomegaly, anemia, hyperlipidemia, hypothyroidism, and malnutrition. Genetic testing indicated compound heterozygous variations in the MARS1 gene. This mutation can cause interstitial lung and liver disease, which is a severe rare disorder that typically manifests in infancy or early childhood. It is inherited in an autosomal recessive manner and characterized by early-onset respiratory insufficiency and liver disease in infants or young children. Since its first reported case in 2013, as of June 2023, only 38 related cases have been reported worldwide. This article reports the multidisciplinary diagnosis and treatment of interstitial lung and liver disease in an infant caused by MARS1 gene mutation.

Biopsia pulmonar en la enfermedad pulmonar difusa por minitoracotomía o cirugía torácica videoasistida / Lung Biopsy in Diffuse Lung Disease by Minithoracotomy or Video-Assisted Thoracic Surgery

RESUMEN Introducción: La enfermedad pulmonar intersticial difusa constituye un grupo heterogéneo de lesiones con varias características comunes entre las cuales resaltan la inflamación y cicatrización del órgano. Por lo general, se requiere la obtención de tejido parenquimatoso para el diagnóstico definitivo. Objetivos: Describir los resultados obtenidos, según el método de minitoracotomía o cirugía torácica videoasistida, para obtener las muestras hísticas para estudio histopatológico. Métodos: Se realizó un estudio observacional, longitudinal y prospectivo de 52 pacientes consecutivos, con diagnóstico de enfermedad pulmonar intersticial difusa, a quienes se les practicó la toma de muestras tisulares obtenidas mediante cirugía torácica videoasistida o minitoracotomía en el Hospital Clínico Quirúrgico "Hermanos Ameijeiras" entre el 2001 y el 2018. Se estudió la edad y el sexo de los pacientes, la técnica quirúrgica empleada y las complicaciones y mortalidad. Los resultados se exponen en tablas, en números absolutos y relativos. Resultados: Predominó el sexo femenino (59,6 por ciento). La técnica quirúrgica más utilizada fue la minitoracotomía (75,0 por ciento) en pacientes entre 41-50 años, con 15 enfermos. La afección más frecuente fue la fibrosis pulmonar con un 78,8 por ciento. En dos enfermos intervenidos mediante cirugía torácica videoasistida no fue posible obtener tejido para biopsia (15,4 por ciento). Hubo dos complicaciones en pacientes operados mediante minitoracotomía. Conclusiones: La cirugía torácica videoasistida permite una amplia exploración de la superficie pulmonar, pero la biopsia abierta puede tener la misma efectividad para la obtención de muestras hísticas pulmonares, con un mínimo por ciento de complicaciones y bajo índice de mortalidad(AU)

ABSTRACT Introduction: Diffuse interstitial lung disease makes up a heterogeneous group of lesions with several common characteristics, among which inflammation and scarring of the organ stand out. Generally, obtaining parenchymal tissue is required for definitive diagnosis. Objectives: To describe the outcomes of using the method of minithoracotomy or video-assisted thoracic surgery to obtain tissue samples for histopathological study. Methods: An observational, longitudinal and prospective study was carried out with 52 consecutive patients with a diagnosis of diffuse interstitial lung disease. Tissue samples obtained by video-assisted thoracic surgery or mini-thoracotomy were taken at Hermanos Ameijeiras Clinical-Surgical Hospital, between 2001 and 2018. The age and sex of the patients, the surgical technique used, and complications and mortality were studied. The results are presented in tables, in absolute and relative numbers. Results: The female sex predominated (59.6 percent). The most widely used surgical technique was minithoracotomy (75.0 percent) in patients between 41-50 years (15 patients). The most frequent condition was pulmonary fibrosis, accounting for 78.8 percent. In two patients who underwent video-assisted thoracic surgery, it was not possible to obtain any tissue for biopsy (15.4 percent). There were two complications in patients operated on by minithoracotomy. Conclusions: Video-assisted thoracic surgery allows wide exploration of the lung surface, but open biopsy can be just as effective in obtaining lung tissue samples, with a minimum percentage of complications and a low mortality rate(AU)

Familial pulmonary fibrosis: a heterogeneous spectrum of presentations / Fibrose pulmonar familiar: um espectro heterogêneo de apresentações

ABSTRACT Objective: To describe the clinical, functional, and radiological features of index cases of familial pulmonary fibrosis (FPF) in Brazil. Methods: We evaluated 35 patients with FPF - of whom 18 (51.4%) were women - with a median age of 66.0 years (range, 35.5-89.3 years). All of the patients completed a standardized questionnaire, as well as undergoing pulmonary function tests and HRCT of the chest. In 6 cases, lung tissue samples were obtained: from surgical biopsies in 5 cases; and from an autopsy in 1 case. Results: A history of smoking and a history of exposure to birds or mold were reported in 45.7% and 80.0% of the cases, respectively. Cough and marked dyspnea were reported by 62.8% and 48.6% of the patients, respectively. Fine crackles were detected in 91.4% of the patients. In 4 patients, the findings were suspicious for telomere disease. The median FVC and DLCO, as percentages of the predicted values, were 64.9% (range, 48.8-105.7%) and 38.9% (range, 16.0-60.0%), respectively. Nine patients had reduced DLCO despite having normal spirometry results. Regarding HRCT, patterns typical of usual interstitial pneumonia were found in 6 patients (17.1%). In 25 cases (71.5%), the HRCT features were consistent with a diagnosis other than idiopathic pulmonary fibrosis. In 11 cases (31.4%), the radiological patterns were uncharacteristic of interstitial lung disease. Of the six lung tissue samples analyzed, four showed interstitial pneumonia with bronchiolocentric accentuation, and, on the basis of the clinical and radiological data, the corresponding patients were diagnosed with hypersensitivity pneumonitis. Conclusions: Patients with FPF can present with a wide variety of clinical features. Most HRCT scans of these patients exhibit patterns not typical of usual interstitial pneumonia. The family history of fibrotic lung diseases should be investigated in all patients under suspicion, regardless of their age.

RESUMO Objetivo: Descrever as características clínicas, funcionais e radiológicas de um grupo de casos índice diagnosticados com fibrose pulmonar familiar (FPF) no Brasil. Métodos: Trinta e cinco pacientes com FPF (18 mulheres; 51,4%), com mediana de idade de 66,0 anos (variação: 35,5-89,3 anos), responderam a um questionário padronizado e foram submetidos a testes de função pulmonar e TCAR de tórax. Tecido pulmonar foi obtido para revisão em 6 casos: a partir de biópsias cirúrgicas em 5 e de autópsia em 1. Resultados: Antecedentes de tabagismo e de exposição a aves ou mofo foram referidos por 45,7% e 80,0% dos casos, respectivamente. Tosse e dispneia significante foram referidas por 62,8% e 48,6% dos pacientes, respectivamente. Estertores finos foram detectados em 91,4% dos indivíduos. Em 4 pacientes, os achados levantaram suspeitas de doença dos telômeros. As medianas da CVF e da DLCO foram, respectivamente, de 64,9% (variação: 48,8-105,7%) e 38,9% (variação: 16,0-60,0%) em porcentagem dos valores previstos. Apesar de espirometria normal, 9 pacientes exibiram DLCO reduzida. Em relação às TCAR, padrões típicos de pneumonia intersticial usual foram encontrados em 6 pacientes (17,1%). Em 25 casos (71,5%) os achados tomográficos foram mais consistentes com um diagnóstico de não relacionado a fibrose pulmonar idiopática. Em 11 pacientes (31,4%) o padrão radiológico foi incaracterístico para doença pulmonar intersticial. Das seis amostras de tecido pulmonar analisadas, quatro mostraram pneumonias intersticiais com acentuação bronquiolocêntrica e, em função de outros dados clínicos e radiológicos, pneumonite de hipersensibilidade foi diagnosticada. Conclusões: Pacientes com FPF podem apresentar características clínicas diversas. A maioria das TCAR desses pacientes exibe padrões não típicos de pneumonia intersticial usual. A pesquisa da história clínica de outros casos de pneumopatias fibrosantes na família deve ser feita em todos os pacientes em investigação, independentemente da idade.

Síndrome de DRESS con compromiso pulmonar extenso: una presentación inhabitual / Drug rash with eosinophilia and systemic symptoms or DRESS syndrome: report of one case

Drug rash with eosinophilia and systemic symptoms or DRESS Syndrome is a rare, serious and potentially fatal adverse drug reaction. It is characterized by widespread morbilliform and edematous skin lesions, associated with eosinophilia, lymphadenopathy and internal organ involvement and unusually associated with pulmonary symptoms. We report a 47-year-old male with DRESS syndrome, manifested with typical skin lesions and extensive pulmonary involvement, responding satisfactorily to systemic corticosteroids.

Enfermedad pulmonar intersticial por IgG4 / IgG4-related interstitial lung disease

Las enfermedades relacionadas con inmunoglobulina G4 (IgG4) son un grupo heterogéneo de cuadros clínicos que pueden afectar un solo órgano o tener compromiso sistémico. Se presenta el caso de una mujer de 55 años, internada por un cuadro de tos seca, fiebre, disnea progresiva e insuficiencia respiratoria. La tomografía de tórax evidenció áreas de vidrio esmerilado difusas, patrón reticular y consolidación alveolar. Recibió tratamiento habitual para neumonía de la comunidad y corticoides sistémicos, presentando buena evolución y otorgándose el alta. Al mes se reinterna por estenosis subglótica, progresión de infiltrados pulmonares y aumento del volumen palpebral y de las glándulas submaxilares. Se realizaron biopsias transbronquial y de glándulas salivales que mostraron infiltración por IgG4. También se detectó aumento de los niveles de IgG4 en plasma. Recibió tratamiento con inmunosupresores evolucionando con buena respuesta.

IgG4-related disease is a heterogeneous group of diseases that can affect a single organ or manifest as a systemic disease. We present the case of a 55-year-old female, admitted for dry cough, fever, progressive dyspnea and respiratory failure. Chest CT showed areas of diffuse ground glass, reticular pattern and alveolar consolidation. She received treatment for community acquired pneumonia and systemic corticosteroids with good response. One month later, she was admitted again due to subglottic stenosis, progression of pulmonary infiltrates, and increased palpebral and submaxillary glands volume. Transbronchial and salivary gland biopsies showed infiltration by IgG4. Increased levels of plasma IgG4 were also detected. Immunosuppressive therapy was given with good response.

Dermatomiositis asociada al autoanticuerpo anti-MDA5 / Dermatomyositis associated with anti-MDA5 autoantibody

La dematomiositis es una miopatía inflamatoria idiopática con espectro clínico variable. En los últimos años se ha identificado un número de autoanticuerpos específicos de miositis útiles para el diagnóstico, la clasificación y el pronóstico de las diversas formas de la enfermedad, entre los que se encuentra el anti-MDA5. Este anticuerpo se asocia al desarrollo de úlceras cutáneas, enfermedad intersticial pulmonar rápidamente progresiva, mortalidad temprana y mal pronóstico por lo que la detección del mismo, en un contexto clínico adecuado, plantea la necesidad de un tratamiento inmunosupresor agresivo. Describimos un caso de dermatomiositis hipomiopática, (es decir, con afección muscular leve) que presentaba compromiso cutáneo específico, enfermedad pulmonar intersticial y anticuerpo anti-MDA5 que respondió favorablemente al tratamiento combinado con ciclofosfamida, gamaglobulina y corticoides.

Dematomyositis is an idiopathic inflammatory myopathy with a variable clinical spectrum. In recent years, a number of myositis-specific antibodies have been identified including anti-MDA5, which is us eful for diagnosis, prognosis and classification of the diverse clinical forms of the disease. This antibody is associated with cutaneous ulcers, rapidly progressive interstitial lung disease, early mortality and poor prognosis, so the detection of this antibody in a suitable clinical context, raises the need for an aggressive immunosuppressive treatment. We describe a case of dermatomyositis classified as hypomyopathic (i.e. involving mild muscle weakness), presenting specific skin lesions, interstitial lung disease, and presence of anti-MDA5 antibody that had a favorable response to combined treatment with cyclophosphamide, gamma globulin and corticosteroids.

Caracterización clínica, serológica y patrón radiológico de una cohorte unicéntrica de pacientes con enfermedad pulmonar difusa / Clinical, serological and radiological pattern characterization of a monocentric cohort of patients with diffuse lung disease

Diffuse Lung Disease (DLD) is an important cause of morbidity and mortality, however in Chile we are lacking of epidemiological data on this condition. Our aim is communicate the first report of a prospective registry of DLD patients treated at bronchopulmonary unit of DIPRECA hospital. Methods: Cross-sectional study in patients referred to our bronchopulmonary unit under suspicion of DLD. Diagnosis was confirmed by chest computed tomography and informed consent was approved by patients. Data regarding clinical, serological, pulmonary function tests and echocardiography were collected from 2014 up to date. Results: 30 patients were analysed, their median of age was 76.5 years-old (Interquartile Range 68-80), 56.7% were women, median duration of disease: 4 years (IQR 1-10.6) and 43% has smoking history Most frequent signs and symptoms were crackles (97%), dyspnoea (90%) and cough (57%). Comorbidities: 3% had asthma, 3% chronic obstructive pulmonary disease and 6.7% connective tissue diseases. Radiological findings: 20% had DLD with usual interstitial pneumonia pattern (UIP), 23% DLD possible UIP, 30% DLD inconsistent with UIP, 14% chronic hypersensitivity pneumonitis and 13% nonspecific interstitial pneumonia. Serology: 18% had positive rheumatoid factor of which only one case had rheumatoid arthritis, 67% had positive antinuclear antibodies (ANA), 17% ANCA positive of which only one case of clinical vasculitis. Spirometry was mainly normal (52%) or restrictive (45%). Echocardiography showed pulmonary hypertension mainly mild in 52% of patients. No significant association was found between titles of ANA ≥ 1/320 and gender, smoking or radiological pattern. Conclusions: Our demographic and radiological findings are similar to those reported in literature; however, the highlights in our cohort are the increased frequency of female gender and positive ANA without history or clinical manifestation of connective tissue diseases.

La enfermedad pulmonar difusa (EPD) es causa importante de morbimortalidad; a pesar de esto no tenemos datos epidemiológicos en Chile. Nuestro objetivo es comunicar el primer reporte del registro prospectivo de pacientes con EPD atendidos en la unidad de broncopulmonar del hospital DIPRECA. Métodos: Estudio de corte transversal en pacientes derivados alpoliclínico broncopulmonar del hospital DIPRECA por sospecha de EPD. En caso de confirmación diagnóstica por tomografía computada de tórax y consentimiento informado aprobado por los pacientes, se compilaron datos clínicos, serológicos, pruebas de función pulmonar y ecocardiografía, desde 2014 hasta la fecha. Resultados: Se analizaron 30 pacientes la mediana de su edad fue 76,5 años (rango intercuartílico 68-80), 56,7% eran mujeres, duración mediana de la enfermedad: 4 años (RIC 1-10,6)y 43% con antecedentes de tabaquismo. Los síntomas y signos más frecuente fueron crujidos (97%), disnea (90%) y tos (57%). Comorbilidades: 3% tenía asma, 3% enfermedad pulmonar obstructiva crónica y 6,7% enfermedades del tejido conectivo. Hallazgos radiológicos: 20% tenía EPD con patrón de neumonía intersticial usual (UIP), 23% EPD posible UIP, 30% EPD inconsistente con UIP, 14% neumonitis por hipersensibilidad crónica y 13% neumonía intersticial no específica. Serología: 18% tenía factor reumatoide positivo de ellos sólo uno de los casos tenía artritis reumatoide, el 67% tenía anticuerpos antinucleares (ANA) positivos, 17% ANCA positivo de ellos sólo un caso tenía historia de vasculitis clínica. La espirometría fue mayoritariamente normal (52%) o restrictiva (45%). Ecocardiografía detectó hipertensión pulmonar mayoritariamente leve en 52% de los pacientes. No se encontró asociación significativa entre los títulos de ANA ≥ 1/320 en relación a género, tabaquismo o patrón radiológico. Conclusiones: Nuestros hallazgos demográficos y radiológicos son similares a los de la literatura; sin embargo, destaca en nuestra cohorte la mayor frecuencia de género femenino y ANA positivos sin historia o manifestación clínica de enfermedades del tejido conectivo.

Pleuroparenchymal fibroelastosis: report of two cases in Brazil / Fibroelastose pleuroparenquimatosa: relato de dois casos no Brasil

ABSTRACT Pleuroparenchymal fibroelastosis (PPFE) is a rare lung disease. It can be idiopathic or associated with any one of various conditions. To our knowledge, this is the first report of two cases of PPFE in Brazil. Our first patient presented with pleural and subpleural fibrosis in the upper lobes; a spiculated nodule in the left upper lobe; and a mild reticular pattern in the lower lobes. Surgical lung biopsy revealed PPFE in the upper lobes, including the nodule, and unclassified interstitial pneumonia in the left lower lobe. Our second patient had a history of exposure to domestic birds, indicating a risk of hypersensitivity pneumonitis, and presented with advanced lung disease, predominantly in the upper lobes, together with subpleural fibrosis.That patient underwent lung transplantation. In the explant specimen, PPFE and granulomas were identified, suggesting hypersensitivity pneumonitis as an associated cause.

RESUMO A fibroelastose pleuroparenquimatosa (FEPP) é uma doença pulmonar rara, podendo ser idiopática ou associada a diversas condições. Pelo que sabemos, este é o primeiro relato de dois casos de FEPP no Brasil. Nosso primeiro paciente apresentava fibrose pleural e subpleural nos lobos superiores, um nódulo espiculado no lobo superior esquerdo e um padrão reticular discreto nos lobos inferiores. A biópsia pulmonar cirúrgica demonstrou FEPP nos lobos superiores, incluindo no nódulo, e pneumonia intersticial não classificada no lobo inferior esquerdo. Nosso segundo paciente tinha história de exposição a aves domésticas, indicando um risco de pneumonite de hipersensibilidade, e doença pulmonar avançada predominando em lobos superiores, com fibrose subpleural. Esse paciente foi submetido a transplante pulmonar. No espécime do explante, FEPP e granulomas foram identificados, sugerindo pneumonite de hipersensibilidade como causa associada.

Hard metal lung disease: a case series / Doença pulmonar por metal duro: uma série de casos

ABSTRACT Objective: To describe diagnostic and treatment aspects of hard metal lung disease (HMLD) and to review the current literature on the topic. Methods: This was a retrospective study based on the medical records of patients treated at the Occupational Respiratory Diseases Clinic of the Instituto do Coração, in the city of São Paulo, Brazil, between 2010 and 2013. Results: Of 320 patients treated during the study period, 5 (1.56%) were diagnosed with HMLD. All of those 5 patients were male (mean age, 42.0 ± 13.6 years; mean duration of exposure to hard metals, 11.4 ± 8.0 years). Occupational histories were taken, after which the patients underwent clinical evaluation, chest HRCT, pulmonary function tests, bronchoscopy, BAL, and lung biopsy. Restrictive lung disease was found in all subjects. The most common chest HRCT finding was ground glass opacities (in 80%). In 4 patients, BALF revealed multinucleated giant cells. In 3 patients, lung biopsy revealed giant cell interstitial pneumonia. One patient was diagnosed with desquamative interstitial pneumonia associated with cellular bronchiolitis, and another was diagnosed with a hypersensitivity pneumonitis pattern. All patients were withdrawn from exposure and treated with corticosteroid. Clinical improvement occurred in 2 patients, whereas the disease progressed in 3. Conclusions: Although HMLD is a rare entity, it should always be included in the differential diagnosis of respiratory dysfunction in workers with a high occupational risk of exposure to hard metal particles. A relevant history (clinical and occupational) accompanied by chest HRCT and BAL findings suggestive of the disease might be sufficient for the diagnosis.

RESUMO Objetivo: Descrever aspectos relacionados ao diagnóstico e tratamento de pacientes com doença pulmonar por metal duro (DPMD) e realizar uma revisão da literatura. Métodos: Estudo retrospectivo dos prontuários médicos de pacientes atendidos no Serviço de Doenças Respiratórias Ocupacionais do Instituto do Coração, localizado na cidade de São Paulo, entre 2010 e 2013. Resultados: Entre 320 pacientes atendidos no período do estudo, 5 (1,56%) foram diagnosticados com DPMD. Todos os pacientes eram do sexo masculino, com média de idade de 42,0 ± 13,6 anos e média de tempo de exposição a metal duro de 11,4 ± 8,0 anos. Os pacientes foram submetidos a avaliação clinica, história ocupacional, TCAR de tórax, prova de função pulmonar, broncoscopia com LBA e biópsia pulmonar. Todos apresentaram distúrbio ventilatório restritivo. O achado de imagem à TCAR de tórax mais frequente foi de opacidades em vidro fosco (em 80%). Em 4 pacientes, o LBA revelou presença de células gigantes multinucleadas. Em 3, foi diagnosticada pneumonia intersticial por células gigantes na biópsia pulmonar. Houve o diagnóstico de pneumonia intersticial descamativa associada à bronquiolite celular em 1 paciente e de pneumonite de hipersensibilidade em 1. Todos foram afastados da exposição e tratados com corticoide. Houve melhora em 2 pacientes e progressão da doença em 3. Conclusões: Apesar de ser uma entidade rara, a DPMD deve ser sempre considerada em trabalhadores com risco ocupacional elevado de exposição a metais duros. A história clínica e ocupacional associada a achados em TCAR de tórax e LBA sugestivos da doença podem ser suficientes para o diagnóstico.

Neumonía intersticial inducida por bloqueo androgénico máximo como tratamiento de cáncer de próstata avanzado: Report of one case / Fatal interstitial lung disease associated with maximum androgen blockade

Maximum androgen blockade is the standard endocrine treatment for advanced prostate cancer. Interstitial lung disease in different degrees of severity, with low mortality and excellent response to treatment may appear with its use. We report a 77 years old patient with advanced prostate cancer who developed severe and progressive respiratory failure associated to bilateral pulmonary infiltrates, attributed to the direct effect of maximum androgen blockade. Despite the therapeutic efforts, the patient died. Lung pathology revealed Usual Interstitial Pneumonia.

Serum Clara cell 16-kDa protein levels and lung impairment in systemic sclerosis patients / Níveis séricos de proteína de células de Clara de 16 kDa e comprometimento pulmonar em pacientes com esclerose sistêmica

ABSTRACT Objective: To assess clinical utility of serum Clara cell 16-kDa protein measurements in relation with staging system for systemic sclerosis associated interstitial lung disease. Materials and methods: Serum levels of Clara cell 16-kDa protein were determined by ELISA in 28 systemic sclerosis patients and 30 healthy controls, and correlated with staging system for systemic sclerosis associated interstitial lung disease in systemic sclerosis patients. Lung involvement was assessed functionally (body plethysmography, diffusing capacity of the lung for carbon monoxide) and radiologically (an average disease extent on high resolution computed tomography of the lungs) in SSc patients. Results: We observed statistically significant differences in serum Clara cell 16-kDa protein levels between systemic sclerosis patients and healthy controls only in non-smokers. However, serum Clara cell 16-kDa protein concentrations were significantly elevated in patients with high resolution computed tomography extent >20% in comparison to patients with high resolution computed tomography extent <20% (p = 0.01). They correlated positively with average disease extent on high resolution computed tomography (p = 0.04), an extent of a reticular pattern on high resolution computed tomography (p < 0.01), and negatively with a total lung capacity (p = 0.03) and the results of the 6-min walk test (p < 0.01). Conclusions: Clara cell 16-kDa protein levels can be considered as a supplemental serum biomarker for systemic sclerosis associated interstitial lung disease.

RESUMO Objetivo: Avaliar a utilidade clínica das medições séricas da proteína de células de Clara de 16-kDa (CC16) em relação ao sistema de estadiamento para doença pulmonar intersticial associada a esclerose sistêmica (DPI-ES). Materiais e métodos: Foram determinados os níveis séricos de CC16 por ELISA em 28 pacientes com ES e 30 controles saudáveis e correlacionados com o sistema de estadiamento para DPI-ES em pacientes com ES. O envolvimento pulmonar foi avaliado funcionalmente (pletismografia corporal, capacidade de difusão de monóxido de carbono) e radiologicamente (extensão média da doença na tomografia computadorizada de alta resolução dos pulmões, TCAR) em pacientes com ES. Resultados: Foram encontradas diferenças estatisticamente significativas nos níveis séricos de CC16 entre pacientes com ES e controles saudáveis apenas em não tabagistas. No entanto, as concentrações séricas de CC16 eram significativamente elevadas em pacientes com extensão > 20% na TCAR em comparação com pacientes com extensão < 20% na TCAR (p = 0,01). Os níveis séricos de CC16 se correlacionaram positivamente com a extensão média da doença na TCAR (p = 0,04) e com a extensão de padrão reticular na TCAR (p < 0,01) e negativamente com a capacidade pulmonar total (CPT) (p = 0,03) e com os resultados do teste de caminhada de seis minutos (p < 0,01). Conclusões: Os níveis de CC16 podem ser considerados como biomarcadores séricos suplementares para a DPI-ES.

Perfil clínico radiológico de 18 pacientes con síndrome antisintetasas atendidos en Policlínico de Pulmón Reumatológico, Instituto Nacional del Tórax / Clinic and radiologic profile of 18 patients with antisynthetase syndrome, treated in a Rheumatologic Lung Disease Clinic, Instituto Nacional del Torax

Connective Tissue Diseases (CTD) can manifest as Interstitial lung disease (ILD). ILD is a common manifestation of Anti-synthetase syndrome (AS). The main pattern of ILD in AS is nonspecific interstitial pneumonia (NSIP) with or without elements of organizing pneumonia (OP). Other less common forms include usual interstitial pneumonia (UIP) and nonspecific forms. Objectives: Describe radiological and clinical profile of 18 patients with ILD due to AS, evaluated in Instituto Nacional del Torax (INT) between 2013 and 2015. Highlighting the importance of Myositis Panel in patients being evaluated for ILD. Methods: Review of clinical records and lung CT of 76 patients with ILD and suspected AS, seen at INT between august 2013 and July 2015. Results: The diagnosis of AS was made in 18 of 76 patients, with female predominance and mean age of 46.5 years . In most patients the diagnosis of AS and ILD was simultaneous. The most frequent AS antibody was Jo-1, followed by PL-12. Less than half had ANA (+). The predominant radiographic pattern was NSIP / OP. Half of the patients had myositis. Conclusions: AS should be suspected in patients under study for ILD, especially NSIP / OP, and may occur without myositis and with negative ANA. It is essential to have new immunological tests such as a Myositis Panel, which will allow us to diagnose AS with subtle clinical features and negative or inconclusive serology...

Las Enfermedades del tejido conectivo (ETC) se pueden manifestar como Enfermedad Pulmonar Difusa (EPD). El Síndrome Antisintetasas (SAS) con mucha frecuencia presenta EPD. La forma de expresión más frecuente en SAS es la neumonía intersticial no específica (NSIP) con o sin elementos de neumonía en organización (OP). Otras formas menos frecuentes son la neumonía intersticial usual (UIP) y formas inespecíficas. Objetivos: Describir el perfil clínico radiológico de 18 pacientes con EPD secundaria a SAS, atendidos en el Instituto Nacional del Tórax (INT) entre los años 2013 y 2015. Destacar la importancia del Panel de Miositis en pacientes con EPD en estudio. Métodos: Revisión de ficha clínica y TAC pulmonar de 76 pacientes con EPD y sospecha de SAS, atendidos en INT entre agosto 2013 y julio 2015. Resultados: En 18 de 76 pacientes se hizo el diagnóstico de SAS, predominio femenino, edad promedio 46,5 años. En la mayoría el diagnóstico reumatológico y pulmonar fue simultáneo, el anticuerpo antisintetasa más frecuente fue Jo-1, seguido de PL 12. Menos de la mitad tuvo ANA (+). El patrón radiológico predominante fue NSIP/OP. La mitad de los pacientes no presentaron miositis. Conclusiones: El SAS debe ser sospechado en el estudio de pacientes con EPD, especialmente NSIP/OP y se puede presentar sin miositis y ANA (-). Es indispensable contar con nuevos exámenes inmunológicos como el Panel de Miositis, que permite diagnosticar SAS con clínica sutil y serología habitual negativa o no concluyente...

Clinico-pathological Analysis of the Lungs from Patients with Lung Transplantation in a Single Institute in Korea

Recently, the numbers of lung transplantation (LT) has been increased in Korea. However, post-LT outcome has not been successful in all patients, which may be partially affected by the primary lung disease. Therefore comprehensive understanding in original pathological diagnosis of patients with LT would be needed for achieving better clinical outcome. To address this issue, we performed clinico-pathological analysis of the explanted lungs from 29 patients who underwent LT over a 9-yr period in Seoul National University Hospital. Among them, 26 patients received single (1/26) or double (25/26) LT, while heart-lung transplantation was performed in 3 patients. The final clinico-pathological diagnoses were idiopathic pulmonary fibrosis/usual interstitial pneumonia (UIP) (n = 6), acute interstitial pneumonia (AIP)/diffuse alveolar damage (DAD) (n = 4), AIP/non-specific interstitial pneumonia with DAD (n = 1), collagen vascular disease-related interstitial lung disease (CVD-ILD)/DAD (n = 3), CVD-ILD/UIP (n = 1), lymphangioleiomyomatosis (n = 1), bronchiectasis (n = 4), pulmonary arterial hypertension (n = 2), tuberculosis (n = 1), bronchiolitis obliterans (BO) (n = 1), and lung cancer (n = 1). Moreover, 4 patients who had chemotherapy and hematopoietic stem cell transplantation due to hematologic malignancy showed unclassifiable interstitial pneumonia with extensive fibrosis in the lungs. Our study demonstrates that pathology of the explanted lungs from Korean patients with LT is different from that of other countries except for interstitial lung disease and bronchiectasis, which may be helpful for optimization of selecting LT candidates for Korean patients.

Interpretation of autoantibody positivity in interstitial lung disease and lung-dominant connective tissue disease / Interpretacao da positividade de autoanticorpos na doenca pulmonar intersticial e colagenose pulmao dominante

The initial evaluation of patients with interstitial lung disease (ILD) primarily involves a comprehensive, active search for the cause. Autoantibody assays, which can suggest the presence of a rheumatic disease, are routinely performed at various referral centers. When interstitial lung involvement is the condition that allows the definitive diagnosis of connective tissue disease and the classical criteria are met, there is little debate. However, there is still debate regarding the significance, relevance, specificity, and pathophysiological role of autoimmunity in patients with predominant pulmonary involvement and only mild symptoms or formes frustes of connective tissue disease. The purpose of this article was to review the current knowledge of autoantibody positivity and to discuss its possible interpretations in patients with ILD and without clear etiologic associations, as well as to enhance the understanding of the natural history of an allegedly new disease and to describe the possible prognostic implications. We also discuss the proposition of a new term to be used in the classification of ILDs: lung-dominant connective tissue disease.

A avaliação inicial de pacientes com doença pulmonar intersticial (DPI) envolve primordialmente a busca ativa e detalhada por uma etiologia. A pesquisa rotineira de autoanticorpos é comum em diferentes centros e permite sugerir a presença de alguma doença do espectro reumatológico. Quando o acometimento pulmonar intersticial é a condição que permite o diagnóstico firmado de uma colagenose bem estabelecida, preenchendo os critérios clássicos, há pouco debate. Entretanto, ainda existe muita discussão sobre o significado, a relevância, a especificidade e o papel fisiopatológico da autoimunidade nos pacientes que tenham prioritariamente acometimento respiratório e apenas algum indício leve ou frustro de colagenose. O propósito dessa revisão foi apresentar o conhecimento atual e discutir possibilidades de interpretação da positividade de autoanticorpos em pacientes com DPI que não tenham associações etiológicas inequívocas, assim como aumentar o entendimento da história natural de uma possível nova doença e descrever possíveis implicações prognósticas. Discutimos ainda a proposição de uma nova terminologia na classificação das DPIs, a colagenose pulmão dominante.

Morphometric evaluation of nitric oxide synthase isoforms and their cytokine regulators predict pulmonary dysfunction and survival in systemic sclerosis

Because histopathological changes in the lungs of patients with systemic sclerosis (SSc) are consistent with alveolar and vessel cell damage, we presume that this interaction can be characterized by analyzing the expression of proteins regulating nitric oxide (NO) and plasminogen activator inhibitor-1 (PAI-1) synthesis. To validate the importance of alveolar-vascular interactions and to explore the quantitative relationship between these factors and other clinical data, we studied these markers in 23 cases of SSc nonspecific interstitial pneumonia (SSc-NSIP). We used immunohistochemistry and morphometry to evaluate the amount of cells in alveolar septa and vessels staining for NO synthase (NOS) and PAI-1, and the outcomes of our study were cellular and fibrotic NSIP, pulmonary function tests, and survival time until death. General linear model analysis demonstrated that staining for septal inducible NOS (iNOS) related significantly to staining of septal cells for interleukin (IL)-4 and to septal IL-13. In univariate analysis, higher levels of septal and vascular cells staining for iNOS were associated with a smaller percentage of septal and vascular cells expressing fibroblast growth factor and myofibroblast proliferation, respectively. Multivariate Cox model analysis demonstrated that, after controlling for SSc-NSIP histological patterns, just three variables were significantly associated with survival time: septal iNOS (P=0.04), septal IL-13 (P=0.03), and septal basic fibroblast growth factor (bFGF; P=0.02). Augmented NOS, IL-13, and bFGF in SSc-NSIP histological patterns suggest a possible functional role for iNOS in SSc. In addition, the extent of iNOS, PAI-1, and IL-4 staining in alveolar septa and vessels provides a possible independent diagnostic measure for the degree of pulmonary dysfunction and fibrosis with an impact on the survival of patients with SSc.

Tobacco smoking related interstitial lung diseases.

Smoking is a leading cause of death worldwide and is the important proximate cause of the most common noncommunicable respiratory disease, chronic obstructive pulmonary disease (COPD). Smoking is causally related to the development of certain forms of interstitial lung diseases (ILDs) including desquamative interstitial pneumonia (DIP), respiratory bronchiolitis associated interstitial lung disease (RB-ILD), pulmonary Langerhans’ cell histiocytosis (LCH), idiopathic pulmonary fibrosis (IPF) and acute eosinophilic pneumonia (AEP), among others. It is important to understand this causal relationship, as well as the natural history and prognosis of these diseases. The response to treatment of ILDs in general is quite dismal. For most of the ILDs, the only definitive treatment measure remains oxygen therapy and lung transplantation. As lung transplantation is still in its infancy and is unaffordable for a majority of patients with ILD in India, most of these patients can only hope to receive palliative supportive care. However, patients with tobacco smoking related ILDs have better outcomes, and progression of these disease ceases with smoking cessation. We review here, the varied clinical, radiological, pathological features, and the progression and outcome in this group of ILDs. Better understanding of these diseases, including making “smoking cessation” a central goal of management will improve overall outcomes.

Lymphatic fluctuation in the parenchymal remodeling stage of acute interstitial pneumonia, organizing pneumonia, nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis

Because the superficial lymphatics in the lungs are distributed in the subpleural, interlobular and peribroncovascular interstitium, lymphatic impairment may occur in the lungs of patients with idiopathic interstitial pneumonias (IIPs) and increase their severity. We investigated the distribution of lymphatics in different remodeling stages of IIPs by immunohistochemistry using the D2-40 antibody. Pulmonary tissue was obtained from 69 patients with acute interstitial pneumonia/diffuse alveolar damage (AIP/DAD, N = 24), cryptogenic organizing pneumonia/organizing pneumonia (COP/OP, N = 6), nonspecific interstitial pneumonia (NSIP/NSIP, N = 20), and idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP, N = 19). D2-40+ lymphatic in the lesions was quantitatively determined and associated with remodeling stage score. We observed an increase in the D2-40+ percent from DAD (6.66 ± 1.11) to UIP (23.45 ± 5.24, P = 0.008) with the advanced process of remodeling stage of the lesions. Kaplan-Meier survival curves showed a better survival for patients with higher lymphatic D2-40+ expression than 9.3%. Lymphatic impairment occurs in the lungs of IIPs and its severity increases according to remodeling stage. The results suggest that disruption of the superficial lymphatics may impair alveolar clearance, delay organ repair and cause severe disease progress mainly in patients with AIP/DAD. Therefore, lymphatic distribution may serve as a surrogate marker for the identification of patients at greatest risk for death due to IIPs.

Enfisema pulmonar intersticial persistente en recién nacido: caso clínico / Persistent interstitial pulmonary emphysema in the newborn: clinical case

Persistent Interstitial Pulmonary Emphysema (PIPE) is a syndrome characterized by air leak to the perivascular tissue in the lung, affecting newborns with history of mechanical ventilation. It is also characterized by lack of reabsorption of air in the gap in some areas and giant cell formation. Case Report: A 35-week preterm newborn is presented. Moan and retraction were observed, with oxygen requirements. At the hospital, the diagnosis of transient respiratory distress syndrome was done, requiring nasal CPAP support. At 12 hours of life a sudden clinical deterioration was noted, and a tension pneumothorax of the right lung was confirmed. Pneumothorax was drained with chest tube and high frequency ventilation was initiated. A chest X-ray showed reexpansion of right lung and greater confluence baseline images suggesting bronchopneumonia. After discontinuing ventilatory support, 2 chest CT images show a persistent interstitial pulmonary emphysema in the right lung. Patient was discharged at 13 days of life. Discussion: PIPE is a syndrome that must be suspected within the differential diagnosis of cystic lung diseases in the newborn. Its identification allows the exclusion of similar entities, and avoid unnecessary surgeries since PIPE may lead to spontaneous resolution.

El enfisema pulmonar intersticial persistente (EPIP) es un síndrome que se caracteriza por escape aéreo del tejido perivascular del pulmón afectando a recién nacidos (RN) con antecedentes de ventilación mecánica. Caso clínico: RN pretérmino de 35 semanas AEG producto de cesárea que evoluciona con quejido y retracción requiriendo oxigenoterapia. Se hospitaliza con diagnóstico de síndrome de dificultad respiratorio transitorio, requiriendo apoyo con CPAP nasal. A las 12 horas de vida presenta brusco deterioro clínico, causado por un neumotórax a tensión del pulmón derecho el cual se drena con tubo pleural y se conecta a ventilación de alta frecuencia. El control radiográfico muestra reexpansión del pulmón derecho, evoluciona favorablemente extubándose al cuarto día, TAC de tórax muestra imágenes pulmón derecho compatibles con un enfisema pulmonar intersticial persistente. Se da de alta a los 13 días de vida. Discusión: El diagnóstico de EPIP se basa principalmente en la sospecha clínica y radiográfica, teniendo el TAC pulmonar un rol fundamental, con imágenes características de líneas centrales gruesas asociadas a grandes puntos rodeados de imágenes radiolúcidas, que corresponden a quistes. El manejo depende de cada caso. La cirugía se reserva según evolución y extensión del enfisema. Conclusiones: La identificación del EPIP nos permite excluir otras entidades parecidas y evitar cirugías innecesarias, ya que la evolución del EPIP puede incluso ir hacia la resolución espontánea.

Neumonía intersticial linfoidea asociada a inmunodeficiencia común variable / Interstitial lymphoid pneumonia associated with common variable immunodeficiency

La neumonía intersticial linfoidea (NIL) es una rara entidad, descripta como hiperplasia no neoplásica del tejido linfoide pulmonar y clasificada dentro de las enfermedades intersticiales idiopáticas. Se la ha descripto asociada a infección por HIV, fenómenos autoinmunes, hipergamaglobulinemia policlonal o menos frecuentemente a hipogammaglobulinemia. Presentamos una paciente de 66 años de edad con diabetes mellitus, síndrome de Sjögren e hipertensión arterial, derivada a nuestro centro por tos seca y disnea clase funcional II-III. En el examen físico presentaba rales tipo “velcro” bibasales y esplenomegalia. Los estudios de laboratorio evidenciaron plaquetopenia (50 000/mm³) e hipogammaglobulinemia; la tomografía axial computarizada (TAC) de tórax mostró compromiso intersticial bibasal, con nódulos peribroncovasculares menores a un centímetro. Se realizó una videotoracoscopia con biopsia pulmonar, la anatomía patológica mostró hallazgos compatibles con neumonía intersticial linfoidea. Se inició tratamiento con metilprednisona 40 mg/día vía oral e infusión endovenosa de gammaglobulina 500 mg/kg, mensual, evolucionando con mejoría clínico-radiológica. Por persistencia de plaquetopenia, asociada a hiperesplenismo, se realizó esplenectomía con buena respuesta. En la anatomía patológica no se observo clonalidad linfoide.

The interstitial lymphoid pneumonia (LIP) is an uncommon disorder, described as non-neoplastic lung lymphoid tissue hyperplasia and classified as an interstitial lung disease. It has been described in association with HIV infection, autoimmune disorders, policlonal hypergammaglobulinemia and less frequently, with hypogammaglobulinemia. We report the case of a 66 year old female patient with a history of diabetes, Sjögren syndrome and hypertension. She was referred to our hospital due to a dry cough and dyspnea (FC II-III). The physical examination showed bilateral dry crackles and splenomegaly. Laboratory studies showed thrombocytopenia (50 000/ mm³) and hypogammaglobulinemia. A computed tomography thoracic scan showed interstitial bilateral basal lung infiltrates with small peribroncovascular nodules. A lung biopsy was made by thoracoscopy and reported LIP. Initial treatment consisted of oral methilprednisone, 40 mg daily, and once a month intravenous gammaglobulin 500 mg/kg, with good clinical and radiological response. A splenectomy was done due to persistent thrombocytopenia associated with hypersplenism, with good response of the platelets counts. No lymphoid clonal or other associated disease was detected.