Pulmonary hemosiderosis in children with Down syndrome: a national experience

Pulmonary hemosiderosis is a rare lung disease characterised by the triad hemoptysis, iron deficiency anaemia, alveolar and/or interstitial opacities on lung imaging. Bronchoalveolar lavage (BAL) and/or lung biopsy ascertain the diagnosis. The BAL fluid is bloody with a hemosiderin-laden macrophage ratio above 30% and/or a Golde score higher than 50 [1]. Its frequency is poorly documented, but some authors hypothesised an incidence of 0.24–1.23 per million [2]. In children, very few cases are described worldwide. An association with celiac disease (Lane-Hamilton syndrome) and cow milk protein intolerance (Heiner syndrome) has been reported [3‐6]. However, apart from the disease-specific condition, the aetiology and the pathophysiology of pulmonary hemosiderosis remain unknown. It is a chronic disease that commonly evolves in successive relapses separated by periods of remission. The prognosis is highly variable from a unique exacerbation with a complete recovery to multiple relapses with a risk of evolution toward lung fibrosis and terminal respiratory insufficiency. Corticosteroids are the mainstay of the treatment, with some children receiving also immunosuppressive drugs [7]. The French reference centre for rare lung diseases network RespiRare® previously reported a paediatric study population of 25 children aged 0.8 to 14 years old at diagnosis [8]. Two important findings were observed: 5 (20%) children presented with both pulmonary hemosiderosis and Down syndrome (DS), a percentage higher than expected; and at least one tested autoantibody was found positive in 50%. The present study aimed to investigate the newly documented relationships between pulmonary hemosiderosis and DS in the RespiRare® network.

Pulmonary hemosiderosis is a very rare disease in children, and its pathophysiology remains unclear. We report here our national experience through the RespiRare® network. This study highlights the surprising over-representation of DS in pulmonary hemosiderosis paediatric patients. DS is the most common genetic disorder, with a prevalence reaching 140 per 100,000 children [11]. Therefore, in our pulmonary hemosiderosis cohort population of 34 patients, 0 to 1 patient with DS was expected. However, nine children, i.e., around a quarter of the pulmonary hemosiderosis population, presented with DS. Pulmonary hemosiderosis in DS patients has not been reported on so far, except through isolated case reports [12, 13]. Moreover, based on our national findings, the estimated prevalence of pulmonary hemosiderosis in children reaches 1.85 per 1,000,000 children, compared to 138.5 per 1,000,000 DS children.

Patients with and without DS displayed remarkable differences. In the DS group, six patients out of 9 were younger than 3 years old at diagnosis, whereas in the non-DS patients, two-thirds of the patients were older than 3 years old [8, 14‐16]. Although hemoptysis is a classic sign of the disease, it was present in fewer than half of the patients, whereas dyspnoea was the most frequent respiratory symptom. DS patients seemed to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more secondary PAH and a major risk of fatal evolution.

In this study, autoimmunity stigma was documented in a large majority of the patients in both groups (75%, n = 24). The link between pulmonary hemosiderosis and the presence of circulating autoantibodies is not clearly understood in patients with no valid diagnosis criteria for vasculitis [8]. DS, particularly in men, is known to be associated with a high incidence of autoimmune disorders such as thyroiditis, hypothyroidism, type 1 diabetes, Addison disease, celiac disease, and other, rarer, disorders, including primary sclerosing cholangitis [17]. Lungs are not considered a privileged target for DS autoimmunity, but autoantibodies are frequently found in DS patients even with no evidence of clinical autoimmune disease [18]. Recent studies reported the crucial role in DS autoimmune dysfunction of the autoimmune regulator protein (AIRE) located on chromosome 21. AIRE is selectively expressed in the thymus and is a transcription factor for many tissue-restricted antigens that enhance the generation of regulatory T-cells and consecutively induce a central tolerance. It is presumed to protect against autoimmune diseases. Bi-allelic mutations of AIRE are associated with an autoimmune disease that is similar to the spectrum of autoimmunity observed in DS [19]. In DS, despite three expressed copies of AIRE, the overall AIRE expression was shown to be reduced compared to controls. All together, these findings favour a central role of AIRE in DS autoimmune disorders [20, 21]. Autoimmunity could be one of the links between DS and pulmonary hemosiderosis. In our study, several antibodies were found exclusively in DS or non-DS patients, but the majority of the patients had positive circulating antibodies, with no significant differences between groups. Surprisingly, DS patients did not receive more immunosuppressive agents than those of the non-DS group (P = 0.41). The reasons for fewer prescriptions of immunosuppressive drugs in DS patients are unclear. A hypothesis could be that clinicians were avoiding the risk of major sensitivity to chemotherapy in DS patients [22‐24].

Another hypothesis to explain the association between pulmonary hemosiderosis and DS could be an altered alveolar and vascular development of the lungs. It is known that children with DS have more microscopic pulmonary malformations and present an increased risk for PAH development, independently from cardiac malformations [25]. Histological descriptions have shown elements in favour of arrested lung development such as alveolar simplification, persistence of a double capillary network, prominence of a bronchial circulation or, more recently, intrapulmonary bronchopulmonary anastomoses [26]. Lung epithelial development is closely related to signalling from the vascular compartment: an inhibition of the vascular endothelial growth factor (VEGF) induces an altered angiogenesis and an abnormal alveolar structure development in the foetus [27]. Several anti-angiogenic factors are located on chromosome 21: endostatin (COL18A1), beta-amyloid protein (APP), and regulator of calcineurin 1 (RCAN1). These factors are overexpressed during the DS foetal period due to the three copies of the genes. It has recently been shown that their up-regulation in DS lung tissues was associated with a reduced vessel density and an increase of the vessel wall thickness compared to non-DS lung tissues [28]. The in-utero capillary development of the DS foetus is consistent with the hypothesis of an altered maturation of the capillary network of the alveoli and the absence of regression of the thick arterial musculature of the pulmonary vessels [29]. This impaired vascular development could be responsible for an altered alveolar maturation with simplified large alveoli. The reduced total alveolar surface associated with an abnormal capillary network could constitute a risk factor for hypoxemia, PAH and alveolar hemorrhage.

Patients with DS have additional risk factors for PAH due to chronic hypoxia and recurrent hypoxic events such as frequent congenital heart diseases, lung infections, recurrent aspirations, and obstructive sleep apnea syndrome (OSAS) [30]. OSAS is observed in up to half of adult DS patients [31]. In children, extreme prevalence between 0 and 100% has been reported in small cohorts [30, 32, 33]. Multiple factors can explain OSAS in children with DS, but the main causes include hypotonia, facial dysmorphia with macroglossia and narrow upper airways. It has also been suggested that tonsillar growth in the first months of life could increase the airway collapse [34]. Central apnoea reported in DS patients can also increase the OSAS severity. Untreated OSAS increases chronic hypoxia and, subsequently, PAH development. Altogether, in DS patients, the severity of pulmonary hemosiderosis could be due to the combination of a higher susceptibility to autoimmune lesions of the alveolar capillary, an abnormal lung capillary bed and a higher PAH risk. These pathophysiologic hypotheses could shed further new light on possible abnormal lung maturation in non-DS patients with pulmonary hemosiderosis.

This study reports for the first time a higher risk of severe pulmonary hemosiderosis in DS paediatric patients. Because alveolar bleeding symptoms can be inconspicuous, it could be suggested to perform a chest X-ray in all DS patients with chronic unexplained anaemia and/or chronic, unexplained dyspnoea. At this stage, only hypotheses can be proposed on the links between DS and pulmonary hemosiderosis such as an increased risk of PAH. If such a hypothesis is confirmed by further studies, systematic sleep investigations in DS patients could be proposed to screen for OSAS and to prevent PAH. For all pulmonary hemosiderosis patients, with or without DS, autoimmune explorations are critical at diagnosis and may be repeated regularly. In the era of genomic research, DS patients’ aggregation in such a rare disease could be a real opportunity to link chromosome 21 genes to new pathophysiologic clues for pulmonary hemosiderosis.