Metabolic, not microbial, pathogenesis likely for ADA-SCID lung disease
Published Date: 27/11/17Access Full Text Article
medwireNews: The underlying cause of the respiratory disease observed in patients with adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID) may be metabolic rather than microbial in nature, research suggests.
“Clinicians should be aware of this possibility and correct metabolic abnormalities either through enzyme replacement or haematopoietic stem cell transplant [HSCT], in addition to treating infectious complications”, say H Bobby Gaspar (Great Ormond Street Hospital National Health Service Trust, London, UK) and co-authors.
They compared 21 children diagnosed with ADA-SCID between 2000 and 2010 with 19 control patients who were diagnosed with X-linked SCID during the same period. Both sets of patients presented at similar ages, at a median of 2.0 months (range 1 week–2 years) and 4.5 months (range 1 week–9 months), respectively.
The groups were also comparable on the whole with respect to respiratory symptoms, with similar proportions of patients experiencing no, mild, moderate or severe symptoms. Gaspar et al note that mild symptoms were observed more frequently in children with ADA deficiency (47.6 vs 26.3%), whereas those with X-linked disease were more likely to have moderate symptoms (23.8 vs 42.1%), but the differences were not statistically significant.
The majority of patients in the ADA-SCID and X-linked SCID groups displayed abnormal radiological findings, at 90.0% and 88.8%, respectively. Commonly observed features included interstitial infiltrates, patchy opacification and bronchial wall thickening, which are indicative of inflammation and infection.
But evaluation of respiratory cultures from nasopharyngeal aspirates and broncheoalveolar lavage, where appropriate, showed that ADA-SCID patients were significantly less likely to have a positive microbiological test than controls, with corresponding rates of 33.3% and 89.4%.
There were also significant differences in terms of the isolated microbiological organisms – for instance, no child with ADA deficiency had a Pneumocystis jirovecii infection, while the organism was isolated from 11 of the 19 children with X-linked SCID.
In light of these data, published in the Journal of Clinical Immunology, the study authors propose that the high risk for opportunistic infections in patients with ADA-SCID “is not necessarily related to an infective cause but perhaps to a metabolic lung pathology driven by the purinergic defects seen in ADA deficiency.”
Interestingly, they found no correlation between erythrocyte deoxyadenosine triphosphate levels at diagnosis and the severity of lung symptoms, but it is possible that the erythrocyte concentrations “do not reflect the tissue levels which would be the critical factor in [the] development of respiratory disease.”
Gaspar et al remark that physicians may hesitate to initiate enzyme replacement therapy (ERT) prior to HSCT in patients newly diagnosed with ADA-SCID due to concerns that “ERT may reduce any selective advantage ADA replete cells will have at transplantation.”
But they suggest: “[I]n ADA-SCID patients with lung changes and symptoms, ERT should be commenced in addition to antimicrobial therapy while a donor search is undertaken. Detoxification of the lung environment is likely to improve respiratory symptoms and there is little data to suggest that ERT shortly before HSCT adversely affects donor cell engraftment or function.”
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