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. 2023 Apr 24;9(2):00733-2022.
doi: 10.1183/23120541.00733-2022. eCollection 2023 Mar.

Diffuse alveolar haemorrhage in children: an international multicentre study

Astrid Madsen Ring  1 , Nicolaus Schwerk  2 , Nural Kiper  3 , Ayse Tana Aslan  4 , Paul Aurora  5 , Roser Ayats  6 , Ines Azevedo  7 , Teresa Bandeira  8 , Julia Carlens  2 , Silvia Castillo-Corullon  9 , Nazan Cobanoglu  10 , Basil Elnazir  11 , Nagehan Emiralioğlu  3 , Tugba Sismanlar Eyuboglu  4 , Michael Fayon  12 , Tugba Ramaslı Gursoy  4 , Claire Hogg  13 , Karsten Kötz  14 , Bülent Karadag  15 , Vendula Látalová  16 , Katarzyna Krenke  17 , Joanna Lange  17 , Effrosyni D Manali  18 , Borja Osona  19 , Spyros Papiris  18 , Marijke Proesmann  20 , Philippe Reix  21 , Lea Roditis  22 , Sune Rubak  23 , Nisreen Rumman  24 , Deborah Snijders  25 , Florian Stehling  26 , Laurence Weiss  27 , Ebru Yalcın  3 , Fazilcan Zirek  10 , Andrew Bush  28 , Annick Clement  29 , Matthias Griese  30 , Frederik Fouirnaies Buchvald  1 , Nadia Nathan  29   31 , Kim Gjerum Nielsen  1   30   31
Affiliations

Diffuse alveolar haemorrhage in children: an international multicentre study

Astrid Madsen Ring et al. ERJ Open Res. .

Abstract

Background: Paediatric diffuse alveolar haemorrhage (DAH) is a rare heterogeneous condition with limited knowledge on clinical presentation, treatment and outcome.

Methods: A retrospective, descriptive multicentre follow-up study initiated from the European network for translational research in children's and adult interstitial lung disease (Cost Action CA16125) and chILD-EU CRC (the European Research Collaboration for Children's Interstitial Lung Disease). Inclusion criteria were DAH of any cause diagnosed before the age of 18 years.

Results: Data of 124 patients from 26 centres (15 counties) were submitted, of whom 117 patients fulfilled the inclusion criteria. Diagnoses were idiopathic pulmonary haemosiderosis (n=35), DAH associated with autoimmune features (n=20), systemic and collagen disorders (n=18), immuno-allergic conditions (n=10), other childhood interstitial lung diseases (chILD) (n=5), autoinflammatory diseases (n=3), DAH secondary to other conditions (n=21) and nonspecified DAH (n=5). Median (IQR) age at onset was 5 (2.0-12.9) years. Most frequent clinical presentations were anaemia (87%), haemoptysis (42%), dyspnoea (35%) and cough (32%). Respiratory symptoms were absent in 23%. The most frequent medical treatment was systemic corticosteroids (93%), hydroxychloroquine (35%) and azathioprine (27%). Overall mortality was 13%. Long-term data demonstrated persistent abnormal radiology and a limited improvement in lung function.

Conclusions: Paediatric DAH is highly heterogeneous regarding underlying causes and clinical presentation. The high mortality rate and number of patients with ongoing treatment years after onset of disease underline that DAH is a severe and often chronic condition. This large international study paves the way for further prospective clinical trials that will in the long term allow evidence-based treatment and follow-up recommendations to be determined.

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Conflict of interest statement

Conflicts of interest: T. Bandeira reports personal fees from Sanofi and other support from Boehringer Ingelheim, outside the submitted work. Conflicts of interest: E.D. Manali reports other from Boehringer Ingelheim, other from Bering, other from Hoffman la Roche, outside the submitted work. Conflicts of interest: S. Papiris reports grants and other support from Boehringer Ingelheim and Hoffman la Roche, and other support from Savara, outside the submitted work. Conflicts of interest: M. Griese reports grants, personal fees and nonfinancial support from Boehringer Ingelheim for an advisory board on nintedanib, outside the submitted work. Conflicts of interest: The remaining authors have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Inclusion process and distribution of patients with diffuse alveolar haemorrhage (DAH). IPH: idiopathic pulmonary haemosiderosis; AID: autoimmune disease; chILD: childhood interstitial lung disease.
FIGURE 2
FIGURE 2
Symptoms and clinical presentation. The proportion of symptoms in each subgroup reported as percentages. Note: one patient may have more than one symptom. DAH: diffuse alveolar haemorrhage; IPH: idiopathic pulmonary haemosiderosis; chILD; childhood interstitial lung disease.
FIGURE 3
FIGURE 3
Medical treatment. a) Percentage of patients in each subgroup treated with systemic corticosteroids (CCS), hydroxychloroquine (HCQ), azathioprine or none of the above. b) Percentage of patients receiving different combination of treatment in each subgroup. Only patients who have received treatment are included. DAH: diffuse alveolar haemorrhage; IPH: idiopathic pulmonary haemosiderosis; chILD: childhood interstitial lung disease.
FIGURE 4
FIGURE 4
Radiology and follow-up. High-resolution computed tomography (HRCT) of two patients before and after medical treatment. a) Pre-treatment HRCT of a female patient with presentation of anaemia and recurrent lower respiratory infections with first appearance at age 2.1 years. HRCT was performed at time of diagnosis at age 4.8 years. b) Latest HRCT performed on same patient after 11 years of treatment with pulse methylprednisolone and hydroxychloroquine due to several relapses. HRCT shows incomplete response to treatment. Patient is still treated with pulses of methylprednisolone and hydroxychloroquine. c) Pre-treatment HRCT of female patient with presentation of cough, dyspnoea, tachypnoea, cyanosis, haemoptysis and recurrent lower airway infection at age 6 months. HRCT was performed at time of diagnosis at 2 years of age. d) Most recent HRCT after 7 years of treatment with pulse methylprednisolone and azathioprine due to several relapses. HRCT shows almost complete regression of pathological changes. Patient is out of treatment and considered healthy.
FIGURE 5
FIGURE 5
Patient outcome in the DAH cohort and the different subgroups presented as percentage: healthy; chronic clinically stable (chronic condition with impaired lung function and/or persistent abnormal radiology but off medication for DAH); active clinically stable (under current treatment); unstable (symptomatic and/or impaired lung function despite treatment); alive but unknown condition; unknown; and dead. DAH: diffuse alveolar haemorrhage; IPH: idiopathic pulmonary haemosiderosis; chILD; childhood interstitial lung disease.
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