COVID-19 in children and adolescents: MIS(-C)-taken diagnoses.

Multisystem inflammatory syndrome in children (MIS-C) is an inflammatory condition associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is characterized by fever, gastro-intestinal symptoms, cardiovascular complications, conjunctivitis, skin involvement, elevated inflammatory markers, and coagulation abnormalities. The current ongoing COVID-19 pandemic causes an increased alertness to MIS-C. In combination with the heterogeneous clinical spectrum, this could potentially lead to diagnostic blindness, misdiagnosis of MIS-C, and overtreatment with expensive IVIG treatment. This report demonstrates the challenge of accurately distinguishing MIS-C from other more common inflammatory pediatric diseases, and the need to act with caution to avoid misdiagnoses in the current pandemic. We present a case series of 11 patients suspected of MIS-C based on the current definitions. Three of them were eventually diagnosed with a different disease. CONCLUSION: Current definitions and diagnostic criteria lack specificity which potentially leads to misdiagnosis and overtreatment of MIS-C. We emphasize the need to act with caution in order to avoid MIS(-C)-taken diagnoses in the current pandemic. WHAT IS KNOWN: • A pediatric multisystem inflammatory disease associated with SARS-CoV-2 has been described (MIS-C). • There are three definitions being used for MIS-C, all including fever for at least 24 h, laboratory evidence of inflammation, clinically severe illness with multi-organ (≥ 2) involvement, and no alternative plausible diagnosis. WHAT IS NEW: • MIS-C has a heterogeneous clinical spectrum without distinctive features compared to more common childhood diseases. Current definitions and diagnostic criteria for MIS-C lack specificity which leads to misdiagnosis and overtreatment. • Amid the current excessive attention to COVID-19 and MIS-C, pediatricians should remain vigilant to avoid mistaken diagnoses.

Towards remote monitoring in pediatric care and clinical trials-Tolerability, repeatability and reference values of candidate digital endpoints derived from physical activity, heart rate and sleep in healthy children.

BACKGROUND: Digital devices and wearables allow for the measurement of a wide range of health-related parameters in a non-invasive manner, which may be particularly valuable in pediatrics. Incorporation of such parameters in clinical trials or care as digital endpoint could reduce the burden for children and their parents but requires clinical validation in the target population. This study aims to determine the tolerability, repeatability, and reference values of novel digital endpoints in healthy children. METHODS: Apparently healthy children (n = 175, 46% male) aged 2-16 were included. Subjects were monitored for 21 days using a home-monitoring platform with several devices (smartwatch, spirometer, thermometer, blood pressure monitor, scales). Endpoints were analyzed with a mixed effects model, assessing variables that explained within- and between-subject variability. Endpoints based on physical activity, heart rate, and sleep-related parameters were included in the analysis. For physical-activity-related endpoints, a sample size needed to detect a 15% increase was calculated. FINDINGS: Median compliance was 94%. Variability in each physical activity-related candidate endpoint was explained by age, sex, watch wear time, rain duration per day, average ambient temperature, and population density of the city of residence. Estimated sample sizes for candidate endpoints ranged from 33-110 per group. Daytime heart rate, nocturnal heart rate and sleep duration decreased as a function of age and were comparable to reference values published in the literature. CONCLUSIONS: Wearable- and portable devices are tolerable for pediatric subjects. The raw data, models and reference values presented here can be used to guide further validation and, in the future, clinical trial designs involving the included measures.

Development of Novel, Value-Based, Digital Endpoints for Clinical Trials: A Structured Approach Toward Fit-for-Purpose Validation.

Novel digital endpoints gathered via wearables, small devices, or algorithms hold great promise for clinical trials. However, implementation has been slow because of a lack of guidelines regarding the validation process of these new measurements. In this paper, we propose a pragmatic approach toward selection and fit-for-purpose validation of digital endpoints. Measurements should be value-based, meaning the measurements should directly measure or be associated with meaningful outcomes for patients. Devices should be assessed regarding technological validity. Most importantly, a rigorous clinical validation process should appraise the tolerability, difference between patients and controls, repeatability, detection of clinical events, and correlation with traditional endpoints. When technically and clinically fit-for-purpose, case building in interventional clinical trials starts to generate evidence regarding the response to new or existing health-care interventions. This process may lead to the digital endpoint replacing traditional endpoints, such as clinical rating scales or questionnaires in clinical trials. We recommend initiating more data-sharing collaborations to prevent unnecessary duplication of research and integration of value-based measurements in clinical care to enhance acceptance by health-care professionals. Finally, we invite researchers and regulators to adopt this approach to ensure a timely implementation of digital measurements and value-based thinking in clinical trial design and health care. SIGNIFICANCE STATEMENT: Novel digital endpoints are often cited as promising for the clinical trial of the future. However, clear validation guidelines are lacking in the literature. This paper contains pragmatic criteria for the selection, technical validation, and clinical validation of novel digital endpoints and provides recommendations for future work and collaboration.

IL-10 signaling in dendritic cells controls IL-1ß-mediated IFNγ secretion by human CD4+ T cells: relevance to inflammatory bowel disease.

Uncontrolled interferon γ (IFNγ)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4+ T cells. Deficiency in IL-10 signaling dramatically increased IL-1ß release by moDCs. IL-1ß boosted IFNγ secretion by CD4+ T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1ß expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFNγ-secreting CD4+ T cells in humans and identifies IL-1ß as a potential classifier for a subgroup of IBD patients.

Effects of immunomodulation in classic infantile Pompe patients with high antibody titers.

PURPOSE: To evaluate whether immunomodulation can eliminate high sustained antibody levels, and thereby improve clinical outcome in classic infantile Pompe patients receiving enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA). METHODS: Three patients (two cross-reactive immunologic material (CRIM) negative) with high sustained antibodies received a three-week treatment protocol with Rituximab and Bortezomib, followed by daily Rapamycin and monthly IVIG. Patients received 40 mg/kg/week rhGAA. Antibody titers were measured using ELISA. Neutralizing effects on cellular uptake were determined. Clinical efficacy was measured in terms of (ventilator-free) survival, reduction in left ventricular mass index (LVMI) and improvement in motor function. RESULTS: Before immunomodulation anti-rhGAA antibody titers ranged from 1:156,250 to 1:781,250 and at last assessment from 1:31,250 to 1:156,250. Neutralizing effects of anti-rhGAA antibody titers (observed in two patients) disappeared. Infusion-associated reactions were no longer present. Immunomodulation resulted in substantial increases of aspartate transaminase, alanine transaminase, and creatine kinase levels. The two CRIM-negative patients who could walk at start of immunomodulation maintained their ability to walk; the patient who had lost this ability did not regain it. CONCLUSIONS: To some extent, the immunomodulation protocol used in our study reduced antibody titers, but it did not eliminate them. Overall, there have been few reports on secondary immunomodulation, and various protocols have been applied. Future research should seek to identify the most successful immunomodulation protocol in patients with high sustained titers.

Trends in paediatric inpatient antibiotic therapy in a secondary care setting.

There is growing attention for antimicrobial stewardship in paediatrics. Currently, little is known about secondary care antibiotic practice. We analysed trends in time with respect to inpatient antibiotic use in a secondary paediatric care setting. Total inpatient antibiotic consumption per year (2010-2015) and antibiotic prescriptions for urinary tract infection (UTI) and lower respiratory tract infection (LRTI) were analysed. Variables were total, antibiotic-specific, and intravenous days of therapy (DOT/100PD) and for UTI/LRTI treatment type, route and duration. Third-generation cephalosporin use decreased (DOT/100PD 11.6 in 2011 vs. 5.1 in 2015; p < 0.001); intravenous antibiotics were prescribed less often (p = 0.06). These findings were confirmed for the specific diseases: third-generation cephalosporin use decreased for both UTI (93% vs. 45%; p = 0.002) and LRTI (14% vs. 6%; p = 0.18); the duration of intravenous therapy decreased (UTI p = 0.02; LRTI p < 0.001). Median LRTI treatment duration was 9.2 days in 2008 and 6.6 in 2015 (p < 0.001); penicillin prescriptions were more narrow in spectrum (p = 0.02). CONCLUSION: A decrease in third-generation cephalosporin use and intravenous route was identified. LRTI treatment was significantly shorter and more narrow in spectrum. This could be explained by awareness and interventions in the context of antimicrobial stewardship. A decrease in antibiotic use is also feasible and important in non-tertiary paediatric wards. What is Known: • Antimicrobial stewardship programmes are effective in reduction of total and broad-spectrum antibiotic use in tertiary paediatric hospitals • The majority of hospitalised paediatric patients are admitted at general, secondary care wards, often for infectious diseases What is New: • Antimicrobial stewardship interventions in secondary care are also effective in establishing a reduction in broad-spectrum antibiotic use, intravenous route and days on antibiotic therapy.

IgE-expressing memory B cells and plasmablasts are increased in blood of children with asthma, food allergy, and atopic dermatitis.

Despite the critical role of soluble IgE in the pathology of IgE-mediated allergic disease, little is known about abnormalities in the memory B cells and plasma cells that produce IgE in allergic patients. We here applied a flow cytometric approach to cross-sectionally study blood IgE+ memory B cells and plasmablasts in 149 children with atopic dermatitis, food allergy, and/or asthma and correlated these to helper T(h)2 cells and eosinophils. Children with allergic disease had increased numbers of IgE+CD27- and IgE+CD27+ memory B cells and IgE+ plasmablasts, as well as increased numbers of eosinophils and Th2 cells. IgE+ plasmablast numbers correlated positively with Th2 cell numbers. These findings open new possibilities for diagnosis and monitoring of treatment in patients with allergic diseases.

Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2.

BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations). AIM: To study the mutation spectrum in ICF syndrome. MATERIALS AND METHODS: Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members. RESULTS: We describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta-analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients. DISCUSSION: The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort. CONCLUSION: Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.

Virological and Social Outcomes of HIV-Infected Adolescents and Young Adults in The Netherlands Before and After Transition to Adult Care.

BACKGROUND: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure. METHODS: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements. RESULTS: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition. CONCLUSIONS: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group.

Diagnostic Performance of Galactomannan Antigen Testing in Cerebrospinal Fluid.

Testing cerebrospinal fluid (CSF) for the presence of galactomannan (GM) antigen may help in diagnosing cerebral aspergillosis (CA). However, the use of the CSF GM test as a diagnostic test has been little studied. We evaluated its diagnostic performance by comparing the CSF GM optical density indexes (ODI) at different cutoffs in patients with probable and proven CA to those in patients without CA. Patients from 2 tertiary referral hospitals with suspected CA between 2004 and 2014 and in whom CSF GM ODI had been determined were selected. European Organization for Research and Treatment of Cancer/Invasive Infectious Diseases Study Mycoses Group (EORTC/MSG) definitions of invasive aspergillosis and CA were used, but with the exclusion of the test to be validated (i.e., the CSF GM test) as a microbiological EORTC/MSG criterion. The study population consisted of 44 patients (4 with proven CA, 13 with probable CA, and 27 with no CA). Of the 17 patients with CA, 15 had a CSF GM ODI of ≥2.0. Of 27 patients without CA, 26 had a CSF GM ODI of <0.5 and 1 had a CSF GM ODI of 8.2. When a GM CSF ODI cutoff of 1.0 was used, the sensitivity, specificity, and positive and negative predictive values were 88.2%, 96.3%, 93.8%, and 92.9%, respectively. The same results were found when a CSF GM ODI cutoff of 0.5 or 2.0 was used. Testing GM in CSF has a high diagnostic performance for diagnosing CA and may be useful to diagnose or virtually rule out the infection without the need for a cerebral biopsy.

Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy.

PURPOSE: To analyze the data of the national registry of all Dutch primary immune deficiency (PID) patients, according to the European Society for Immunodeficiencies (ESID) definitions. RESULTS: In the Netherlands, 745 patients had been registered between 2009 and 2012. An overall prevalence of 4.0 per 100,000 inhabitants was calculated. The most prevalent PID was 'predominantly antibody disorder (PAD)' (60.4%). In total, 118 transplantations were reported, mostly hematopoietic stem cell transplantations (HSCT). Almost 10% of the PID patients suffered from a malignancy, in particular 'lymphoma' and 'skin cancer'. Compared to the general Dutch population, the relative risk of developing any malignancy was 2.3-fold increased, with a >10-fold increase for some solid tumors (thymus, endocrine organs) and hematological disease (lymphoma, leukemia), varying per disease category. CONCLUSIONS: The incidence rate and characteristics of PID in the Netherlands are similar to those in other European countries. Compared to the general population, PID patients carry an increased risk to develop a malignancy.

Levels of somatic hypermutations in B cell receptors increase during childhood.

Somatic hypermutation (SHM) is an important step in antigen-driven B cell development creating B lymphocytes expressing high-affinity antibody receptors. It is known that the peripheral B lymphocyte compartments of healthy children and adults differ considerably. However, the development of SHM with age has not been studied in detail previously. Therefore, we used the immunoglobulin (Ig)κ-restriction enzyme hot-spot mutation assay (Igκ-REHMA) to gain an estimation of SHM levels in different age groups in order to relate this to the size of the memory B lymphocyte subpopulations. We show that the level of SHM increases rapidly during the first 2 years of life. This reflects the changes of the memory B cell subpopulations, but also changes in the SHM within memory B cell subsets, probably reflecting an increase of secondary memory B cell responses.

T-cell receptor Vß skewing frequently occurs in refractory cytopenia of childhood and is associated with an expansion of effector cytotoxic T cells: a prospective study by EWOG-MDS.

Immunosuppressive therapy (IST), consisting of antithymocyte globulin and cyclosporine A, is effective in refractory cytopenia of childhood (RCC), suggesting that, similar to low-grade myelodysplastic syndromes in adult patients, T lymphocytes are involved in suppressing hematopoiesis in a subset of RCC patients. However, the potential role of a T-cell-mediated pathophysiology in RCC remains poorly explored. In a cohort of 92 RCC patients, we prospectively assessed the frequency of T-cell receptor (TCR) ß-chain variable (Vß) domain skewing in bone marrow and peripheral blood by heteroduplex PCR, and analyzed T-cell subsets in peripheral blood by flow cytometry. TCRVß skewing was present in 40% of RCC patients. TCRVß skewing did not correlate with bone marrow cellularity, karyotype, transfusion history, HLA-DR15 or the presence of a PNH clone. In 28 patients treated with IST, TCRVß skewing was not clearly related with treatment response. However, TCRVß skewing did correlate with a disturbed CD4(+)/CD8(+) T-cell ratio, a reduction in naive CD8(+) T cells, an expansion of effector CD8(+) T cells and an increase in activated CD8(+) T cells (defined as HLA-DR(+), CD57(+) or CD56(+)). These data suggest that T lymphocytes contribute to RCC pathogenesis in a proportion of patients, and provide a rationale for treatment with IST in selected patients with RCC.

Paediatric reference values for the peripheral T cell compartment.

Immunophenotyping of blood lymphocyte subpopulations is an important tool in the diagnosis of immunological and haematological diseases. Paediatric age-matched reference values have been determined for the major lymphocyte populations, but reliable reference values for the more recently described T lymphocyte subpopulations, like different types of memory T lymphocytes, recent thymic emigrants, regulatory T cells and CXCR5(+) helper T lymphocytes, are not sufficiently available yet. We determined reference values for the absolute and relative sizes of T lymphocyte subpopulations in healthy children using the lysed whole blood method, which is most often used in diagnostic procedures. When the absolute numbers of some or all T lymphocyte subpopulations fall outside these reference ranges, this may indicate disease. The reference values show the course of T lymphocyte development in healthy children. Absolute T lymphocyte numbers increase 1.4-fold during the first months of life, and after 9-15 months, they decrease threefold to adult values; this is mainly caused by the expansion of recent thymic emigrants and naive cells. Helper and cytotoxic T lymphocytes show the same pattern. Regulatory T cells increase in the first 5 months of life and then gradually decrease to adult values, although the absolute numbers remain small. The relative number of CXCR5(+) cells within the CD4(+) CD45RO(+) T lymphocytes increases during the first 6 months of life and then remains more or less stable around 20%.

Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation?

BACKGROUND: Non-infective cutaneous granulomas with unknown pathogenesis occur in various primary immunodeficiencies (PIDs) including ataxia telangiectasia (A-T). OBJECTIVE: To find a common immunological denominator in these cutaneous granulomas. METHODS: The dermatological and immunological features of 4 patients with A-T and cutaneous granulomas were described. The literature on skin granulomas in A-T and in other PIDs is reviewed. RESULTS: All 4 A-T patients had progressive granulomas on their limbs and showed decreased IgG and IgA concentrations with normal IgM levels. They had a marked decrease in B cells and naïve T cells coinciding with the appearance of the cutaneous granulomas. Similar B- and T-cell abnormalities were described in patients with other PIDs with skin granulomas. CONCLUSIONS: We hypothesize that the pathogenesis of these skin granulomas is related to immune dysregulation of macrophages due to the absence of naïve T cells with an appropriate T-cell receptor repertoire and the unopposed activity of γδ T cells and/or natural killer cells.

Age-matched reference values for B-lymphocyte subpopulations and CVID classifications in children.

Age-matched reference values are generally presented with 5th and 95th percentiles as 'normal' reference range. However, they are mostly determined in relatively small groups, which renders this presentation inaccurate. We determined reference values for B-lymphocyte subpopulations in healthy children with the statistical method of tolerance intervals that deals far better with the relatively small numbers tested, and compared these to the cut-off values used in the currently used EUROclass classification for common variable immunodeficiency disorders (CVID) in children. CVID is a heterogeneous group of primary immunodeficiency diseases characterized by low serum immunoglobulin levels and inadequate response to vaccination. Disease-modifying heterozygous amino acid substitutions in TACI are found in around ±10% of CVID patients. Interestingly, we found that age is the primary determinant of TACI-expression on B-lymphocytes, independent of switched memory B-lymphocyte numbers. Immunophenotyping of B-lymphocyte subpopulations is increasingly used to classify patients with CVID into subgroups with different clinical prognosis according to the composition of their B-lymphocyte compartment. These classifications were mainly developed with data obtained in adults. Because of the maturing paediatric immune system, they may not be equally applicable in children: our and other age-matched reference values show great changes in the composition of the B-lymphocyte compartment during development. Although the greatest changes in B-lymphocyte subpopulations occur below the age of 2 years, when the diagnosis of CVID cannot yet be made, it is likely that a classification developed in adults cannot be used to classify the prognosis of children.

Correction of murine Rag1 deficiency by self-inactivating lentiviral vector-mediated gene transfer.

Severe combined immunodeficiency (SCID) patients with an inactivating mutation in recombination activation gene 1 (RAG1) lack B and T cells due to the inability to rearrange immunoglobulin (Ig) and T-cell receptor (TCR) genes. Gene therapy is a valid treatment option for RAG-SCID patients, especially for patients lacking a suitable bone marrow donor, but developing such therapy has proven challenging. As a preclinical model for RAG-SCID, we used Rag1-/- mice and lentiviral self-inactivating (SIN) vectors harboring different internal elements to deliver native or codon-optimized human RAG1 sequences. Treatment resulted in the appearance of B and T cells in peripheral blood and developing B and T cells were detected in central lymphoid organs. Serum Ig levels and Ig and TCR Vß gene segment usage was comparable to wild-type (WT) controls, indicating that RAG-mediated rearrangement took place. Remarkably, relatively low frequencies of B cells produced WT levels of serum immunoglobulins. Upon stimulation of the TCR, corrected spleen cells proliferated and produced cytokines. In vivo challenge resulted in production of antigen-specific antibodies. No leukemia development as consequence of insertional mutagenesis was observed. The functional reconstitution of the B- as well as the T-cell compartment provides proof-of-principle for therapeutic RAG1 gene transfer in Rag1-/- mice using lentiviral SIN vectors.

TACI mutations and disease susceptibility in patients with common variable immunodeficiency.

The most prevalent primary immunodeficiency is common variable immunodeficiency (CVID). Mutations have been described in four genes, ICOS, CD19, BAFF-R and TNFRSF13B (encoding TACI), together associated with 10-15% of CVID cases. We investigated a family with CVID and identified the heterozygous C104R TNFRSF13B mutation in two of the three index-children with CVID, a mother with selective immunoglobulin A deficiency, a mother with recurrent infections and a healthy grandfather. Remarkably, we did not find the TNFRSF13B mutation in the third index-child with CVID, despite his hypogammaglobulinaemia and decreased response to unconjugated pneumococcal vaccine. This family illustrates that TNFRSF13B mutations induce disease susceptibility rather than cause disease directly. Apparently, other genetic or environmental factors, still to be identified, contributed to the development of CVID in this family. Consequently, TNFRSF13B mutations must be interpreted with caution in the clinical setting.

Low level IGF-1 and common variable immune deficiency: an unusual combination.

A relation between growth hormone (GH) deficiency and immunoglobulin deficiency has been suggested previously in a few cases. We describe a patient with an insulin-like growth factor 1 (IGF-1) deficiency and common variable immune deficiency and briefly review earlier publications on the possible interaction between IGF-1 and the immune system. IGF-1 is the downstream mediator of GH. In this patient, GH and IGF-1 levels were both low. The GH response to a GH-releasing hormone test was normal whereas no subsequent IGF-1 response was seen. In our cohort of 14 patients with hypogammaglobulinaemia, two turned out to have slightly decreased IGF-1 serum levels and one patient with a thymoma had an increased IGF-1 level. Even though IGF-1 may be connected to B lymphocyte differentiation, in this patient we hypothesise there is a common impairment in the IGF-1 and IgG pathways.