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Individuals with primary immunodeficiencies who are infected with vaccine-derived polioviruses may continue to shed poliovirus for months and go undetected by surveillance programmes of acute flaccid paralysis. These patients therefore pose a risk of initiating poliovirus outbreaks that jeopardize efforts towards global polio eradication. To identify these individuals, we designed a study protocol for the establishment of a network for surveillance of immunodeficiency-related vaccine-derived poliovirus in India. In the first step we identified recognized centres in India that could diagnose and enrol patients with primary immunodeficiency disorder into the study. Stool sample collection from study sites, culture, isolation, characterization of enteroviruses and reporting to study sites was carried out at the National Institute of Virology Mumbai Unit, as per the WHO national polio surveillance project protocol. In the first phase of the study from January 2020 to December 2021, we implemented the protocol at seven study sites at different medical institutes to determine the proportion of poliovirus infections in primary immunodeficiency disorder patients of India. We later expanded the study by including an additional 14 medical institutes across the country in the second phase running from January 2022 to December 2023. We believe this study protocol will help other countries to initiate immunodeficiency-related vaccine-derived poliovirus surveillance to identify and follow up patients who are long-term excretors of vaccine-derived poliovirus. Integration of immunodeficiency-related poliovirus surveillance with acute flaccid paralysis surveillance of the existing poliovirus network will enhance continuous screening of patients with primary immunodeficiency disorder in the future. [ABSTRACT FROM AUTHOR]

Interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency is a primary immune deficiency of the innate immune system. Children with this condition are susceptible to life-threatening bacterial infections. IRAK-4 deficiency results in reduced or absent systemic features of inflammation despite overwhelming infection. We present 2 siblings who died in infancy after rapidly progressive Pseudomonas sepsis and meningitis. There was diagnostic uncertainty in the firstborn infant because of significant intracranial hemorrhages. This was confounded by a failure to mount an inflammatory response. As such, it was difficult to distinguish between possible nonaccidental injuries and an infectious cause. Perimortem genetic analysis of the second-born infant identified a known mutation in IRAK-4. We intend to raise awareness of IRAK4 deficiency, highlight the importance of considering primary immune deficiencies in the differential of unusually severe infection, document progressive intracranial radiologic changes seen in overwhelming Pseudomonas meningitis and discuss the differences in the radiologic features seen in abusive head trauma within this age group. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory disorder characterized by hypercytokinemia caused by excessive activation of cytotoxic T cells and macrophages. HLH is caused by a variety of factors and is classified into primary and secondary HLH. Familial HLH (FHL) types 1–5, X‐linked lymphoproliferative syndrome types 1 and 2, and FHL syndrome with hypopigmentation are all examples of primary HLH. Secondary HLH, on the other hand, is linked to infections, malignant tumors, autoimmune diseases, and other diseases. The causes of HLH vary, and finding the underlying disease is critical for diagnosis and treatment. The majority of HLH is caused by the aforementioned conditions; however, approximately 10% of cases are caused by rare diseases such as inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Novel IEI, such as RhoG, MAP kinase activating death domain, TIM3, and ZNFX1 deficiencies, have recently been identified as causes of HLH. IEM patients are rarely associated with HLH. Surprisingly, children with lysinuric protein intolerance and lysosomal acid lipase deficiency (Wolman disease) frequently develop HLH. This review focuses on the most recent knowledge of HLH caused by rare diseases such as IEI and IEM. [ABSTRACT FROM AUTHOR]

Background: X-linked hyper-immunoglobulin M (XHIGM), a primary immunodeficiency syndrome caused by mutations in the CD40 ligand gene(CD40LG), presents with recurrent respiratory infections in pediatric patients. We aimed to evaluate the spectrum of clinical features and respiratory pathogens in pediatric patients with XHIGM in China.Methods: We retrospectively reviewed seven pediatric patients who were diagnosed with XHIGM and received follow-up treatment at the Guangzhou Women and Children's Medical Center between January 2010 and January 2021. We determined their clinical characteristics, causative pathogens, and prognosis by performing peripheral immunological and genetic tests.Results: There were seven boys with age ranging from 4-20 months (median age, 13 months). Four of the seven respiratory infections were caused by Talaromyces marneffei(T. marneffei). Two patients had viral infections caused by cytomegalovirus (CMV) and human adenovirus respectively. One patient had a mixed infection caused by Pneumocystis carinii and CMV. Except for one child who died of respiratory failure, one patient received hematopoietic stem cell transplantation (HSCT) and recovered well, the other five patients survived with regular infusions of intravenous immunoglobulin (IVIg) during the follow-up period. Six patients had reduced antibody levels, especially IgG, IgA, and IgE levels. Increased serum IgM levels were detected in four cases, and three cases presented normal IgM levels at onset. All children were diagnosed with XHIGM with CD40LG variation. Three novel mutations were identified in the present study.Conclusions: Our study suggests that respiratory infections usually begin within 2 years old, fungi and viruses are important pathogens causing respiratory infections in children with XHIGM. In endemic areas, T. marneffei is the common pathogen of respiratory tract infection in children with the disease. [ABSTRACT FROM AUTHOR]

Background: Previously, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency was categorized as a subtype of common variable immune deficiency. Research shows that LRBA deficiency is caused by dysregulation of T cell activation and expansion; it is placed under the category of immune dysregulation with cytotoxic T lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency. Cohort studies have revealed a broad spectrum of clinical manifestations and variable phenotype expression, including immune dysregulation [enteropathy, autoimmune cytopenia, interstitial lung disease (ILD), etc.] on 1 hand and immune deficiency (hypogammaglobulinemia, recurrent infections, bronchiectasis, etc.) on the other hand. Chronic lung disease is frequently seen in LRBA deficiency and is associated with poor outcomes. Case Presentation: This case report evaluates a female who presented with recurrent pneumonia and bronchiectasis but did not respond to treatment; she was lastly diagnosed with ILD with detailed clinical, radiological, and pathological workup. Conclusions: The respiratory characteristics of patients with LRBA deficiency should be investigated, monitored, and treated from the time of its diagnosis. The awareness and involvement of pulmonologists to pulmonary morbidity of patients with LRBA deficiency in workup and clinical decision making are crucial. [ABSTRACT FROM AUTHOR]

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is an immune deregulation disorder with varied clinical presentation which clinically overlaps with widespread tropical infections. Methods: We conducted a retrospective chart review of children diagnosed with HLH at our center from February‐2017 to October‐2020. Results: Out of the nine diagnosed patients, genetic predisposition was present in three children; two had identified infectious triggers. The mean age of presentation was 30 months with male predominance. The most common clinical findings were fever, organomegaly, and pancytopenia. The median value of fibrinogen was‐156 mg/dL, ferritin‐12 957 ng/mL and for triglycerides‐349 mg/dL, respectively. In children with identified genetic predisposition, serum ferritin levels were usually more than 10 000 ng/mL. The majority of our patients had evidence of hemophagocytosis on bone marrow examination. In our experience, although nonspecific, very high ferritin and serum triglycerides with low fibrinogen in a patient with bi‐cytopenia, pancytopenia was the most suggestive evidence of HLH. Genetic evaluation in our series identified three children, one with primary HLH genetic mutation and two with underlying immune deficiency syndrome. The presence of HLH in the accelerated phase of Chediak‐Higashi and AD Hyper IgE syndrome with HLH is extremely rare. Leishmaniasis (in nonendemic area) and Ebstein‐Barr virus (EBV) was identified as an infectious trigger in two cases. Most of our cases received treatment as per HLH 2004 protocol. Three children died during the initial diagnosis and treatment. HLH with subcutaneous panniculitis‐like T‐cell lymphoma recovered well. Conclusion: HLH remains a life‐threatening disorder associated with a variety of underlying illnesses as highlighted by our case series. [ABSTRACT FROM AUTHOR]

STAT3 hyper-immunoglobulin E syndrome (STAT3-HIES) is a rare primary immunodeficiency syndrome characterized by elevated serum immunoglobulin E levels, eczema, recurrent skin and respiratory tract infections, and several gastrointestinal (GI) problems. GI manifestations, such as gastroesophageal reflux disease, dysphagia, abdominal pain, gut dysmotility, bowel perforation, eosinophilic esophagitis, and diarrhea, have been reported in 60% of patients. Until now, there was no efficient treatment that could effectively manage all aspects of the syndrome. In this report, we present the case of a 21-year-old man who suffered from undetectable pathogenic refractory diarrhea that persisted >21 days despite aggressive antibiotic and steroid treatment since he was 2 years old. STAT3 Int10(22)A > G splicing mutation-caused STAT3-HIES was diagnosed by next-generation sequencing. The patient had suffered recurrent intestinal and colon perforations since he was 10 years old. He had received multiple surgeries and continuous systemic intravenous immunoglobulin therapy to manage his GI symptoms. However, refractory diarrhea occurring >5 to 6 times per day with severe eczematous dermatitis and frequent abscess formation remained threats to his life. Dupilumab 300 mg every 3 weeks was prescribed to control his skin problems, but the patient's diarrhea also completely subsided. As such, it appears that dupilumab may not only effectively treat the skin inflammation but also the GI manifestation-related inflammation of STAT3-HIES refractory to traditional immunomodulators. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess associations between neutrophil‐related primary immunodeficiencies (PIDs) and the presence of periodontal disease and other oral diseases and response to periodontal treatment. Background: Presence of neutrophil‐related PIDs is thought to be a major risk factor for development of periodontitis. Methods: This study had both a cross‐sectional and cohort design. Twenty‐four children (age 4–16) with PIDs and 24 age‐matched systemically healthy subjects received a dental clinical examination, including measures of probing pocket depths (PPD), clinical attachment loss (CAL) and bleeding on probing (BOP). Those found to be affected by periodontal disease were offered periodontal treatment and reassessed 6 months later. Results: Diagnosis of PIDs was associated with increased odds of presence of periodontal disease (p =.008 adjusted for age, gender, plaque, OR = 10.0, 95% CI = 1.83–54.38) and with continuous measures of periodontal disease such as number of PPDs >4 mm, mean PPD and mean CAL (all p <.001) and BOP (p =.001). However, only 7 out of 24 children were diagnosed with periodontitis. PIDs were also associated with a history of oral ulcers (p =.001, OR 12.47, 95% CI 2.71–57.29). An improvement in periodontal parameters (PPD and CAL) was detected following oral hygiene instructions and non‐surgical periodontal therapy. Conclusion: Although children affected by neutrophil‐associated PIDs exhibited a higher prevalence of periodontal disease compared with systemically healthy children, severe periodontitis was rarely seen. This suggests that good systemic control of the PIDs may reduce their impact on the periodontium. [ABSTRACT FROM AUTHOR]

Objectives: A prior T cell depletion induced by HIV infection may carry deleterious consequences in the current COVID‐19 pandemic. Clinical data on patients co‐infected with HIV and SARS‐CoV‐2 are still scarce. Methods: This multicentre cohort study evaluated risk factors for morbidity and mortality of COVID‐19 in people living with HIV (PLWH), infected with SARS‐CoV‐2 in three countries in different clinical settings. COVID‐19 was clinically classified as to be mild‐to‐moderate or severe. Results: Of 175 patients, 49 (28%) had severe COVID‐19 and 7 (4%) patients died. Almost all patients were on antiretroviral therapy (ART) and in 94%, HIV RNA was below 50 copies/mL prior to COVID‐19 diagnosis. In the univariate analysis, an age 50 years or older, a CD4+ T cell nadir of < 200/µl, current CD4+ T cells < 350/µl and the presence of at least one comorbidity were significantly associated with severity of COVID‐19. No significant association was found for gender, ethnicity, obesity, a detectable HIV RNA, a prior AIDS‐defining illness, or tenofovir (which was mainly given as alafenamide) or protease inhibitor use in the current ART. In a multivariate analysis, the only factor associated with risk for severe COVID‐19 was a current CD4+ T cell count of < 350/µl (adjusted odds ratio 2.85, 95% confidence interval 1.26‐6.44, p=0.01). The only factor associated with mortality was a low CD4 T cell nadir. Conclusions: In PLWH, immune deficiency is a possible risk factor for severe COVID‐19, even in the setting of virological suppression. There is no evidence for a protective effect of PIs or tenofovir alafenamide. [ABSTRACT FROM AUTHOR]

Objective: Primary immunodeficiencies (PIDs) consist of genetically heterogeneous disorders. The spectrum can include infectious diseases, malignancy, allergy, and autoimmunity. We aimed to analyze the frequency and variety of autoimmune diseases (ADs) in PIDs and describe their clinical and laboratory features. Materials and Methods: Ninety-two patients with PID followed by Ege University Medical Faculty between 2000 and 2017 were enrolled in this retrospective, cross-sectional study. All patients' medical records were reviewed using the demographic information, type of PIDs and ADs, ADs-related autoantibodies, and basic and immunologic laboratory findings. ADs were diagnosed using clinical and complementary paraclinical findings by an immunologist and/or a subspecialist related to the affected organ or system. Results: We evaluated 50 male and 42 female PID patients with a mean age of 40.92 (18-86). Twenty-nine (32 %) patients (15 females/14 males) with a mean age of 43.8 (19-78) had ADs. In our study group, the most commonly detected type of PID with AD is common variable immune deficiency (CVID) (n=17); followed by combined immune deficiency (CID) (n=3), CTLA4 deficiency (n=2), selective IgA deficiency (sIgAD) (n=2), specific IgG subgroup deficiency (n=1), autoimmune polyglandular syndrome (APS) with hypogammaglobulinemia (n=1), dyskeratosis congenita (DC) (n=1), Osler-Rendu-Weber (ORW) syndrome with CVID-like PID (n=1), and cartilage-hair hypoplasia (CHH) (n=1). According to systematic assessments, ADs resulted in endocrinologic 14%, dermatologic 10.8%, rheumatologic 9.7%, gastroenterological 9.7%, hematological 8.6%, and neurologic disorders 1%. The frequency of ADs was higher in CVID cases than other types of PIDs (p <0.05). Basic and immunologic laboratory findings of the PIDs with and without ADs were analyzed and compared; however, no statical significant difference was obtained between the groups. Conclusion: We have analyzed the frequency and variety of ADs in a adult PID cohort in Turkey. Patients presenting with multiple ADs should be screened for having an underlying PID. [ABSTRACT FROM AUTHOR]

Primary immune regulatory disorders (PIRDs) are a group of diseases belonging to inborn errors of immunity. They usually exhibit lymphoproliferation, autoimmunities, and malignancies, with less susceptibility to recurrent infections. Unlike classical primary immune deficiencies, autoimmune manifestations, such as cytopenias, enteropathy can be the first symptom of diseases, and they are typically resistant to treatment. Increasing awareness of PIRDs among specialists and a multidisciplinary team approach would provide early diagnosis and treatment that could prevent end-organ damage related to the diseases. In recent years, many PIRDs have been described, and understanding the immunological pathways linked to these disorders provides us an opportunity to use directed therapies for specific molecules, which usually offer better disease control than known classical immunosuppressants. In this review, in light of the most recent literature, we will discuss the common PIRDs and explain their clinical symptoms and recent treatment modalities. [ABSTRACT FROM AUTHOR]

It is generally accepted that persons infected with human immunodeficiency virus (HIV) are at an increased risk of infection due to direct destruction of CD4+ lymphocytes and subsequently impaired cell-mediated immunity. Typically, HIV infection is associated with immunoglobulin elevations, but quantitative deficiencies in immunoglobulins have also been rarely described. We present an unusual case of common variable immunodeficiency (CVID) in a HIV-positive patient with recurrent severe respiratory infections. We review epidemiology, clinical presentation, and treatment of primary immunoglobulin deficiency. We also review the relationship between immunoglobulin deficiency and HIV and highlight the importance of recognizing the coexistence of two distinct immunodeficiency syndromes. [ABSTRACT FROM AUTHOR]

Common variable immune deficiency (CVID) is a rare primary immunodeficiency disorder that is characterized by defective antibody production and inadequate B cell differentiation. While frequently recurrent respiratory tract infections are the most prominent clinical feature in CVID patients, CVID is a heterogeneous immune deficiency disorder that involves many systems and organs such as lymphoid hyperplasia, autoimmune cytopenia, chronic lung diseases, granulomatous diseases and susceptibility to malignancy. This may lead to delay in diagnosis and immunoglobulin replacement therapy, not being able to receive antibiotics at the appropriate dose and time, chronic inflammation, and therefore secondary amyloidosis. In this case report it is aimed to present a CVID patient with autoimmune complications and developing renal amyloidosis during follow-up. [ABSTRACT FROM AUTHOR]

Background: Persistent hepatitis E virus (HEV) infection is described in a number of immunosuppressive conditions. We aimed to determine the risk of persistent HEV infection in patients with primary or secondary antibody deficiency.Methods: Two hundred forty-five antibody-deficient patients receiving regular immunoglobulin replacement therapy were tested for HEV RNA and anti-HEV immunoglobulin G (IgG). Immunoglobulin products and plasma specimens obtained from 9 antibody-deficient patients before and after intravenous immunoglobulin (IVIG) therapy, 5 recently treated patients with persistent HEV infection, and 5 healthy patients recovered from acute HEV infection were analyzed for anti-HEV IgG and for antibody reacting with HEV antigen.Results: No antibody-deficient patient had detectable plasma HEV RNA. Anti-HEV IgG was detected in 38.8% of patients. All 10 immunoglobulin products tested contained anti-HEV capable of neutralizing HEV antigen. Plasma samples collected following IVIG infusion therapy demonstrated a higher anti-HEV IgG level and neutralizing activity, compared with samples collected before IVIG therapy. Neutralizing activity was similar to that in healthy patients with recent acute HEV infection.Conclusion: The risk of persistent HEV infection in patients with antibody deficiency appears extremely low. This may be due to passive seroprotection afforded by the ubiquitous presence of anti-HEV in immunoglobulin replacement products. [ABSTRACT FROM AUTHOR]

Primary immune deficiency disease (PIDD) is a hereditary disorder, attributable to inherent defects in diverse elements of the immune system. PIDD causes susceptibility to infections and is frequently associated with a tendency to autoimmunity and/or immune dysregulation. Up-to-date, more than 330 PIDD have been defined and the molecular (genetic) origins for more than 320 of them are described. In this group, primary antibody deficiencies are the most common group and approximately 50% of PIDD patients have this defect. Clinical findings of PIDD typically appear early in life, although cases with delayed onset are progressively more documented. Affected PIDD patients usually manifest in clinic with recurrent infections, severe infections, or both, plus autoimmunity development that are accompanied with most of the PIDD. Timely diagnosis is indispensable for transferring patients to specialized centers and the commencement of proper treatment including stem cell transplantation. Consequently, the prompt diagnosis of PIDD is necessary for best possible management and better outcomes. In this review, a basic approach for the exploration of the most common PIDDs is described, outlining some of the typical clinical findings and most appropriate laboratory investigations from simple complete blood count to advanced genetic tests such as next generation sequencing. [ABSTRACT FROM AUTHOR]

Selective IgA deficiency is defined as absolute or partial when serum IgA level is < 7 mg/dl or 2 SD below normal for age, respectively. Few data are available on partial selective IgA deficiency, as probably most children with low serum IgA are seldom referred to a specialist clinic in common pediatric practice. The aim of our study was to better define the profile of both symptomatic forms and their clinical outcome in a pediatric immunology setting. Thus, clinical and immunological data from 103 symptomatic patients with selective IgA deficiency (53 absolute and 50 partial), 4-18 years of age, were collected at diagnosis and 80 patients (44 absolute and 36 partial) were monitored for a mean period of 5 years. Also, the prevalence of TNFRSF13B mutations has been assessed in 56 patients. The most common clinical features were infections (86/103; 83%), allergy (39/103; 38%), and autoimmunity (13/103; 13%). No significative differences were observed between absolute and partial selective IgA deficiency patients. However, a significative difference in the rate of IgA normalization between partial and absolute selective IgA deficiency patients (33 vs 9%, p = 0.01) was detected. Furthermore, a lower incidence of infections was associated to a normalization reversal compared to a final absolute or partial defect status (12 vs 53 and 64% respectively, p < 0.01).Conclusions: Regardless of a diagnosis of absolute or partial defect, monitoring of symptomatic patients with selective IgA deficiency is recommended overtime for prompt identification and treatment of associated diseases. Further, diagnostic workup protocols should be revisited in children with IgA deficiency. What is Known: ● Selective IgA Deficiency is the most common primary immunodeficiency and is usually asymptomatic. ● Symptomatic pediatric patients with selective IgA deficiency mostly suffer with respiratory and gastrointestinal infections. What is New: ● Symptomatic children with partial IgA defect may have similar clinical, immunological, and genetic features than symptomatic children with absolute IgA deficiency. ● Symptomatic children with partial IgA deficiency deserve accurate monitoring for associated diseases as per children with absolute IgA deficiency. [ABSTRACT FROM AUTHOR]

Primary immunodeficiency (PID) diseases result from genetic defects of the immune system that increase a patient's susceptibility to infections. The types of infections that occur in patients with PID diseases are dictated largely by the nature of the immunodeficiency, which can be defined by dysfunction of cellular or humoral defenses. An increasing number of PID diseases, including those with both cellular and humoral defects, have antibody deficiency as a major feature, and as a result can benefit from immunoglobulin replacement therapy. In fact, the most common PID diseases worldwide are antibody deficiencies and include common variable immunodeficiency, congenital agammaglobulinemia, hyper-IgM syndrome, specific antibody deficiency, and Good syndrome. Although immunoglobulin replacement therapy is the cornerstone of treatment for the majority of these conditions, a thorough understanding of the specific infections for which these patients are at increased risk can hasten diagnosis and guide additional therapies. Moreover, the infection trends in some patients with PID disease who have profound defects of cellular immunity, such as autosomal-dominant hyper-IgE syndrome (Job/Buckley syndrome) or dedicator of cytokinesis 8 (DOCK8) deficiency, suggest that select patients might benefit from immunoglobulin replacement therapy even if their immunodeficiency is not limited to antibody defects. In this review, we provide an overview of the predisposition to infections seen in PID disease that may benefit from immunoglobulin replacement therapy. [ABSTRACT FROM AUTHOR]

The article presents the case study of a 48-year-old male patient with common variable immunodeficiency enteropathy. The patient's medical history is discussed whose common variable deficiency was previously treated with immunosuppressive agents, however, he suffered from side effects and developed chronic norovirus infection and bronchiolitis. The patient received favipiravir that led to mutagenesis in norovirus and died from respiratory failure.

Background: After hematopoietic stem cell transplantation (HSCT) autoimmune hemolytic anemia (AIHA) is a known and fairly common complication. It is often refractory to conventional therapies including corticosteroids, intravenous immunoglobulin, splenectomy, and the more recently described use of monoclonal antibodies. The high morbidity associated with these severe persistent cases elucidates the gaps in alternative therapies available for treatment.Study Design and Methods: We described the successful use of abatacept for severe refractory AIHA after HSCT in three patients.Results: Three pediatric patients with refractory AIHA after allogeneic stem cell transplantation were observed to be unresponsive to multitude immunosuppressive therapies, resulting in persistent transfusion dependency. Treatment with abatacept, a fusion protein that inhibits T-cell activation by binding to CD80/CD86 on antigen-presenting cells (APCs), thus blocking the required CD28 interaction between APCs and T cells, resulted in the resolution of hemolysis.Conclusion: Abatacept may provide significant clinical benefit in the management of AIHA after HSCT. [ABSTRACT FROM AUTHOR]

Nontuberculous mycobacteria (NTM) are categorized as one of the large and diverse groups of environmental organisms which are abundant in water and soil.  NTM cause a variety of diseases in humans that mainly affect the lung. A predisposition to pulmonary NTM is evident in patients with parenchymal structural diseases including bronchiectasis, emphysema, tuberculosis (TB), cystic fibrosis (CF), rheumatologic lung diseases and other chronic diseases with pulmonary manifestations. Lung infections are not the only consequences of being infected by NTM as they can also infect skin and soft tissue and may also cause lymphadenitis (predominantly in young children) and disseminated disease in human immunodeficiency virus (HIV)-infected patients or those with severely compromised immune system. NTM are also found in many subjects without any known risk factors.  Although the recent advances in imaging and microbiologic techniques including gene sequencing have provided a better view of the problems caused by NTM and has enhanced our understanding of the disease, many uncertainties regarding the immunologic response to NTM still exist. There is also limited data on the immunogenetics of NTM infection. Here, the authors reviewed the main immunogenetic defects as well as other immunological conditions which are associated with an increased the risk of NTM infections. [ABSTRACT FROM AUTHOR]

We present a 30-year-old combat veteran with an unclear exposure history, with multiple deployments who was later diagnosed with acute renal failure as a result of light-chain deposition disease. Despite a drastic decline in kappa light chains following chemotherapy; his renal function worsened, and he progressed to end-stage renal disease, requiring hemodialysis. Light-chain-mediated acute tubular interstitial nephritis is an uncommon type of monoclonal gammopathy of renal significance presenting with acute renal failure without significant glomerular disease. Our case illustrates that light-chain-mediated acute tubular interstitial nephritis may present clinically like acute interstitial nephritis and that renal biopsy is critical for diagnosis. We also explore possible links between various environmental and occupational exposures that could have precipitated his disease process at such a young age. [ABSTRACT FROM AUTHOR]

Background: Cough is a common symptom prompting patients to seek medical care. Like patients in the general population, patients with compromised immune systems also seek care for cough. However, it is unclear whether the causes of cough in immunocompromised patients who are deemed unlikely to have a life-threating condition and a normal or unchanged chest radiograph are similar to those in persons with cough and normal immune systems.Methods: We conducted a systematic review to answer the question: What are the most common causes of cough in ambulatory immunodeficient adults with normal chest radiographs? Studies of patients ≥ 18 years of age with immune deficiency, cough of any duration, and normal or unchanged chest radiographs were included and assessed for relevance and quality. Based on the systematic review, suggestions were developed and voted on using the American College of Chest Physicians (CHEST) methodology framework.Results: The results of the systematic review revealed no high-quality evidence to guide the clinician in determining the likely causes of cough specifically in immunocompromised ambulatory patients with normal chest radiographs.Conclusions: Based on a systematic review, we found no evidence to assess whether or not the proper initial evaluation of cough in immunocompromised patients is different from that in immunocompetent persons. A consensus of the panel suggested that the initial diagnostic algorithm should be similar to that for immunocompetent persons but that the context of the type and severity of the immune defect, geographic location, and social determinants be considered. The major modifications to the 2006 CHEST Cough Guidelines are the suggestions that TB should be part of the initial evaluation of patients with cough and HIV infection who reside in regions with a high prevalence of TB, regardless of the radiographic findings, and that specific causes and immune defects be considered in all patients in whom the initial evaluation is unrevealing. [ABSTRACT FROM AUTHOR]

The present study was carried out with the objectives of genotyping Pneumocystis jirovecii at three distinct loci, to identify the single nucleotide polymorphisms (SNPs), and to study its clinical implications in patients with Pneumocystis pneumonia (PCP). Analysis of genetic diversity in P. jirovecii from immunocompromised patients was carried out by genotyping at three distinct loci encoding mitochondrial large subunit rRNA (mtLSU rRNA), cytochrome b (CYB), and superoxide dismutase (SOD) using polymerase chain reaction (PCR) assays followed by direct DNA sequencing. Of the 300 patients enrolled in the present study, 31 (10.33%) were positive for PCP by a specific mtLSU rRNA nested PCR assay, whereas only 15 P. jirovecii could be amplified at the other two loci (SOD and CYB). These positives were further subjected to sequence typing. Important genotypic combinations between four SNPs (mt85, SOD110, SOD215, and CYB838) and clinical outcomes could be observed in the present study, and mt85A, mt85T, and SOD110C/SOD215T were frequently associated with 'negative follow-up'. These SNPs were also noted to be relatively more prevalent amongst circulating genotypes in our study population. The present study is the first of its kind from the Indian subcontinent and demonstrated that potential SNPs of P. jirovecii may possibly be attributed to the clinical outcome of PCP episodes in terms of severity or fatality in different susceptible populations likely to develop PCP during their course of illness. [ABSTRACT FROM AUTHOR]

Rationale: Maintenance of a surface immune barrier is important for homeostasis in organs with mucosal surfaces that interface with the external environment; however, the role of the mucosal immune system in chronic lung diseases is incompletely understood.Objectives: We examined the relationship between secretory IgA (SIgA) on the mucosal surface of small airways and parameters of inflammation and airway wall remodeling in chronic obstructive pulmonary disease (COPD).Methods: We studied 1,104 small airways (<2 mm in diameter) from 50 former smokers with COPD and 39 control subjects. Small airways were identified on serial tissue sections and examined for epithelial morphology, SIgA, bacterial DNA, nuclear factor-κB activation, neutrophil and macrophage infiltration, and airway wall thickness.Measurements and Main Results: Morphometric evaluation of small airways revealed increased mean airway wall thickness and inflammatory cell counts in lungs from patients with COPD compared with control subjects, whereas SIgA level on the mucosal surface was decreased. However, when small airways were classified as SIgA intact or SIgA deficient, we found that pathologic changes were localized almost exclusively to SIgA-deficient airways, regardless of study group. SIgA-deficient airways were characterized by (1) abnormal epithelial morphology, (2) invasion of bacteria across the apical epithelial barrier, (3) nuclear factor-κB activation, (4) accumulation of macrophages and neutrophils, and (5) fibrotic remodeling of the airway wall.Conclusions: Our findings support the concept that localized, acquired SIgA deficiency in individual small airways of patients with COPD allows colonizing bacteria to cross the epithelial barrier and drive persistent inflammation and airway wall remodeling, even after smoking cessation. [ABSTRACT FROM AUTHOR]

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review primary immunodeficiency and related lymphoproliferations.Methods: Primary immunodeficiencies were divided into immune dysregulation, DNA repair defects, low immunoglobulins, and combined immunodeficiencies.Results: Autoimmune lymphoproliferative syndrome (ALPS) is a prototypical immune dysregulation-type immunodeficiency, with defects in T-cell signaling or apoptosis, expansion of T-cell subsets, and predisposition to hemophagocytic lymphohistiocytosis. DNA repair defects directly predispose to malignancy. Low immunoglobulin immunodeficiencies such as common variable immunodeficiency (CVID) have underlying T-cell repertoire abnormalities predisposing to autoimmunity and B-cell lymphoproliferations. The full spectrum of B-cell lymphoproliferative disorders occurs in primary immunodeficiency.Conclusions: Lymphoproliferations in primary immunodeficiency mirror those in other immunodeficiency settings, with monomorphic B- and sometimes T lymphoproliferative disorders enriched in DNA repair defects. Distinctive T-cell subset expansions in ALPS, CVID, and related entities can mimic lymphoma, and recognition of double-negative T-cell or cytotoxic T-cell expansions is key to avoid overdiagnosis. [ABSTRACT FROM AUTHOR]

Widespread use of oral poliovirus vaccine has led to an ≈99.9% decrease in global incidence of poliomyelitis (from ≈350,000 cases in 1988 to 74 cases in 2015) and eradication of wild-type poliovirus serotypes 2 and 3. However, patients with primary immunodeficiency might shed vaccine-derived polioviruses (VDPVs) for an extended period, which could pose a major threat to polio eradication programs. Since 1995, sixteen VDPV populations have been isolated from 14 patients with immunodeficiency in Iran. For these patients, vaccine-associated paralysis, mostly in >1 extremity, was the first manifestation of primary immunodeficiency. Seven patients with humoral immunodeficiency cleared VDPV infection more frequently than did 6 patients with combined immunodeficiencies. Our results raise questions about manifestations of VDPVs in immunodeficient patients and the role of cellular immunity against enterovirus infections. On the basis of an association between VDPVs and immunodeficiency, we advocate screening of patients with primary immunodeficiency for shedding of polioviruses. [ABSTRACT FROM AUTHOR]

Objectives: Patients with primary immunodeficiency diseases (PID) are highly susceptible to various microorganisms. However, no population-based studies have been performed among common viral pathogens, such as respiratory syncytial virus (RSV), rotavirus (RV), varicella-zoster virus (VZV) and influenza virus (IV). The objective of this study was to reveal the clinical burden of these four infections among PID patients in Japan.Methods: We conducted a nationwide survey by sending questionnaires to 898 hospitals with pediatric departments throughout Japan.Results: Nine hundred ten PID patients from 621 hospitals were registered (response rate: 69.2%). Fifty-four of the patients were hospitalized due to these viral infections. The durations of hospitalization due to RSV and RV infections differed significantly in the PID patients with and without cellular immunodeficiency (12.0 vs 6.5 days, p = 0.041; and 14.0 vs 6.0 days, p = 0.031, respectively). There was no significant difference in the duration of hospitalization in PID patients with and without cellular immunodeficiency who were hospitalized with IV infections (7.3 vs 6.1 days, p = 0.53).Conclusions: Special attention should be paid to PID patients with compromised cellular immunity who present with RSV and RV infection due to their high risk for severe disease. [ABSTRACT FROM AUTHOR]

Rationale: Granulomatous-lymphocytic interstitial lung disease (GLILD) has emerged as a major cause of morbidity in patients with common variable immunodeficiency (CVID). While GLILD is among the most serious noninfectious pulmonary complications of CVID, risk factors for this condition have not been reported.Objectives: To identify clinical, physiologic, and serologic risk factors for GLILD in adults with CVID.Methods: Of 345 consecutive adult patients with CVID, we identified 34 in the National Jewish Health research database who had a radiographic-pathologic diagnosis of GLILD evaluated between 2002 and 2014. Each case was age and sex matched to 52 CVID control subjects. We used logistic regression to determine independent predictors of GLILD. A mixed effects model was used to estimate the longitudinal change in percent predicted FVC.Measurements and Main Results: The mean time from CVID diagnosis to GLILD detection was 7.8 years. Compared with matched control subjects, cases were more likely to have a history of autoimmune cytopenia, hypersplenism, polyarthritis, lower marginal zone and switched memory B cells, and restrictive lung function. Multivariate analysis revealed that hypersplenism (odds ratio [OR], 24; 95% confidence interval [CI], 4.5-179.1), polyarthritis (OR, 19; 95% CI, 2.3-206.8), and percent predicted FVC (OR, 0.93; 95% CI, 0.87-0.98) were independently associated with the development of GLILD. The rate of change of percent predicted FVC (slope, P = 0.48) did not vary significantly in patients with GLILD over a mean follow-up of 7 years after diagnosis.Conclusions: Hypersplenism and polyarthritis are strong risk factors for GLILD in patients with CVID. Percent predicted FVC remained stable over time in patients with GLILD. [ABSTRACT FROM AUTHOR]

We characterized 54 adult index patients with reports of frequent or severe bacterial respiratory tract infections at diagnosis of selective subnormal IgG1. Mean age was 50 ± 13 (SD) y; 87.0% were women. Associated disorders included the following: autoimmune conditions 50.0%; hypothyroidism 24.1%; atopy 38.9%; and other allergy 31.5%. In 35.5%, proportions of protective S. pneumoniae serotype-specific IgG levels did not increase after polyvalent pneumococcal polysaccharide vaccination (PPPV). Blood lymphocyte subset levels were within reference limits in most patients. Regressions on IgG1 and IgG3 revealed no significant association with age, sex, autoimmune conditions, hypothyroidism, atopy, other allergy, corticosteroid therapy, or lymphocyte subsets. Regression on IgG2 revealed significant associations with PPPV response (negative) and CD19+ lymphocytes (positive). Regression on IgG4 revealed significant positive associations with episodic corticosteroid use and IgA. Regression on IgA revealed positive associations with IgG2 and IgG4. Regression on IgM revealed negative associations with CD56+/CD16+ lymphocytes. Regressions on categories of infection revealed a negative association of urinary tract infections and IgG1. HLA-A(⁎)03, HLA-B(⁎)55 and HLA-A(⁎)24, HLA-B(⁎)35 haplotype frequencies were greater in 38 patients than 751 controls. We conclude that nonprotective S. pneumoniae IgG levels and atopy contribute to increased susceptibility to respiratory tract infections in patients with selective subnormal IgG1. [ABSTRACT FROM AUTHOR]

CD4+ T follicular helper cells (TFH) were assessed in adult patients with common variable immune deficiency (CVID) classified according to the presence of granulomatous disease (GD), autoimmunity (AI), or both GD and AI (Group I) or the absence of AI and GD (Group II). TFH lymphocytes were characterized by expression of CXCR5 and PD-1. TFH were higher (in both absolute number and percentage) in Group I than in Group II CVID patients and normal controls (N). Within CXCR5+CD4+ T cells, the percentage of PD-1 (+) was higher and that of CCR7 (+) was lower in Group I than in Group II and N. The percentages of Treg and TFH reg were similar in both CVID groups and in N. TFH responded to stimulation increasing the expression of the costimulatory molecules CD40L and ICOS as did N. After submitogenic PHA+IL-2 stimulation, intracellular expression of TFH cytokines (IL-10, IL-21) was higher than N in Group I, and IL-4 was higher than N in Group II. These results suggest that TFH are functional in CVID and highlight the association of increased circulating TFH with AI and GD manifestations. [ABSTRACT FROM AUTHOR]

Background: Fusarium species are ubiquitous environmental fungi that occasionally provoke serious invasive infections in immunocompromised hosts. Among Fusarium species, Fusarium ramigenum, belonging to the Fusarium fujikuroi species complex, has thus far never been found to cause human infections. Here we describe the first case of invasive fusariosis caused by Fusarium ramigenum in a human and also identify immunological deficiencies that most likely contributed to invasiveness.Case Presentation: A 32-year-old Caucasian male with a seemingly insignificant medical history of mild respiratory illness during the preceding two years, developed invasive pulmonary fusariosis. Detailed immunological assessment revealed the presence of common variable immunodeficiency, complicated by a severe impairment of the capacity of T-cells to produce both gamma-interferon and interleukin-17. In-depth microbiological assessment identified the novel human opportunistic pathogen Fusarium ramigenum as cause of the infection.Conclusion: This report demonstrated that an opportunistic invasive fungal infection may indicate an underlying cellular immune impairment of the host. The unexpected invasive infection with Fusarium ramigenum in this case unmasked a complex combined humoral and cellular immunological deficiency. [ABSTRACT FROM AUTHOR]

Rationale: Immunocompromised patients are at high risk for developing severe sepsis. Currently, there are no validated strategies for identifying this group of patients in large administrative databases.Objectives: We set out to define and validate a method that could be used to identify immunocompromised patients with severe sepsis in administrative databases.Methods: Patients were categorized as immunocompromised based on the presence of International Classification of Diseases, 9th revision discharge diagnosis codes and medication data. We validated this strategy by comparing the discriminatory ability of the search algorithm to that of manual chart review.Measurements and Main Results: We identified 4,438 patients at a single academic center with severe sepsis using a definition applied to administrative data described by Angus and colleagues. There were 1,185 (26.7%) who were categorized as immunocompromised based on our novel administrative data search strategy. Compared with identification by medical record review, the new administrative data search strategy had positive and negative predictive values of 94.4% (95% confidence interval [CI], 88.8-97.7%) and 94.3% (95% CI, 91.0-96.6%). The sensitivity and specificity were 87.4% (95% CI, 80.6-92.5%) and 97.6% (95% CI, 95.0-99.9%).Conclusions: Patients who are immunosuppressed are a large subgroup of those with severe sepsis. Following its validation as a search strategy using other large databases, and its adaptation for International Classification of Diseases, 10th revision, this novel method may allow researchers to account for a patient's immune state when examining outcomes. [ABSTRACT FROM AUTHOR]

Background: A small number of individuals with B-cell-related primary immunodeficiency diseases (PIDs) may exhibit long-term (prolonged or chronic) excretion of immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) following infection with oral poliovirus vaccine (OPV). These individuals pose a risk of live poliovirus reintroduction into the population after global wild poliovirus eradication and subsequent OPV cessation. Treatment with polio antiviral drugs may potentially stop excretion in some of these individuals and thus may reduce the future population risk.Methods: We developed a discrete event simulation model to characterize the global prevalence of long-term iVDPV excretors based on the best available evidence. We explored the impact of different assumptions about the effectiveness of polio antiviral drugs and the fraction of long-term excretors identified and treated.Results: Due to the rarity of long-term iVDPV excretion and limited data on the survival of PID patients in developing countries, uncertainty remains about the current and future prevalence of long-term iVDPV excretors. While the model suggests only approximately 30 current excretors globally and a rapid decrease after OPV cessation, most of these excrete asymptomatically and remain undetected. The possibility that one or more PID patients may continue to excrete iVDPVs for several years after OPV cessation represents a risk for reintroduction of live polioviruses after OPV cessation, particularly for middle-income countries. With the effectiveness of a single polio antiviral drug possibly as low as 40% and no system in place to identify and treat asymptomatic excretors, the impact of passive use of a single polio antiviral drug to treat identified excretors appears limited. Higher drug effectiveness and active efforts to identify long-term excretors will dramatically increase the benefits of polio antiviral drugs.Conclusions: Efforts to develop a second polio antiviral compound to increase polio antiviral effectiveness and/or to maximize the identification and treatment of affected individuals represent important risk management opportunities for the polio endgame. Better data on the survival of PID patients in developing countries and more longitudinal data on their exposure to and recovery from OPV infections would improve our understanding of the risks associated with iVDPV excretors and the benefits of further investments in polio antiviral drugs. [ABSTRACT FROM AUTHOR]

The article presents a case study of corticosteroid-responsive longitudinally extensive transverse myelitis and granulomatous lung lesions in a 41-year-old Caucasian woman. She has a previous history of recurrent generalised lymphadenopathy, pyogenic infections and idiopathic thrombocytopenic purpura. The patient's clinical examination and therapeutic managemenent are discussed. It also talks about relatively common immunodeficiency disease and range of neurological syndromes.

Primary immunodeficiency disorders (PIDs) constitute a heterogeneous group of genetic disorders caused by defects in immunity, leading to recurrent infections, autoimmunity, lymphoproliferation and malignancies. Early diagnosis of PIDs is crucial for improving the quality of life in patients with PIDs while a delay in diagnosis, or inadequate treatment, results in an increased mortality and morbidity in affected individuals. Although most cases of PIDs present in children with recurrent and/or severe acute infections, some of the primary immune disorders are diagnosed during adulthood. Some common clues, both in children and adults, help physicians to diagnose PIDs; however, there are some specific clues to the diagnosis of PIDs for each group. This article reviews the important differences in the diagnostic spectrum of PIDs in adults versus children. [ABSTRACT FROM AUTHOR]

The article presents case study of a 15-year-old boy with septic arthritis associated with autosomal dominant hyper IgE syndrome type 1 (HIES). Topics discussed include information on the use of intravenous cefazolin and vancomycin; characteristics of septic arthritis such as severe pain, swelling, redness, heat and joint effusion; and observation of the levels of white blood cell (WBC) count and C-reactive protein (CRP).

Spontaneous pneumothorax occurs in up to 35% of patients with Pneumocystis jirovecii pneumonia. However, spontaneous pneumomediastinum and pneumopericardium are uncommon complications in patients infected with human immunodeficiency virus, with no reported incidence rates, even among patients with acquired immunodeficiency syndrome (AIDS) and P. jirovecii pneumonia. We report a case of spontaneous pneumomediastinum, pneumopericardium, and pneumothorax with respiratory failure during treatment of P. jirovecii pneumonia in a patient with AIDS; the R jirovecii infection was confirmed by performing methenamine silver staining of bronchoalveolar lavage specimens. This case suggests that spontaneous pneumomediastinum and pneumopericardium should be considered in patients with AIDS and P. jirovecii pneumonia. [ABSTRACT FROM AUTHOR]

Background and purpose: Autosomal dominant Hyper IgE syndrome (AD-HIES) is a rare and complex primary immunodeficiency that affects multiple systems. Mutations in signal transducer and activator of transcription 3 ( STAT3) gene cause AD-HIES. These mutations have a dominant-negative effect and the presence of such mutations is associated with a clinical phenotype. We aim to describe genetic and clinical characteristics of patients with AD-HIES in our clinic and to highlight the variability of clinical patterns in the same family. Methods: We describe six patients, four individuals of the same family and two unrelated patients. All patients were given a clinical score based on disease phenotype according to the National Institute of Health (NIH) score. Mutation analysis of STAT3 was done by PCR amplification of all coding exons followed by bidirectional sequencing using the BigDye kit v1.1 and an ABI3700 genetic analyzer (Applied Biosystems). Results: All six patients had DNA binding region point mutations: a proband and his three children with p.Phe384Leu mutation, a patient with p.Arg382Trp substitution and a patient with p.Arg382Gln mutation. All of these mutations were previously reported. Patients differed in infectious, immunologic and somatic features. We observed an extreme variability in disease phenotype within the reported family with one genetically affected patient displaying an 'unaffected' phenotype. Conclusions: Although the genetic cause of AD-HIES is known, more studies are required to better understand the possible additional factors that may affect disease expressivity within families and the clinical diversity of the disease. [ABSTRACT FROM AUTHOR]

Unlabelled: Hyper-IgM syndromes are characterized by normal or elevated serum IgM levels with the absence or reduced levels of other immunoglobulins. There are some patients with defective class-switch recombination (CSR) who do not have CD40L, CD40, AID, and UNG defects. The aim of this study is to determine the B-cell functions of patients with Hyper-IgM type 4 phenotype. Ten patients (seven males and three females) 84.2 ± 16.5 months of age with initial low serum IgG and IgA and high or normal IgM levels were included. Clinically, 50% had recurrent upper respiratory tract, 10% urinary tract, 10% lower respiratory tract infections, and 30% had mixed type infections. Lymphoid hyperplasia, overt autoimmune manifestations, or malignancy was not noted. Seven of 10 patients were studied twice; at the age of 34.2 ± 13.7 and at 86.6 ± 12.3 months. Absolute lymphocyte counts and lymphocyte subsets were normal in all cases. All of them had normal expression of CD40 on B cells and CD40L on activated T cells for males. At first examination, all patients had normal in vitro sCD40L+rIL-4-induced B cell proliferation response and somatic hypermutation but CSR towards IgE was absent. AID and UNG genes did not show any abnormalities. All showed improvement in both clinical findings and Ig levels during the follow-up period of 55.8 ± 14.8 months. Ages for normalization of IgG and IgA were 68.2 ± 8.7 and 70.2 ± 21.6 months, respectively. During the second evaluation: In vitro sCD40L+rIL-4-induced B-cell proliferation was normal in all cases, whereas CSR was still abnormal in five of eight patients. Two of the patients had an increase in in vitro CSR response but still low IgG2 subclass levels. Three patients with initially absent in vitro CSR response also normalized.Conclusion: Clinical manifestations and immunoglobulin levels of the patients with Hyper-IgM type 4 phenotype recovered in late childhood at about 6 years of age. There was a transient CSR defect which was not observed in cases with transient hypogammaglobulinemia of infancy. Detection of a non-AID or non-UNG associated CSR defect in infancy should be confirmed later on since spontaneous recovery may occur. [ABSTRACT FROM AUTHOR]

Serum (1→3)-β-D-Glucan (BG) is a biomarker for Pneumocystis jirovecii pneumonia (PJP). However, information concerning its usefulness for monitoring the clinical course is lacking. We conducted a retrospective study to investigate whether consecutive BG-measurements can be used to assess treatment response in PJP. Analysis of sera from 18 patients during PJP therapy shows that decreasing BG-levels strongly correlate with a favourable clinical course. In contrast, increasing BG-levels were associated with treatment failure or fatal outcome is only 44% of patients. As a consequence, BG-kinetics might be used to confirm treatment success but seem to be of limited value for the identification of treatment failure. [ABSTRACT FROM AUTHOR]

Unlabelled: Hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder, characterized by eczema, recurrent skin and lung infections, and significantly elevated serum IgE level. It was previously diagnosed based on clinical manifestations and laboratory markers that were not specific to the disease. Recent studies have demonstrated that mutations in signal transducer and activator of transcription 3 (STAT3) cause the autosomal dominant or sporadic HIES, which make the disease definitively characterized at molecular level. Here, we reported a 3-year old Chinese boy with neonatal-onset rash and multiple serious Staphylococcus aureus infections including recurrent skin abscesses, liver abscess, sepsis, and destructive pulmonary infection (pneumonia, multiple pulmonary abscesses, pyopneumothorax, and finally, pneumatocele). Genetic study revealed a heterozygous mutation in exon 21 of STAT3 gene (g.66583 A > C, c.1970A > C) in the boy, which resulted in a substitution of tyrosine at the amino acid position 657 to serine (p.Y657S) in the Src homology 2 (SH2) domain of STAT3. Functional prediction with bioinformatics programs of the Sorting Intolerant from Tolerant (SIFT) and the Polymorphism Phenotyping (PolyPhen) reported "deleterious (SIFT score 0.02)" and "probably damaging (PSIC score difference 2.94)" values, respectively. Further study of family members revealed that neither his parents, nor his twin brother carried the mutation, indicating the mutation was likely to occur de novo in our patient.Conclusion: The mutation,p.Y657S,in SH2 domain of STAT3 is a disease-causing mutation in the boy with HIES. [ABSTRACT FROM AUTHOR]