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

Salma G. Abdelhady, Eman M. Fouda, Malak A. Shaheen, Faten A. Ghazal, Ahmed M. Mostafa, Ahmed M. Osman, Andrew G. Nicholson, Heba M. Hamza
ERJ Open Research 2021 7: 00880-2020; DOI: 10.1183/23120541.00880-2020
Salma G. Abdelhady
1Dept of Paediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2Children's Hospital, Pulmonology Unit, Ain Shams University Hospitals, Cairo, Egypt
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  • ORCID record for Salma G. Abdelhady
  • For correspondence: salmagamalhady@gmail.com
Eman M. Fouda
1Dept of Paediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2Children's Hospital, Pulmonology Unit, Ain Shams University Hospitals, Cairo, Egypt
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Malak A. Shaheen
1Dept of Paediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2Children's Hospital, Pulmonology Unit, Ain Shams University Hospitals, Cairo, Egypt
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Faten A. Ghazal
3Dept of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
4Pathology Lab, Ain Shams University Hospitals, Cairo, Egypt
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Ahmed M. Mostafa
5Dept of Thoracic Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
6Cardiovascular and Thoracic Academy, Ain Shams University Hospitals, Cairo, Egypt
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Ahmed M. Osman
7Dept of Radiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Andrew G. Nicholson
8Dept of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
9National Heart and Lung Institute, Imperial College, London, UK
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Heba M. Hamza
1Dept of Paediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2Children's Hospital, Pulmonology Unit, Ain Shams University Hospitals, Cairo, Egypt
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  • FIGURE 1
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    FIGURE 1

    Subject 1: 9-year-old male referred with possible diagnosis of childhood interstitial and diffuse lung disease. He complained of recurrent attacks of dyspnoea and dry cough. He had a strong history of exposure to birds. On presentation, he was tachypnoeic and hypoxic (oxygen saturation 88% at rest in room air). He had marked failure to thrive with first-degree clubbing, and auscultation revealed widespread fine crepitations. Echocardiography showed dilated right side with pulmonary hypertension. a) Axial computed tomography shows bilateral scattered subsegmental consolidative patches associated with few scattered atelectatic bands; b) interlobular and fissural thickening; c) bronchocentric chronic inflammation (low power); d) small poorly formed granuloma (high power) (haematoxylin and eosin c) ×20, d) ×200). Overall, the features are consistent with hypersensitivity pneumonitis. There was a significant clinical improvement on elimination of bird exposure and systemic steroids.

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    FIGURE 2

    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.

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    FIGURE 3

    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.

  • FIGURE 4
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    FIGURE 4

    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).

  • FIGURE 5
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    FIGURE 5

    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).

  • FIGURE 6
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    FIGURE 6

    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.

  • FIGURE 7
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    FIGURE 7

    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).

  • FIGURE 8
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    FIGURE 8

    Subject 16: 9-year-old female, referred for further assessment of her poorly controlled asthma. On presentation she had dyspnoea and hypoxaemia at rest with widespread fine crepitations and wheeze by auscultation and a) notably puffy fingers. Initial lab investigations were nonconclusive. b) Axial computed tomography shows bilateral mainly lower lobar extensive ground-glassing associated with few areas of air trapping, more evidently affecting the right lower lobe, giving a mosiac pattern. c) Histopathology shows bronchocentric interstitial pneumonia: interstitial chronic inflammation, more marked around bronchovascular bundles (low power); d) an occasional focus of organising pneumonia is noted (haematoxylin and eosin c) ×40 d) ×100). In addition, she developed progressive digital tip ulcers, sclerodactyly, in addition to induration proximal to the metacarpophalangeal joint (this appeared later). Overall features confirm the diagnosis of systemic sclerosis.

Tables

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  • TABLE 1

    Classification of enrolled subjects according to their clinical, radiological, laboratory and histopathology features

    HistoryAge at start of symptoms yearsAge at referral yearsFan scoreSpirometryChest CTHistopathologySignificant laboratory/BAL findingsFinal opinion
    1Exposure to doves and chicken495RVDConsolidation, septal thickeningGLDSpecific Dx: chronic HP
    2Exposure to doves and chicken2.53.52Not done#Reticulations/diffuse micronodulesGLDEosinophiliaSpecific Dx: chronic HP
    3Exposure to doves/benzene/hookah3.543Not done#GGO/consolidation/reticulationsInterstitial inflammation more marked around BVBEosinophiliaSpecific Dx: subacute HP
    4Recurrent pneumonias155RVDGGO/air trapping/septal thickeningGLDElevated ESR/DHR: defective responseSpecific Dx: CGD (PID)
    5Recurrent skin abscesses /previous pulmonary TB infection6.5104MVDMultiple findings (figure 2)Not doneElevated ESR/DHR: defective responseSpecific Dx: CGD (PID)
    6Recurrent pneumonias8135RVDGGO/air trapping/septal thickening/reticulations/consolidationGLDElevated ESR/DHR: defective responseSpecific Dx: CGD (PID)
    7Recurrent pustular skin lesions584RVDGGO/air trapping/septal thickeningGLILDElevated ESR/low NK cells and CD4/elevated immunoglobulins/negative viral serologySpecific Dx: GLILD (non-CVID related)
    8Familial death of ILD (uncle)/chILD onset after severe pneumonia685RVDGGO/honey combing/reticulationsSevere fibrotic NSIP (honeycomb lung)Negative viral serology and immune studies
    No evidence of microbial infection (by BAL)
    Specific Dx: IP (fibrotic NSIP-honeycomb lung)¶
    9Dyspnoea since birthSince birth75RVDGGO (with predominant affection of lower lobes), microcystsMixed fibrotic NSIP and DIPSpecific Dx: IP (NSIP/DIP)¶
    10GDD/familial death of undiagnosed ILD (sibling)5.562Not done#GGO/air trappingNSIP (cellular)Specific Dx: IP (NSIP)¶
    11Familial death of undiagnosed ILD in the 4th decade (grandparent)Since birth114MVDEmphysema/lower lobes tiny ground-glass nodules (tree-in-bud pattern)BPIPNegative immune studiesSpecific Dx: IP (BPIP)¶
    12Familial death of undiagnosed ILD in the 4th decade (grandparent)Since birth55RVDAir trapping/hyperinflation/lower lobes tiny ground-glass nodules (tree-in-bud pattern)Parents refused (cases 11 and 12 are siblings)Negative immune studiesSuggestive Dx: familial ILD of unidentified aetiology
    13GDDSince birth84Not done#GGO/air trappingChronic bronchiolitis/interstitial chronic inflammationSpecific Dx: chILD related to SAD with background IP+
    14GDD0.2554NormalGround-glass nodules 2–3 mm (centrilobular and peri-bronchial distribution)Chronic bronchiolitis/interstitial chronic inflammationSpecific Dx: chILD related to SAD with background IP+
    15NICU admission at birth for 2 months/full termSince birth142MVDGGO (a few show crazy paving)Chronic bronchiolitis/interstitial chronic inflammationSpecific Dx: chILD related to SAD with background IP+
    16Puffy fingers/digital tip ulcers/sclerodactyly/induration proximal to MCP (late)484Not done#Bibasilar GGOBPIP + focal OPAbnormal nail-fold capillariesSpecific Dx: Systemic sclerosis
    17Haemoptysis/admitted twice for blood transfusion for severe microcytic anaemia452NormalGGONot doneBAL: HLM >60% of cells/other causes of DAH were excludedSpecific Dx: IPH
    18Haemoptysis/admitted six times for blood transfusion for severe microcytic anaemia5.572RVDGGONot doneBAL: HLM >45% of cells/other causes of DAH were excludedSpecific Dx: IPH
    19Progressive dyspnoea over 2 months11115Not done#Cysts (sparing CPA)/GGO/tiny nodulesDeath before any invasive testsSuggestive Dx: LCH
    2013.54Not done#Cysts (sparing CPA)/GGODropped outSuggestive Dx: LCH
    21History of pulmonary TB3.54.55Not done#GGO/reticulations/atelectatic bandsClinically improving (not done)Negative immune studiesSpecific Dx: post-infectious chILD (post-TB)
    22Start of disease following attack of severe pneumonia664RVDGGOOP and reactive fibrous pleuritisNegative immune studiesSpecific Dx: post-infectious chILD (OP)

    CT: computed tomography; BAL: bronchoalveolar lavage; RVD: restrictive ventilatory dysfunction; GLD: granulomatous lung disease; Dx: diagnosis; HP: hypersensitivity pneumonitis; GGO: ground-glass opacities; BVB: bronchovascular bundles; ESR: erythrocyte sedimentation rate; DHR: dihydrorhodamine test; CGD: chronic granulomatous disease; PID: primary immune deficiency; TB: tuberculosis; MVD: mixed ventilatory dysfunction; GLILD: granulomatous lymphocytic interstitial lung disease; NK: natural killer; CVID: common variable immune deficiency; ILD: interstitial lung disease; chILD: childhood interstitial and diffuse lung diseases; NSIP: nonspecific interstitial pneumonia; IP: interstitial pneumonia; DIP: desquamative interstitial pneumonia; GDD: global developmental delay; BPIP: bronchiolocentric pattern of interstitial pneumonias; SAD: small airways disease; NICU: neonatal intensive care unit; MCP: metacarpophalangeal joint; OP: organising pneumonia; HLM: haemosiderin-laden macrophages; DAH: diffuse alveolar haemorrhage; IPH: idiopathic pulmonary haemosiderosis; CPA: costophrenic angle; LCH: Langerhans cell histiocytosis. #: too young or too dyspnoeic to do the test or suffering from global delay (noncooperative); ¶: further genetic testing required to exclude surfactant dysfunction mutation; +: future genetic studies are also warranted for this group, as symptom onset was at birth or shortly after birth.

    Supplementary Materials

    • Figures
    • Tables
    • Supplementary Material

      Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

      TABLE S1 Comparison between chest X-ray and corresponding chest CT findings among enrolled subjects 00880-2020.tableS1

      TABLE S2 Bronchoscopy and bronchoalveolar lavage (BAL) indications, characteristics and other relevant investigations for selected cases 00880-2020.tableS2

      TABLE S3 Highlights on treatment changes after the diagnostic evaluation 00880-2020.tableS3

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    Spectrum of childhood interstitial and diffuse lung diseases at a tertiary hospital in Egypt
    Salma G. Abdelhady, Eman M. Fouda, Malak A. Shaheen, Faten A. Ghazal, Ahmed M. Mostafa, Ahmed M. Osman, Andrew G. Nicholson, Heba M. Hamza
    ERJ Open Research Apr 2021, 7 (2) 00880-2020; DOI: 10.1183/23120541.00880-2020

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    Spectrum of childhood interstitial and diffuse lung diseases at a tertiary hospital in Egypt
    Salma G. Abdelhady, Eman M. Fouda, Malak A. Shaheen, Faten A. Ghazal, Ahmed M. Mostafa, Ahmed M. Osman, Andrew G. Nicholson, Heba M. Hamza
    ERJ Open Research Apr 2021, 7 (2) 00880-2020; DOI: 10.1183/23120541.00880-2020
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