In the US, the assay of T cell receptor excision circles (TRECs) in newborn dried blood spot specimens to detect severe combined immunodeficiency (SCID) was first piloted in 2008 in the state of Wisconsin. It has been rapidly adopted with 49 states and Puerto Rico now either routinely screening all newborns or planning to do so in 2017. Advances in SCID NBS over the last 9 years have revolutionized the ability to detect SCID and has led to profound improvement in outcomes of affected children.

A strong association between rubella virus (RuV) and chronic granulomas, in individuals with inborn errors of immunity, has been recently established. Both the RA27/3 vaccine and wild-type RuV strains were highly sensitive to a broad-spectrum antiviral drug, nitazoxanide (NTZ), in vitro. However, NTZ treatment, used as a salvage therapy, resulted in little or no improvements of RuV-associated cutaneous granulomas in patients. Here, we report investigations of possible causes of treatment failures in two ataxia-telangiectasia patients. Although a reduction in RuV RNA in skin lesions was detected by real-time RT-PCR, live immunodeficiency-related vaccine-derived rubella viruses (iVDRV) were recovered from granulomas, before and after the treatments. Tizoxanide, an active NTZ metabolite, inhibited replications of all iVDRVs in cultured A549 cells, but the 50% and 90% inhibitory concentrations were 10-40 times higher than those for the RA27/3 strain. There were no substantial differences in iVDRV sensitivities, neither before nor after treatments. Analysis of quasispecies in the E1 gene, a suspected NTZ target, showed no effect of NTZ treatments on quasispecies' complexity in lesions. Thus, failures of NTZ therapies were likely due to low sensitivities of iVDRVs to the drug, and not related to the emergence of resistance, following long-term NTZ treatments.

Background

Cytomegalovirus (CMV) serostatus of recipient (R) and donor (D) influences hematopoietic stem cell transplant (HSCT) outcome. However, it is not a reliable indicator of CMV infection in primary immunodeficiency disorder (PIDD) recipients who are unable to make adequate antigen-specific immunoglobulin (Ig) or who receive intravenous Ig (IVIg) prior to testing.

Objective

Since no data exist on PIDD with unknown CMV serostatus, we aimed to evaluate the relationship between pre-HSCT recipient and donor serostatus and incidence of CMV infection in recipients with unknown serostatus.

Methods

A retrospective analysis of all pediatric PIDD HSCTs (2007-2018) was performed at University of California San Francisco. Recipients were separated into categories based on pre-transplant serostatus: 1) seropositive (R(+)), 2) seronegative (R(-)), and 3) unknown serostatus (R(x)). Patients with pre-HSCT active CMV viremia were excluded.

Results

A total of 90 patients were included, 69% male. The overall incidence of CMV infection was 20%, but varied in R(+), R(-), and R(x) at 80%, 0%, and 14%, (P-value = .0001). Similarly, 5-year survival differed among groups, 60% R(+), 100% R(-), and 90% of R(x) (P-value = .0045). There was no difference in CMV reactivation by donor serostatus (P-value = .29), however, faster time to clearance of CMV was observed for R(x)/D(+) group (median 9.5 days (IQR 2.5-18), P-value = .024).

Conclusion

We identify a novel group of recipients, R(x), with an intermediate level of survival and CMV incidence post-HSCT, when compared to seropositive and seronegative recipients. No evidence of CMV transmission from D(+) in R(-) and R(x) was observed. We believe R(x) should be considered as a separate category in future studies to better delineate recipient risk status.

Severe combined immunodeficiency (SCID) is characterized by severely impaired T-cell development and is fatal without treatment. Newborn screening (NBS) for SCID permits identification of affected infants before development of opportunistic infections and other complications. Substantial variation exists between treatment centers with regard to pretransplantation care, and transplantation protocols for NBS identified infants with SCID, as well as infants with other T-lymphopenic disorders detected by using NBS. We developed approaches to management based on the study of infants identified by means of NBS for SCID who received care at the University of California, San Francisco (UCSF). From August 2010 through October 2016, 32 patients with NBS-identified SCID and leaky SCID from California and other states were treated, and 42 patients with NBS-identified non-SCID T-cell lymphopenia were followed. Our center's approach supports successful outcomes; systematic review of our practice provides a framework for diagnosis and management, recognizing that more data will continue to shape best practices.

In the United States, newborn screening (NBS) is currently recommended for identification of 31 debilitating and potentially fatal conditions. However, individual states determine which of the recommended conditions are screened. The addition of severe combined immunodeficiency (SCID) screening to the recommended NBS panel has been fully instituted by 18 states, with another 11 states piloting programs or planning to begin screening in 2014. Untreated, SCID is uniformly fatal by 2 years of age. Hematopoietic stem cell transplantation usually is curative, but the success rate depends on the age at which the procedure is performed. Short-term implementation costs may be a barrier to adding SCID to states' NBS panels. A retrospective economic analysis was performed to determine the cost-effectiveness of NBS for early (<3.5 months) versus late (≥3.5 months) treatment of children with SCID at 3 centers over 5 years. The mean total charges at these centers for late treatment were 4 times greater than early treatment ($1.43 million vs $365,785, respectively). Mean charges for intensive care treatments were >5 times higher ($350,252 vs $66,379), and operating room-anesthesia charges were approximately 4 times higher ($57,105 vs $15,885). The cost-effectiveness of early treatment for SCID provides a strong economic rationale for the addition of SCID screening to NBS programs of other states.

Regulatory T cells are a population of CD4+ T cells that play a critical role in peripheral tolerance and control of immune responses to pathogens. The purpose of this study was to measure the percentages of two different regulatory T cells subpopulations,

Regulatory T cells are a population of CD4+ T cells that play a critical role in peripheral tolerance and control of immune responses to pathogens. The purpose of this study was to measure the percentages of two different regulatory T cells subpopulations, identified by the presence or absence of CD31 (Recent thymic emigrants and peripherally induced naïve regulatory T cells), in term and preterm infant cord blood. We report the association of prenatal factors, intrauterine exposure to lipopolysaccharide and inflammation and the percentages of these regulatory T cell subpopulations in term and preterm infants. Cord blood samples were collected from both term and preterm infants and mononuclear cells isolated over a Ficoll-Hypaque cushion. Cells were then stained with fluorochrome-labeled antibodies to characterize regulatory T cell populations and analyzed with multi-color flow cytometry. Cord blood plasma C-reactive protein, and lipopolysaccharide were also measured. Placental pathology was also examined. We report a gestational age-dependent difference in the percentage of total regulatory T cells, in which preterm infants of lower gestational ages have an increased percentage of regulatory T cells. We report the presence of two populations of regulatory T cells (CD31+ and CD31-) in cord blood of term and preterm infants and their association with different maternal and fetal characteristics. Factors associated with differences in the percentage of CD31- Tregs included the use of prenatal antibiotics, steroids and magnesium sulfate. In addition, the percentage of CD31- Tregs was significantly higher in cord blood of preterm pregnancies associated with inflammation and prenatal lipopolysaccharide exposure. The peripheral Treg pool of preterm infants could be altered by prenatal exposure to inflammation and chorioamnionitis; however, the clinical implications of this finding are not yet understood.

To evaluate the relationship between knowledge of genetic diagnosis before HSCT and outcome, we reviewed all HSCTs for primary immune deficiencies (PID) performed at UCSF from 2007 through 2018. SCID, a distinct entity identified since 2010 in California by newborn screening and treated early, was considered separately. The underlying genetic condition was known at the time of HSCT in 85% of cases. Graft failure was less frequent in patients with a genetic diagnosis (19% with a genetic diagnosis versus 47% without, p = 0.020). Furthermore, event-free survival and overall survival (OS) at 5 years were better for those with a genetic diagnosis (78% with versus 44% without, p = 0.006; and 93% versus 60% without, p = 0.0002, respectively). OS at 5 years was superior for known-genotype patients with both SCID (p = 0.010) and non-SCID PID (p = 0.010). There was no difference in OS between HSCT done in 2007-2010 compared to more recently (p = 0.19). These data suggest that outcomes of HSCT for PID with known genotype may reflect specific experience and literature, or that a substantial proportion of patients with PID of undetermined genotype may have had underlying conditions for which HSCT may carry greater risk. The higher rate of graft failure in PID with unknown genotype may be in part explained by insufficient conditioning, which in turn could be dictated by compromised organ function in patients undergoing HSCT late in the course. Widespread availability of PID gene sequencing as standard care can provide genetic diagnoses for most patients with PID prior to HSCT, permitting optimization of transplant approach.

To review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases. We systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and "breastmilk," "breast milk," "breastfeeding," or "lactation." From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria. One additional study was added after the literature search based on expert knowledge of an additional article. These 30 studies were reviewed. These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women. Drug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion. Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 1:20 for infliximab. Relative infant dose, a metric comparing the infant with maternal drug dose (<10% is generally considered safe), was evaluated for certolizumab (<1%), rituximab (<1%), and natalizumab (maximum of 5.3%; cumulative effects of monthly dosing are anticipated). Importantly, a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections. The current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development.