Purine nucleoside phosphorylase (PNP) deficiency causes inadequate purine metabolite detoxification, which leads to combined immunodeficiency and variable neurologic symptoms. Hematopoietic stem cell transplantation (HSCT) cures the immunodeficiency, but large studies on the long-term outcomes are lacking. In a retrospective study of the European Society for Blood and Marrow Transplantation, we investigated 46 patients with PNP deficiency from 21 centers. We analyzed the presenting clinical signs and outcomes after HSCT. Cognition (0-3), hearing (0-3), interaction (0-4), movement (0-4), and occupation (0-3) (CHIMO) were scored at the last follow-up (FU) visit (no impairment, 17; mild, 15-16; moderate, 12-14; and severe impairment, <12). The median age at initial presentation was 7.5 (1-48) months. The patients presented with infections (41%), neurological dysfunction (39%), both (15%), or autoimmune disease (5%). At the time of HSCT (median age, 26 [2-192] months), neurological abnormalities were observed in 88% of patients. After a median FU of 7.9 (1.0-22.3) years, 40 patients were alive with a 3-year overall survival (OS)/event-free survival (EFS) probabilities of 86% (confidence interval [CI], 77%-97%)/75% (CI, 64%-89%), respectively. High-level (>50%-100%)/low-level donor chimerism (11%-50%) was observed in 85%/15% of patients, respectively, leading to resolution of T lymphopenia. The median overall CHIMO score was 14 (6-17), while the median scores for each component were 3 (0-3), 3 (1-3), 4 (1-4), 3 (1-4), and 2 (0-3), respectively. Patients who underwent HSCT before 24 months after the initial presentation demonstrated superior OS (P = .049). Neurological symptoms that occurred before 11 months of age were associated with reduced OS (P = .027). While the overall results were satisfactory, earlier diagnosis could further improve outcomes.

Tetratricopeptide repeat domain 7A (TTC7A) deficiency is a primary immunodeficiency due to mutations in the TTC7A gene. It causes intestinal disease and a poorly characterized immunodeficiency, with poor long-term survival. We describe the clinical and immunological characteristics, management, and outcomes of an international cohort of patients with genetically confirmed TTC7A deficiency. Data from 61 patients from 13 countries were retrospectively analyzed. Overall survival was 64% (median follow-up 4.2 years), significantly higher in the inflammatory bowel disease than in the hereditary multiple intestinal atresia group (80 vs. 48%, P < 0.05). Infections represent the leading cause of death. Allogeneic stem cell transplantation was performed in 16 patients to correct the immunodeficiency but was associated with a significant transplant-related mortality (44%). Solid organ transplantation of the small bowel remains exceptionally rare (two patients). Malignancy/autoimmune disorders developed in 4 (6.5%) and 17 (28%) patients, respectively. TTC7A remains difficult to treat, and prognosis is dismal for affected patients. Further understanding of the disease mechanisms and development of innovative treatment approaches are required.

Prunotto et al. describe clinical presentation, immunological status, treatment, and long-term outcomes of a large cohort of pediatric and adult patients affected by an extremely complex and rare immunodeficiency known as TTC7A deficiency for which no clear therapeutic pathway is currently available.

BackgroundTranscription factor forkhead box protein N1 (FOXN1) is the master transcription factor required for differentiation and maintenance of thymic epithelial cells (TECs) and is not only required for embryonic thymus development but also for postnatal thymic maintenance. Autosomal recessive FOXN1 deficiency leads to alopecia, nail dystrophy, and nude severe combined immune deficiency (SCID) due to athymia requiring thymus transplantation. Dominant-negative (DN) heterozygous variants, on the other hand, have incomplete and highly variable phenotypes. We hereby present an international cohort of families carrying dominant-negative mutations with variable clinical presentation, course, and outcomes.MethodsPatient medical records and diagnosing physicians were consulted.ResultsWe present 15 FOXN1 DN heterozygotes from 7 different families across the world, demonstrating highly variable intrafamilial clinical courses and management. Age at diagnosis ranged from 0.2 to 45 years. Eight patients were male, and seven were female. Four individuals were diagnosed through newborn screening (NBS) for SCID. Immunological phenotype included Omenn syndrome (OS) (6/15), SCID-like disease (1/15), combined immunodeficiency (CID) with autoimmunity complications (1/15), T cell lymphopenia (5/15) or antibody deficiency (2/15), and one asymptomatic individual. Herpesviridae-related complications were prominent, including EBV viremia (3/15), Varicella pneumonia (1/15), severe Varicella infection (1/15), and CMV disease (3/15), one of which presented with CMV retinitis. The severity and management of OS were variable: one patient was managed with monitoring alone, one received immunoglobulin replacement therapy (IgRT) alone, one received antimicrobial therapy only, two received IgRT and antimicrobial prophylaxis, and one was treated with prednisone, cyclosporine, IgRT, and broad antimicrobial prophylaxis. One patient underwent hematopoietic stem cell transplantation (HSCT) before the identification of DN-FOXN1 and died from transplant-related complications. No OS patient required HSCT. Up to date, no patient has received a thymic transplant.ConclusionsHeterozygous FOXN1 variants have traditionally been considered mild, with immune function often improving over time and without the need for definitive therapies. However, DN-FOXN1 variants appear to carry a broader clinical spectrum, including OS. In our cohort, OS manifestations were variable and could often be managed with supportive care, including IgRT, antimicrobial prophylaxis, and, when indicated, immunosuppression, and none of the patients has required thymic transplantation to date.

Due to limitations in current therapies (immunoglobulin replacement therapy), complications in X-linked agammaglobulinemia (XLA) such as bronchiectasis may continue to occur, with subsequent significant impacts on health-related quality of life (HRQoL). There were no significant differences in PedsQL 4.0 total scores against UK healthy norms (self 80.98, P = 0.277; parent 79.76, P = 0.465). There were no significant differences in the SF36v2 physical component score (PCS) against UK healthy norms (49.10, P = 0.712). However, XLA patients with bronchiectasis had significantly worse PCS than patients without (47.88 versus 55.14, P < 0.001) and significantly worse PCS than UK healthy norms (P = 0.004). In the absence of bronchiectasis, HRQoL is comparable to UK healthy norms. However, XLA patients with bronchiectasis have significantly worse HRQoL than patients without bronchiectasis and UK healthy norms. These data demonstrate that further work into novel therapies are needed to prevent bronchiectasis to enable XLA patients to have a normal quality of life.

TREC-NBS identifies patients with inborn errors of immunity (IEI) and syndromic features, but uncertainty remains regarding their immunological management. To address this, syndromic patients detected by TREC-NBS in Germany between August 2019 and April 2024 were systematically analyzed, including phenotype, treatment, and outcomes. National registries were screened, and data were completed by the treating centres. A total of 77 syndromic patients were identified, with 22 different gene defects found in 72 individuals (93.5

Background Immunocompromised patients presenting with encephalitis can present a diagnostic conundrum as infection can be caused by a broad range of pathogens, many of which are not detected by standard of care testing pathways. Untargeted metagenomics has proven utility in the diagnosis of such infections, particularly for immunocompromised patients. Methods An immunosuppressed adolescent presented with idiopathic progressive muscle weakness resulting in respiratory failure, 16 years after haematopoeitic stem cell transplant for familial haemophagocytic lymphohistiocytosis type 5. Clinical and radiological findings suggested a diagnosis of isolated central nervous system haemophagocytic lymphohistiocytosis, however the patient demonstrated no improvement on immunosuppressive therapy. Untargeted metagenomics was performed on brain biopsy tissue. Results Clinical metagenomics detected avian paramyxovirus 1 (APMV-1) in the brain tissue 12 days after biopsy, confirmed by targeted PCR and immunohistochemistry. The metagenomics results guided treatment; immunosuppression was stopped and medication with potential activity against RNA viruses started. The patient died 8 months after symptom onset. Conclusions We describe the third published case of fatal encephalitis caused by APMV-1, detectable only in brain parenchyma and only by clinical metagenomics, demonstrating the utility of brain biopsy and metagenomics when investigating encephalitis in immunocompromised patients. Case series review suggests profoundly immunocompromised patients are at risk of severe infection caused by AMPV-1.

Persistent selective T-lymphocytopenia is found both in SCID and congenital athymia. Without molecular diagnosis, it is challenging to determine whether HCT or thymus transplantation ought to be performed. Ex vivo T-lymphopoiesis assays have been proposed to assist clinical decision-making for genetically undefined patients. We investigated 20 T-lymphocytopenic patients, including 13 patients awaiting first-line treatment and 7 patients with failed immune reconstitution after previous HCT or thymus transplantation. Whilst developmental blocks in ex vivo T-lymphopoiesis indicated hematopoietic cell-intrinsic defects, successful T-lymphocyte differentiation required careful interpretation, in conjunction with clinical status, immunophenotyping, and genetic investigations. Of the 20 patients, 13 proceeded to treatment, with successful immune reconstitution observed in 4 of the 6 patients post-HCT and 4 of the 7 patients after thymus transplantation, the latter including two patients who had previously undergone HCT. Whilst further validation and standardization are required, we conclude that assessing ex vivo T-lymphopoiesis during the diagnostic pathway for genetically undefined T-lymphocytopenia improves patient outcomes by facilitating corrective treatment choice.

Unexplained neurological symptoms can pose a diagnostic challenge in patients with inborn errors of immunity (IEI) where the aetiology can be varied, and diverse pathologies may require contrasting treatments. Brain biopsy, the process of sampling brain tissue directly, has historically provided histological and microbiological information and can now be exploited for deep metagenomic next generation analysis (mNGS). We conducted a retrospective analysis of clinical and diagnostic data on paediatric patients with IEI who had a brain biopsy between 2010 and 2022 at a UK tertiary centre where 14 patients fulfilled our search criteria. We report on clinical characteristics, adverse events and the additional impact of mNGS of brain biopsies, where these were conducted. We found that brain biopsy enabled diagnostics with manageable complications in most cases, either by tissue or metagenomics analysis (n = 11/14, 79%). We found that mNGS analysis improved the diagnostic yield of brain biopsy in 29% of IEI cases (n = 4/14). Brain biopsy enabled a change in management in 71% of cases (n = 10/14). This series provides compelling evidence for the safe and purposeful use of brain biopsy in children with IEI.

INTRODUCTION:Cerebrospinal fluid (CSF) cytokines may contribute to immune-mediated processes affecting the central nervous system (CNS). We evaluated CSF cytokine profiles in children with suspected neuroinflammatory conditions to explore their clinical relevance. METHODS:Between 2019 and 2024, CSF from children <18 years were analyzed using BD Biosciences cytokine bead array for interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-alpha (IFN-α), and tumour necrosis-factor-alpha (TNF-α). Clinical phenotyping was conducted. Serum cytokine levels were measured in cases with abnormal CSF, when available. RESULTS:112 patients were included (median age 6 years [IQR 3.6-11.2]; 54 % male). CSF IL-6 was raised in 35/112 (31 %; median 107 pg/ml, IQR 24-329). No other cytokine was raised without concurrent IL-6. Raised CSF IL-6 occurred in 16/50 acquired neuroimmune conditions (including myelin oligodendrocyte glycoprotein antibody-associated disease, seronegative demyelination, seronegative autoimmune encephalitis, and febrile-infection-related epilepsy syndrome), 5/9 CNS infections; 9/17 monogenic autoinflammatory syndromes, and 5/7 cancer treatment-related neurotoxicities. Of the 35 patients with raised CSF IL-6, 21 had serum cytokines tested; 13 (62 %) showed elevated serum IL-6. In demyelinating cases, higher IL-6 was associated with increased CSF protein (p = 0.007). Follow-up CSF samples (n = 16, median 34 days) showed persistent elevation in 7 and normalisation in 9. IL-6 inhibitors (tocilizumab and/or siltuximab) were used in 10 patients with variable outcomes, depending on the underlying etiology. CONCLUSIONS:CSF IL-6 was the most frequently elevated cytokine in our cohort, observed across a range of primary and secondary neuroinflammatory disorders. While not diagnostic of a specific condition, its elevation may help guide treatment decisions.

Transcription factor Forkhead box protein N1 (FOXN1) regulates thymic epithelial cell development. Bi-allelic and compound heterozygote loss-of-function mutations result in nude-severe combined immune deficiency with athymia, alopecia, and nail dystrophy requiring thymus transplantation. Dominant-negative heterozygous variants have incomplete and highly variable phenotypes. We present an international cohort of families carrying dominant negative mutations with variable clinical presentation, course, and outcomes. Patient medical records and diagnosing physicians were consulted. We have access to 11 FOXN1 dominant-negative heterozygotes from 4 families with highly variable intrafamilial clinical courses and management. All variants locate near the C terminus, like variants in Rota et al. [1]. Immunological phenotype included 5/11 with Omenn syndrome (OS) early in life, otherwise presenting as asymptomatic (2/11) or with T cell lymphopenia (4/11), characterized by persistently low naïve T cells, and specific antibody deficiency (1/11) even in middle age. Alopecia and/or nail dystrophy was only noted in 1/11 patients. OS treatments ranged from conservative management (1/5), short-term steroids (1/5), long-term prednisolone alone (1/5), cyclosporine and prednisolone (1/5), and 1/5 OS patients received a bone marrow transplant prior to genetic diagnosis and later expired. (3/11) patients were placed on immunoglobulin replacement therapy. Only 3/11 patients experienced adverse outcomes, with 1/11 deaths. Other adverse outcomes include severe herpesviridae infections: Varicella pneumonia and CMV retinitis, respectively. 2/11 patients experienced EBV viremia and 2/11 with CMV viremia. 1/2 families tested were positive for anti-IFNα autoantibodies. Only one patient is being considered for thymic transplant. This cohort demonstrates intrafamilial variability ranging from asymptomatic symptoms to OS, which has seldom been described in athymia patients. Heterogeneity indicates a need for distinct longitudinal treatment protocols for dominant negative FOXN1 patients, including lifelong protective immunoglobulin replacement therapy, and the possibility of thymic transplant for best outcomes, which has not been performed in FOXN1 heterozygotes before.

ABSTRACT:Signal transduction and activator of transcription 3 hyperimmunoglobulin E syndrome (STAT3-HIES) is a multisystem disorder causing recurrent skin and respiratory infection with bronchiectasis, pneumatoceles, and aspergillosis; lymphoma; and extraimmune manifestations including fractures and vasculopathy. Published data on immune and extraimmune hematopoietic stem cell transplant (HSCT) outcomes focus on case reports or small cohorts. We conducted an international multicenter retrospective study of HSCT in STAT3-HIES. Primary end points were overall survival (OS) and event-free survival (EFS; events were death, graft failure, chronic graft-versus-host disease [GVHD]). We identified 41 patients over a 28-year period. HSCT indication was infection (93%) or lymphoma (7%). Median age at HSCT was 14 years (range, 4-45). Most patients had pre-HSCT respiratory disease (93%), including parenchymal lung disease (68%), and prior suspected/confirmed pulmonary fungal infection (32%). Patients received peripheral blood stem cells (51%) or marrow (49%) from HLA 10/10-matched unrelated donors (44%), matched family donors (44%), mismatched family donors (10%), or 1 9/10-mismatched unrelated donor (2%). Conditioning regimens were predominantly treosulfan-based (59%; with thiotepa, 34%); other patients received busulfan-based (24%) or melphalan-based (17%) regimens. Median follow-up for surviving patients was 5 years (0.8-28). The 5-year OS was 93%, and 5-year EFS 90%. Cumulative incidence of grade 2 to 4 acute GVHD was 22%. Median whole blood donor chimerism at latest follow-up was 100%. Eighty-seven percent of patients have reduced or no bacterial or fungal respiratory infection. After HSCT, 20% developed new skeletal fractures. This worldwide study expanded data on HSCT for STAT3-HIES to 41 patients; despite significant pre-HSCT pulmonary morbidity, OS was high, and patients have improved skin and respiratory disease though the impact on extraimmune manifestations appears limited.

This case aims to highlight the role dermatologists have in identifying inborn errors of immunity, particularly in patients who do not respond to eczema treatments and those with concurrent food allergies and severe recurrent infections. A 1-year-old boy with severe allergies to eggs, nuts, milk and sesame, with a history of anaphylaxis, presented to dermatology for the management of generalized severe atopic dermatitis with prominent facial and scalp involvement. Despite prompt treatment with topical corticosteroids and topical calcineurin inhibitors there was no improvement in the skin. Additionally, he had repeated severe infections including impetiginized eczema, eczema herpeticum, eczema molluscatum, respiratory tract infections, and chronic otitis media leading to hearing loss. His height was on the 9th centile and weight on the 25th centile. Initial bloods suggested anaemia: haemoglobin 98 g L−1 with leucocytosis (17.7 × 109 cells L−1), neutrophilia (9.6 × 109 cells L−1) and lymphopenia (4.7 × 109 cells L−1). He also had a high IgE level of 27 804 IU mL−1. This raised the suspicion of an inborn error of immunity, and he subsequently underwent genetic studies. Gene sequencing studies revealed a DOCK8 deletion of exons 6–14 and c.2660C>G, p.(Ser887*) compound heterozygosity. Deficiency of the dedicator of cytokinesis 8 gene (DOCK8) is a combined type of T- and B-cell immunodeficiency, previously known as autosomal recessive hyper-IgE syndrome. The patient was started on immunoglobulin infusions and dupilumab, with some improvement in his eczematous rash, before receiving a 100% matched unrelated-donor haematopoietic stem cell transplantation (HSCT). Early recognition of this condition and definitive treatment with HSCT is important due to the associated high morbidity and mortality of DOCK8 deficiency. Clinically, patients present with severe eczema, multiple food allergies, environmental allergies and asthma, and are at an increased risk of developing severe and difficult-to-treat viral, bacterial and fungal infections. Cutaneous viral infections, including varicella zoster, molluscum contagiosum, herpes simplex and human papillomaviruses tend to be common. Certain localizations of eczema in the retroauricular, axillary, groin and back areas have been described in the literature. Morphology ranges from distinctive papulopustular, vesicular rashes to abscesses. Infected dermatitis due to Staphylococcus aureus or viral infections is thought to be related to DOCK8 mutations. However, the molecular link between DOCK8 deficiency and atopic skin inflammation remains unknown. This case highlights the importance of considering inborn errors of immunity in such cases of severe eczema associated with apparent immune dysregulation and susceptibility to recurrent infections.

AIMS:Children with primary immunodeficiency (PID) and secondary antibody deficiency (SAD) often require immunoglobulin replacement therapy due to low plasma immunoglobulin G (IgG) levels and recurrent infections. Existing pharmacokinetic models for immunoglobulin in PID patients predominantly focus on adults, with limited attention to secondary antibody deficiencies and a lesser emphasis on paediatric populations. This study aims to investigate the pharmacokinetic properties of IgG in paediatric patients with PID and SAD. METHODS:Population pharmacokinetic analysis for PID and SAD children treated with intravenous immunoglobulin at a tertiary paediatric centre was conducted using NONMEM® (7.5.1). Dosing simulations to achieve therapeutic levels of 6 and 8 gL-1 were performed. RESULTS:A population pharmacokinetic analysis of 64 patients (median age 4.08 years, range 0.06-16.8) was performed. A two-compartment model with first-order elimination, incorporating both additive and proportional residual error, adequately described the data. Interindividual variability was modelled on clearance, volume of distribution and baseline IgG levels, with allometric scaling to a 70-kg body weight applied a priori. The estimated clearance was 0.308 L-1 day-1 70 kg-1 (95% CI 0.23, 0.67), and the volume of distribution was 10.96 L-1 70 kg-1 (95% CI 5.97, 15.79). Patients with SAD exhibited a lower clearance rate of 54% compared with PID patients. Dosing simulations indicated that the recommended SAD dosing regimen maintained therapeutic IgG levels in the simulated population. However, only 44.8% to 51.9% of patients with PID achieved target IgG levels with the standard regimen. CONCLUSIONS:This study provides insights into immunoglobulin pharmacokinetics in paediatric PID and SAD patients, guiding optimised dosing strategies. Administering a loading dose would improve the probability of maintaining therapeutic IgG levels during the 4-week dosing interval.

Cytomegalovirus (CMV) infection is a significant complication in paediatric haematopoietic stem cell transplant (HSCT), with substantial morbidity and mortality. While pre-emptive treatment guided by CMV viral load thresholds helps prevent end-organ disease, paediatric protocols have largely been extrapolated from adult populations without robust validation. This prospective interventional study aimed to determine an optimal viral load threshold for initiating pre-emptive CMV therapy in paediatric HSCT patients and test the impact of this threshold in real-world practice. Initially, 219 paediatric HSCT patients from 2009 to 2016 were considered, with weekly CMV quantitative polymerase chain reaction (qPCR) monitoring and treatment initiation at 2500 IU/mL. A mathematical model was developed to analyse CMV kinetics, morbidity and mortality, suggesting a threshold of 1000 IU/mL would be most suitable to prevent adverse outcomes. Subsequently, the new treatment threshold was implemented, and outcomes were then compared with a second cohort of 344 patients treated under the new guidelines from 2017 to 2021. There were significant reductions in CMV viral loads, CMV-associated end-organ disease (27/117, 23.1% vs. 4/98, 4.1%) and mortality (36/117, 30.8% vs. 19/98, 19.4%). These findings support a new evidence-based viral load threshold of 1000 IU/mL or less for pre-emptive treatment in paediatric HSCT recipients to optimise clinical outcomes.