Spectrum of childhood interstitial and diffuse lung diseases at a tertiary hospital in Egypt

a, b) Subject 4: 5-year-old female patient, presented with severe failure to thrive and third-degree clubbing. She had profound hypoxaemia (oxygen saturation 80% at rest in room air), with widespread fine crepitations and severe pulmonary hypertension. a) Axial computed tomography (CT) shows bilateral scattered central and peripheral patchy areas of ground-glass opacities (GGO) and septal thickening. This is associated with a few areas of air trapping, giving a mosaic pattern; b) lung histopathology shows granulomas surrounded by a rim of chronic inflammatory cells (haematoxylin and eosin ×20). Thorough immunological testing was performed after the biopsy, and dihydrorhodamine (DHR) testing showed an abnormal response, confirming the diagnosis of chronic granulomatous disease. c, d) Subject 5: a 10-year-old male patient who presented with childhood interstitial and diffuse lung disease and was later diagnosed with chronic granulomatous disease (CGD). He had severe initial clinical presentation with hypoxia at rest (in room air) and marked failure to thrive. c) Axial CT shows bilateral peripheral and central large patchy areas of GGO with areas of air trapping giving a mosiac pattern, associated with septal thickening and a few mainly lower lobar emphysematous changes and central cystic changes. A large consolidative patch is noted affecting the anterior segment of the right upper lobe; d) abnormal bronchial thickening and minimal tractional bronchiectasis. Biopsy was planned, but it was deferred as he started to suffer from recurrent skin and deep-organ abscesses requiring surgical drainage. Further immune tests were done and DHR testing showed an abnormal response, confirming the diagnosis of CGD.

Subject 7: 8-year-old female had history of persistent dry cough and dyspnoea. She is the second child of first-degree consanguineous parents. In addition to the pulmonary symptoms, she had bouts of self-limiting noninfective diarrhoea and a) pustular skin lesions. In addition, she had a history of paediatric intensive care unit admission with severe sepsis which marked the disease onset. On presentation to us, she was tachypnoeic and hypoxic with widespread fine crepitations and wheeze by auscultation. An immunological profile showed elevated immunoglobulins and transient positivity of perinuclear anti-neutrophil cytoplasmic antibodies, which disappeared later on. Cluster of differentiation markers show borderline low natural killer cells and CD4 levels. Flow spirometry showed a restrictive pattern. b) Axial computed tomography shows bilateral mosaic appearance of both lung lobes (ground-glass appearance alternating with areas of air trapping), with peri-bronchial wall thickening and pre-septal thickening. c) Histopathology shows bronchocentric inflammation and granulomatous inflammation. d) Granuloma (high power). Haematoxylin and eosin c) ×40 and d) ×200. Histopathology findings were consistent with a granulomatous lymphocytic interstitial lung disease spectrum. Dihydrorhodamine test was normal and repeat immune studies showed persistent elevation of immunoglobulin levels, excluding underlying common variable immune deficiency.

Subject 8: 8-year-old female patient referred for further assessment. She complained of chronic dry cough and progressive dyspnoea. She has a history of familial death with undiagnosed interstitial lung disease in the fifth decade (uncle). On presentation to us she was tachycardic, tachypnoeic and hypoxic (oxygen saturation 88% in room air). In addition, she had severe cachexia with third-degree clubbing. Echocardiography showed severe pulmonary hypertension with dilated right atrium and ventricle. a, b) Axial computed tomography shows bilateral predominantly upper lobar and peripheral ground-glass opacities associated with peripheral reticular infiltration and honeycombing. c) Histopathology shows that the lung architecture is completely lost, with replacement by end-stage (honeycomb) fibrosis (haematoxylin and eosin ×40).

Subject 9: 7-year-old female, referred for further assessment. She had a history of dyspnoea shortly after birth, associated with failure to thrive. Her condition deteriorated to dyspnoea at rest and attacks of cyanosis. On presentation, she was markedly distressed, with respiratory rate 70 breaths·min⁻¹, heart rate 150 beats·min⁻¹ (tachycardia with gallop) and hypoxia (oxygen saturation 85% in room air, at rest). In addition, she had third-degree clubbing and marked failure to thrive. She had bilateral fine crepitations on auscultation with accentuated second heart sound and tender hepatomegaly. Echocardiography showed dilated right ventricle and severe pulmonary hypertension. Axial computed tomography shows a) bilateral (predominantly upper lobar) subpleural and intraparenchymal microcysts and b) bilateral diffuse pulmonary ground-glass opacities, with predominant affection of both lower lobes. Histopathology shows c) predominance of alveolar macrophage accumulation and d) diffuse and uniform interstitial chronic inflammation and mild fibrosis, characteristic of nonspecific interstitial pneumonia. This mixed histological pattern (fibrotic nonspecific interstitial pneumonia and desquamative interstitial pneumonia) in the paediatric age group is suggestive of an underlying surfactant protein disorder (haematoxylin and eosin c, d) ×100).

Subjects 11 and 12: two affected siblings with a history of grandparent death of undiagnosed interstitial lung disease (ILD) in the fourth decade. a, b) Computed tomography (CT) images from the older sibling: a) diffuse pan-lobar pulmonary emphysema with areas of air trapping, abnormal bronchial wall thickening; b) bilateral lower lobar scattered tiny ground-glass nodules showing tree-in-bud appearance. c, d) CT images from the younger sibling: c) air trapping and hyperinflation; d) bilateral few peripheral lower lobar tiny ground-glass nodules with a few of them giving tree-in-bud appearance. The younger sibling presented with a worse clinical picture (severity score 5) and her spirometry showed a restrictive defect. The older sibling presented with significant symptoms and signs and hypoxia at rest and her spirometry showed mixed obstructive and restrictive defect, with negative reversibility test. e, f) Histopathology of the older sibling, with findings consistent with idiopathic bronchiolocentric pattern of interstitial pneumonias: e) peribronchiolar inflammation (low power); f) peribronchiolar metaplasia (higher power) (haematoxylin and eosin e) ×40 f) ×100). Grocott stain for fungi was negative. General causes of diffuse parenchymal lung disease were thoroughly excluded as well as immune deficiency and α₁-antitrypsin deficiency. A specific cause for this histological pattern couldn't be precisely identified, but a strong family history with two siblings having respiratory symptoms since birth and grandparent death due to ILD raises serious concerns for an underlying genetic disorder.

a, b) Subject 13: Male patient referred to our hospital by the age of 8 years with history of worsening dyspnoea and bouts of cyanosis. He had a history of recurrent attacks of dyspnoea and dry cough since birth, in addition to global developmental delay of unidentified aetiology. An initial diagnosis of bronchial asthma was made in primary care, yet there was no significant improvement on conventional asthma management. On presentation to us, he was tachypnoeic and hypoxic (oxygen saturation 89% in room air, at rest). Examination revealed marked failure to thrive, in addition to fine crepitaions and wheeze by auscultation. a) Axial computed tomography (CT) shows multiple scattered patchy areas of ground-glass opacities alternating with few areas of air trapping, giving a mosaic pattern; b) histopathology shows chronic bronchiolitis (haematoxylin and eosin ×40). c, d) Subject 14. c) Axial CT shows bilateral scattered tiny pulmonary ground-glass nodules 2–3 mm on average showing centrilobular and peribronchial distribution; d) histopathology shows chronic bronchiolitis with airway lumens focally containing mucin (haematoxylin and eosin ×20).