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Background With the recent approval of COVID‐19 vaccines, recovered COVID‐19 subjects who are vaccinated may be ideal candidates to donate COVID‐19 convalescent plasma (CCP). Case Series Eleven recovered COVID‐19 patients were screened to donate CCP. All had molecularly confirmed COVID‐19, and all but one were antibody positive by chemiluminescence immunoassay (DiaSorin) prior to vaccination. All were tested again for antibodies 11–21 days after they were vaccinated (Pfizer/Moderna). All showed dramatic increases (~50‐fold) in spike‐specific antibody levels and had at least a 20‐fold increase in the IC50 neutralizing antibody titer based on plaque reduction neutralization testing (PRNT). The spike‐specific antibody levels following vaccination were significantly higher than those seen in any non‐vaccinated COVID‐19 subjects tested to date at our facility. Conclusion Spike‐specific and neutralizing antibodies demonstrated dramatic increases following a single vaccination after COVID‐19 infection, which significantly exceeded values seen with COVID‐19 infection alone. Recovered COVID‐19 subjects who are vaccinated may make ideal candidates for CCP donation.

A Renal Genetics Clinic (RGC) was established to optimize diagnostic testing, facilitate genetic counseling, and direct clinical management.Retrospective review of patients seen over a two-year period in the RGC.One hundred eleven patients (mean age: 39.9 years) were referred to the RGC: 65 for genetic evaluation, 19 for management of a known genetic disease, and 18 healthy living kidney donors (LKDs) and their 9 related transplant candidates for screening. Forty-three patients underwent genetic testing with a diagnosis in 60% of patients including 9 with Alport syndrome, 7 with autosomal dominant polycystic kidney disease (ADPKD), 2 with genetic focal segmental glomerulosclerosis (FSGS), 2 with PAX2-mediated CAKUT, and 1 each with autosomal recessive polycystic kidney disease (ARPKD), Dent, Frasier, Gordon, Gitelman, and Zellweger syndromes. Four of 18 LKDs were referred only for APOL1 screening. For the remaining 14 LKDs, their transplant candidates were first tested to establish a genetic diagnosis. Five LKDs tested negative for the familial genetic variant, four were positive for their familial variant. In five transplant candidates, a genetic variant could not be identified.An RGC that includes genetic counseling enhances care of renal patients by improving diagnosis, directing management, affording presymptomatic family focused genetic counseling, and assisting patients and LKDs to make informed decisions.

Purpose A Renal Genetics Clinic (RGC) was established to optimize diagnostic testing, facilitate genetic counseling, and direct clinical management. Methods Retrospective review of patients seen over a two-year period in the RGC. Results One hundred eleven patients (mean age: 39.9 years) were referred to the RGC: 65 for genetic evaluation, 19 for management of a known genetic disease, and 18 healthy living kidney donors (LKDs) and their 9 related transplant candidates for screening. Forty-three patients underwent genetic testing with a diagnosis in 60% of patients including 9 with Alport syndrome, 7 with autosomal dominant polycystic kidney disease (ADPKD), 2 with genetic focal segmental glomerulosclerosis (FSGS), 2 with PAX2-mediated CAKUT, and 1 each with autosomal recessive polycystic kidney disease (ARPKD), Dent, Frasier, Gordon, Gitelman, and Zellweger syndromes. Four of 18 LKDs were referred only for APOL1 screening. For the remaining 14 LKDs, their transplant candidates were first tested to establish a genetic diagnosis. Five LKDs tested negative for the familial genetic variant, four were positive for their familial variant. In five transplant candidates, a genetic variant could not be identified. Conclusion An RGC that includes genetic counseling enhances care of renal patients by improving diagnosis, directing management, affording presymptomatic family focused genetic counseling, and assisting patients and LKDs to make informed decisions.

BackgroundWith the recent approval of COVID-19 vaccines, recovered COVID-19 subjects who are vaccinated may be ideal candidates to donate COVID-19 convalescent plasma (CCP).Case SeriesThree recovered COVID-19 patients were screened to donate CCP. All had molecularly confirmed COVID-19, and all were antibody positive by chemiluminescence immunoassay (DiaSorin) prior to vaccination. All were tested again for antibodies 11 to 21 days after they received the first dose of the vaccine (Pfizer). All showed dramatic increases (∼50 fold) in spike-specific antibody levels and had at least a 20-fold increase in the IC50 neutralizing antibody titer based on plaque reduction neutralization testing (PRNT). The spike-specific antibody levels following vaccination were significantly higher than those seen in any non-vaccinated COVID-19 subjects tested to date at our facility.ConclusionSpike-specific and neutralizing antibodies demonstrated dramatic increases following a single vaccination post COVID-19 infection which significantly exceeded values seen with COVID-19 infection alone. Recovered COVID-19 subjects who are vaccinated may make ideal candidates for CCP donation.

Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM Pegunigalsidase alfa, a novel PEGylated, covalently crosslinked form of α-galactosidase A developed as enzyme replacement therapy (ERT) for Fabry disease (FD), was designed to increase plasma half-life and reduce immunogenicity, thereby enhancing efficacy compared with available products. Symptomatic adults with FD participated in this open-label, 3-month dose-ranging study, followed by a 9-month extension. Three cohorts were enrolled in a stepwise manner, each receiving increased doses of pegunigalsidase alfa: 0.2, 1.0, 2.0 mg/kg, via intravenous infusion every other week. Pharmacokinetic analysis occurred on Day 1 and Months 3, 6, and 12. Kidney biopsies at baseline and Month 6 assessed peritubular capillary globotriaosylceramide (Gb3) content. Renal function, cardiac parameters, and other clinical endpoints were assessed throughout. Treatment-emergent adverse events (AEs) and presence of immunoglobulin G (IgG) antidrug antibodies (ADAs) were assessed. Sixteen patients completed 1 year's treatment. Mean terminal plasma half-life (each cohort) ranged from 53 to 121 hours. All 11 male and 1 of 7 female patients presented with classic FD phenotype, in whom renal peritubular capillary Gb3 inclusions were reduced by 84%. Mean estimated glomerular filtration rate was 111 mL/min/1.73 m 2 at baseline, remaining stable throughout treatment. Three patients developed treatment-induced IgG ADAs; following 1 year's treatment, all became ADA-negative. Nearly all treatment-emergent AEs were mild or moderate. One patient withdrew from the study following a serious related AE. Pegunigalsidase alfa may represent an advance in ERT for FD, based on its unique pharmacokinetics and apparent low immunogenicity.

Pegunigalsidase alfa, a novel α-galactosidase-A enzyme for the treatment of Fabry disease (FD) is a stable, homo-dimeric PEGylated protein, previously demonstrated (Hughes et al, LDN-2016) to have substantially improved pharmacokinetics (PK) parameters compared to the two currently available enzyme replacement therapies (ERTs). The ongoing phase 3 trial “BRIGHT” (PB-102-F50, NCT03180840) is an open-label switch-over study assessing safety, PK, and efficacy of pegunigalsidase alfa (2 mg/kg) given every 4 weeks for 52 weeks to FD patients previously treated with either agalsidase alfa or agalsidase beta. Aim of the study: to explore a more convenient dosing regimen exploiting the improved PK characteristics of pegunigalsidase alfa, as shown by PK modelling from the Phase 1-2 study results (Warnock et al, LDN-2017). The trial will enroll up to 30 patients without severe clinical symptoms and relatively slow disease progression, as evaluated by the investigator. Pegunigalsidase alfa plasma levels are measured at multiple time points before, during, and up to 28±3 days post-infusion for PK evaluation. Preliminary PK results, from the first 15 patients, show a half-life of ~80 hours and persistent plasma levels over the entire 4-week dosing interval, with a mean concentration on day 28 post-infusion of 138 ± 42 ng/mL. The Area Under the Curve (AUC) of day 0-28 was found to be 2,126,091 ng*h/mL, of which the mean partial AUC during the 4th week was ~30,000 ng*h/mL confirming the study assumption. The AUC of day 0-28 is significantly greater than agalsidase beta (AUC0-∞

As other states have added Lysosomal Storage Disorderls (LSDs) to their newborn screening (NBS) programs, some families have crossed borders and sought confirmatory testing and follow-up care in Iowa. With the addition of Pompe disease and Mucopolysaccharidosis type I (MPS I) to the Recommended Uniform Screening Panel (RUSP) in 2013 and 2015, respectively, states in the Midwest (including Missouri, Illinois, Minnesota, Wisconsin, and Nebraska) have begun screening for a variety of LSDs. While Iowa does not presently screen for LSDs on NBS, four children have come to our genetics clinic for second tier testing based on positive Fabry disease Illinois NBS results. Three males from Illinois with A143T GLA mutations were seen in our clinic for follow-up NBS testing. Two of these were siblings for familial mutation analysis and the third needed confirmatory testing for Fabry disease and subsequent familial analysis for at-risk members. We now follow the three boys and five additional positive family members. Another male infant was referred to us by his primary care provider for a presumptive positive Fabry NBS. The child and subsequently his mother were found to have a c.1072_1074del mutation in the GLA gene. Mutation analysis is pending on additional family members. A Fabry family identified by Missouri newborn screening on a male child relocated to Iowa and is now in our care. Since moving to Iowa they have had two additional children, both with Fabry disease. Two children with MPS 1 pseudodeficiencies, one confirmed and one pending confirmation, were sent to us from Illinois for second tier testing. As the number of LSD patients identified through NBS increases due to surrounding states, we will adapt our clinic processes to incorporate the influx of patients and their families. This experience will prove valuable if and when Iowa begins NBS for LSDs.

Fabry disease (FD) is a pan-ethnic, X-linked, progressive lysosomal storage disorder caused by pathogenic mutations in the GLA gene. Published case reports and abstracts suggest that decreased reproductive fitness may occur in males with FD. In order to understand the impact of FD on reproductive fitness and increase the accuracy of reproductive genetic counseling, this study examines a large, multi-centered population of individuals with FD to determine if males have reduced reproductive fitness. Study data were collected on 376 patients through two, gender-specific surveys distributed across the United States and Canada. The number of biological live-born children among individuals with FD was compared to statistics from the general population. Information was also collected on reduced sperm count, depression, pain, use of assisted reproductive technology, and reproductive choice. On average, females affected by FD had more biological live-born children (1.8) than males affected by FD (1.1). However, males affected by FD had an increased mean number of biological children (1.1) compared to the mean number of biological children fathered by men in the United States (0.9). Sixteen of the 134 males with FD reported oligospermia, which suggests that an infertility work up may be indicated for males having difficulty impregnating their partners. In our large multicenter sample, males and females with FD do not exhibit reduced reproductive fitness; on average they have more biological children than the general population in the United States. This information should assist clinicians in providing accurate reproductive genetic counseling and treatment for individuals with FD.

Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified. Trial Registration ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01196871","term_id":"NCT01196871"}}NCT01196871

An infant who received haploidentical BM for severe combined immunodeficiency (SCID) developed acute, reversible complete heart block in association with an exacerbation of GVHD. Respiratory distress and myocardial dysfunction were also seen with this and previous GVHD exacerbations. The patient had not received chemotherapy or radiation prior to BMT. The complete heart block resolved after 1 week of intensive immunosuppression. The association of complete heart block with GVHD is important because the heart block is potentially reversible with prompt, aggressive control of the GVHD.

We prospectively studied immune reconstitution in 102 children who underwent T-lymphocyte depleted bone marrow transplants using either closely matched unrelated donors or partially matched familial donors by assaying total lymphocyte counts (TLC), T-cell subsets, B cells, and natural killer cells. TLC, CD3+, and CD4+ T-cell counts remained depressed until 2 to 3 years posttransplant, whereas CD8+ T-cell counts normalized by 18 months, resulting in an inverted CD4:CD8 ratio until 12 months posttransplant. Although the percentage of NK cells was elevated early posttransplant, their absolute numbers remained normal. CD20+ B cells were depressed until 12 to 18 months posttransplant. Factors affecting immunophenotypic recovery were analyzed by nonparametric statistics. Younger patients tended to have higher TLC posttransplant. Higher marrow cell doses were not associated with hastened immunophenotypic recovery. Graft-versus-host disease (GVHD) and/or its treatment significantly delayed the immune reconstitution of CD3+, CD4+, and CD20+ cells. The presence of cytomegalovirus was associated with increased CD8+ counts and a decrease in the percentages of CD4+ and CD20+ cells.

Acute lymphoblastic leukemia of childhood is the most common malignant disease in children greater than 1 year of age. Chemotherapy has improved the survival of children with this disorder. More than 95% of children will achieve a remission with chemotherapy. However, 30% of children with acute lymphoblastic leukemia who achieved a remission will have a relapse sometime after successful remission-inducing chemotherapy. Although a second remission can be induced in most of these children, in 10-40% a remission cannot be induced or they relapse shortly thereafter and develop refractory leukemia. We present in this preliminary report the early results of therapy for refractory leukemia with an intensive preparative regimen for bone marrow transplantation including etoposide, cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Transplantation was done in twenty-three patients with refractory leukemia. Projected survival at 917 days after transplantation in these patients is 43.4% +/- 11%. The survival of these patients so far is similar to the survival of children with acute lymphoblastic leukemia transplanted in second remission. All patients treated with this regimen who had transplantation in relapse were free of leukemia 27 days after transplantation. The results of this preliminary report suggest that an intensive preparative regimen can improve the outlook of refractory leukemia and may rescue some patients who otherwise would have died of their disease.

T cell depletion (TCD) of marrow is a proven method of graft-versus-host disease (GVHD) prophylaxis in allogeneic bone marrow transplantation (BMT). Nonetheless, TCD is associated with an increased risk of developing post transplant lymphoproliferative disorder (PTLD). Between 1986 and 1998, 241 pediatric patients at the University of Iowa underwent BMT using ex vivo TCD of marrow from mismatched related or matched unrelated donors. Additional GVHD prophylaxis included antithymocyte globulin (ATG) or anti lymphocyte globulin (ALG) post transplant (in vivo TCD). A total of 30 cases of PTLD were identified based upon a combination of clinical, histological, and immunological features. Nearly all cases occurred within 3 months post BMT. A statistically significant increase in PTLD incidence was noted for patients treated with ATG vs ALG (33 vs 9%). While grade I–II acute GVHD was more common in patients receiving ATG vs ALG, no difference in grade III–IV GVHD or overall survival was noted between the two groups. Assessment of immune recovery at various times post BMT revealed significantly fewer T cells in the ATG-treated group, suggesting the deleterious effect of ATG may be due to excessive depletion of donor-derived Epstein–Barr virus-specific cytotoxic T cells. Thus, caution should be exercised in the use of anti-T-cell antibody therapy for additional GVHD prophylaxis in the setting of TCD BMT.

Shwachman-Diamond syndrome (SDS) is a rare genetic disorder characterized by pancreatic insufficiency, short stature, skeletal abnormalities and bone marrow dysfunction. Patients with SDS have varying degrees of marrow aplasia, which can be severe or progress to leukemic transformation. While allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for the hematologic disturbances of SDS, a recent review of the literature reveals few survivors. Poor outcome with HSCT is often related to excessive cardiac and other organ toxicity from transplant preparative therapy. We describe two young children with SDS who developed aplastic anemia and subsequently underwent successful allografting using a non-cardiotoxic conditioning regimen. Case 1 received marrow from an HLA-identical sibling while case 2 received partially matched umbilical cord blood from an unrelated donor. Both patients are presently alive and well with sustained donor engraftment and excellent hematopoietic function at 36 and 22 months post-HSCT.

Children who require a marrow transplant may receive such hematopoietic cells from one of many sources. This study reviews the experience of one center with 58 children who received marrow from unrelated donors over a 10-year period. These children had a variety of malignant and non-malignant diseases. During that time period, only three of these children had failed to meet engraftment criteria. All donor marrow specimens were T-lymphocyte depleted using an antibody/complement methodology. No difference was demonstrated in outcome between donors who were perfectly HLA-DR–DNA matched versus those who were only partially matched. The increased size of various marrow donor registries has increased the number of potential donors available for these patients. The lack of a requirement for perfect matching means that there is an ever-increasing number of donors available. No graft-versus-host disease (GvHD) or grade III-IV GvHD was associated with a poorer outcome. Stable, long-term engraftment with minimal morbidity has been demonstrated in these children as evidenced by stability of survival curves by two years after marrow transplant.

Reconstitution of the immune system following T-cell-depleted bone marrow transplantation (BMT) in children has yet to be fully elucidated. Thus, we prospectively studied the recovery of immune function in 64 children who underwent T-lymphocyte-depleted marrow transplants using either matched family member donors or matched unrelated donors. We measured in vitro posttransplantation proliferative responses to phytohemagglutinin (PHA), concanavalin A, pokeweed mitogen, and Candida albicans antigen and assessed unidirectional allogeneic mixed-lymphocyte culture (MLC) responses at various times. A total of 129 healthy individuals served as normal controls for these assays. Responses to T-cell mitogens normalized within 12 months posttransplantation, while MLC responses normalized by 9 months. The presence of graft-versus-host disease (grade II or greater) and cytomegalovirus infection was associated with delays in immune function recovery. Importantly, immune function recovery correlated temporally with a rise in peripheral lymphocyte count. In contrast, the CD4/CD8 ratio was not predictive of immune recovery. Knowledge of immune function recovery may guide clinicians in devising strategies to minimize the risk of infection post-BMT.

David Warnock, Daniel Bichet, Myrl Holida, Ozlem Goker-Alpan, Kathy Nicholls, Mark Thomas, Francois Eyskens, Suma Shankar, Majed Dasouki, Franklin Johnson, Pol Boudes, University of Alabama at Birmingham, Birmingham, AL, USA, Hopital du Sacre-Coeur, Montreal, QC, Canada, University of Iowa Children's Hospital, Iowa City, IA, USA, O&O Alpan, LLC, Springfield, VA, USA, Royal Melbourne Hospital, Parkville, Australia, Linear Clinical Research, Perth WA, Australia, Universitair Ziekenhuis Antwerpen, Edegem, Belgium, Emory University, Decatur, GA, USA, University of Kansas, Kansas City, KS, USA, Amicus Therapeutics, Cranbury, NJ, USA

Acute atrial fibrillation appreciably alters atrial physiology by increasing atrial blood flow and atrial oxygen consumption. To determine the effects of atrial fibrillation on atrial vasodilator reserve atrial fibrillation was produced in dogs by electrical atrial stimulation. Reactive hyperaemic responses were measured using Doppler crystals fixed to the sinus node artery and to an adjacent right ventricular branch artery during sinus rhythm, after 20 minutes of atrial fibrillation, and after systemic administration of chromonar (a potent coronary dilator) during atrial fibrillation. During sinus rhythm the peak to resting blood flow velocity ratio after a 20 s occlusion of the sinus node artery was 3.2(1) (mean(SEM)). A 20 s occlusion of a right ventricular branch artery during sinus rhythm resulted in a significantly larger response (5.9(0.7). The repayment to debt area ratio in response to a 20 s occlusion was 1.1(0.2) for the sinus node artery but 3.9(1.0) for a right ventricular branch. During atrial fibrillation the peak to resting velocity ratio was substantially decreased in the sinus node artery (2.3(0.6)) but was not significantly changed in the right ventricular branch (4.4(0.6)). Atrial fibrillation plus chromonar abolished reactive hyperaemia in both the sinus node artery and the right ventricular branch vessel. Right atrial blood flow (microspheres) increased from 45(4) in sinus rhythm to 106(19) ml X min-1 X 100 g-1 in atrial fibrillation and to 208(22) ml X min-1 X 100 g-1 after chromonar administration during atrial fibrillation. Thus the quantitative characteristics of coronary reactive hyperaemia in the right atrium were substantially different from those in the right ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)