This study suggested that long-term low-dose glucocorticoid maintenance therapy could improve the prognosis of IPH and prevent the recurrence of alveolar hemorrhage. However, possible side effects should be monitored. This study provides a clinical basis for the prognosis and detection of adverse effects in children with long-term glucocorticoid therapy for IPH.
The typical clinical symptoms of IPH were cough, shortness of breath with hemoptysis and respiratory symptoms, microcytic hypochromic anemia, and pulmonary infiltrates on chest imaging. However, in pediatric patients, respiratory symptoms are often lacking in the early stages of the disease, resulting in a late diagnosis and an increased rate of misdiagnosis 7. In a previous study, the mean time from onset to diagnosis was 10.46 months 13. Most children were diagnosed within 1 year of onset in our study, which is consistent with the previous literature 14.
Glucocorticoids are the first-line drugs for treating IPH that can improve the clinical manifestations in all stages of IPH by inhibiting inflammatory response, reducing bleeding and hematocrit uptake by macrophages, and delaying pulmonary fibrosis 11,12. In our study, acute alveolar hemorrhage was treated with glucocorticoids, and the patients treated with glucocorticoids alone were likely to achieve clinical remission, suggesting that glucocorticoids not only control acute alveolar hemorrhage but that maintenance treatment with low-dose glucocorticoids can reduce the recurrence of alveolar hemorrhage.
The long-term use of glucocorticoids can affect the growth and development of children and cause cataracts; however, this is easily overlooked compared with severe recurrent alveolar hemorrhage. In our study, cataracts occurred in four children who had more than three recurrences and had been using glucocorticoid for more than 4 years during the follow-up period, and the mean age of cataract onset was 6 years. Therefore, the occurrence of cataracts should be monitored in preschool and school-age children on long-term glucocorticoid use.
In our study, 33/195 (16.9%) of the children had a short stature, of which 39.4% (13/33) had recurrent alveolar hemorrhage. In addition, 20/33 (60.6%) had a history of > 5 years (including one patient in clinical remission). The rate of short stature in recurrent cases was significantly higher than in non-recurrent cases. Patients with recurrent alveolar hemorrhage are more likely to receive repeated high-dose oral corticosteroids, which might be an important factor affecting the height of children with recurrent IPH. Indeed, although corticosteroids are required for the management of a number of conditions in children, including IPH, their use is associated with growth retardation and impaired bone health 15. The cumulative dosage of corticosteroids is associated with a slower linear growth 16,17. This is a problem worthy of attention by clinicians and further research.
Immunosuppressants can be considered for children with recurrent alveolar hemorrhage who are receiving glucocorticoid maintenance therapy18. Immunosuppressants can effectively reduce both the recurrence of alveolar hemorrhage and the side effects of repeated high-dose glucocorticoids in children. Commonly used immunosuppressive agents include hydroxychloroquine, 6-mercaptopurine, azathioprine, cyclophosphamide, and methotrexate 10. In our study, 27.69% (54/195) of children received a combination of glucocorticoid and immunosuppressive agents, including 39 cases of azathioprine and 11 cases of hydroxychloroquine, and the outcomes of 66.67% (36/54) cases were improved, including 32 cases remained stable, and four cases discontinued the medication and achieved clinical remission. These results suggest that most relapsed patients can benefit from the combination of immunosuppressive therapy (including azathioprine or hydroxychloroquine).
There are some limitations in this study. This was an observational study with a relatively small sample size. Besides, no controls were included. Furthermore, as a retrospective study, the possible side effect such as adrenocortical function was not recorded. Thus, the result should be further confirmed in a larger randomized controlled study.