Children with ADA SCID commonly suffer from a
Children with ADA-SCID commonly suffer from a variety of opportunistic infections, including viral, fungal, and mycobacterial infections. Due to defects in T7 High Yield RNA Synthesis and IG production, they are also susceptible to infection with encapsulated bacteria such as Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Persistent infections with opportunistic organisms, including Candida albicans, VZV, Aspergillus, and Cryptosporidium are not uncommon and may lead to serious complications or death. Infections of the respiratory tract (upper respiratory tract, rhinitis, bronchitis, nasopharyngitis, pneumonia, and sinusitis) and gastrointestinal tract (gastroenteritis/enteritis along with diarrhea) were the most frequently reported AEs in this study. UTIs were identified as events of special interest because the observed overall incidence (especially in males) was higher than expected. Importantly, all male patients with UTIs also had conditions that predispose for UTI, and the rate of UTIs in the 3-year follow-up period was comparable to those estimated for the general US pediatric population. No males reported UTIs during the 7-year and >8-year follow-up phases. During the 3-year and 7-year follow-up phases, the rate of Candida infection was higher than that published for the general UK pediatric population, but the rate of Varicella infection was comparable to other socialized European children. During the 3-year follow-up period, gastroenteritis occurred at a higher rate than is observed for the general pediatric population, but there were no reports of gastroenteritis during the 7-year and ≥8-year follow-up periods. Infection incidence rates were highest in the pre-treatment to 3-month hospitalization period and decreased with time, a finding expected in subjects undergoing immune reconstitution. Generally, incidence rates dropped over time until they were similar to those reported for the general pediatric population. AEs in the blood and lymphatic system organ class (including anemia, neutropenia, and thrombocytopenia) were most frequently reported during the 3-month follow-up phase. As expected, the majority of these events occurred within the first 35 days post-GT, indicating that they were likely a consequence of conditioning with busulfan; granulocytopenia, thrombocytopenia, and anemia are all adverse drug reactions reported for busulfan therapy. Hepatic events were identified as special interest due to the known association of busulfan with elevations in transaminases and hepatic veno-occlusive disease (VOD). The incidence of hepatic enzyme increases peaked immediately following busulfan treatment during 3-month follow-up and then declined. These events are consistent with those commonly associated with bone marrow transplantation and are likely reduced in number and severity due to the low-dose regimen applied here. No VOD events were reported. CNS abnormalities are frequently reported manifestations of ADA-SCID, including in long-term survivors of bone marrow transplantation (BMT). Reported neurological deficits include cognitive impairment (mental retardation, low IQ, reduced verbal skills, and learning disabilities), behavioral abnormalities, sensorineural hearing deficits, motor dysfunction, developmental delays, hypotonia, and abnormal brain MRIs. PEG-ADA treatment prior to SCT does not seem to correct these impairments, despite the previously reported improvement of neurologic manifestations in two patients following reduction of metabolite concentrations. In a cross-sectional study of 105 patients with congenital immunodeficiencies surviving after SCT (56 of whom had SCID or ADA-SCID), it was reported that the underlying genetic disease, presence of ADA-SCID, and consanguinity were each associated with a worse intelligence outcome. Moreover, patients who had a more severe clinical course (i.e., admission to the intensive care unit) had a worse neurocognitive outcome post-SCT. Lower socioeconomic status was also associated with poor outcomes, while the age at transplantation, length of stay in the hospital, and conditioning regimen were not considered significant risk factors. Unsurprisingly, most patients described here reported neurological findings at baseline despite prior receipt of ERT. These manifestations may have been related to the underlying ADA-SCID pathology, sequelae from previous infections (e.g., meningitis, otitis media), and/or prior antibiotic treatment (e.g., gentamycin). Here, we report additional neurologic and hearing AEs post GT; however, we are unable to differentiate between the underlying disease state and GT-related procedures/medications (SCT, busulfan conditioning, and antibiotic prophylaxis/treatment) as potentially contributing factors. There was no indication that baseline neurological AEs improved following GT.