History Of Recurrent Infections Research Articles

Severe Congenital Neutropenia with ELANE gene mutation, on G-CSF therapy; a case report

Abstract Introduction/Objective Severe congenital neutropenia (SCN) is a genetic syndrome characterized by a deficiency of mature neutrophils in the bone marrow and peripheral blood. The disease is caused by various gene mutations, with ELANE gene mutations accounting for 50% to 60% of cases. Methods/Case Report We report a case of a 12-year-old male patient with severe congenital neutropenia, positive for the ELANE gene mutation. He has a history of recurrent infections and unexplained fevers since childhood. He has been receiving G-CSF treatment for ten years but is now exhibiting a diminished response to it. Analysis of the bone marrow biopsy reveals trilineage hematopoiesis, maturing myeloid with a rise in eosinophils, maturing erythroid, megakaryocytes normal in number and morphology with significantly reduced iron reserves in normocellular bone marrow. On immunostaining, CD34, CD14, or CD117 stains were negative. Neither monocytes nor granulocytes were CD56 positive. Increased monocyte counts coincide with partial CD14 loss. Lymphocytes make up 10% of all cells and consist of Polytypic B-cells, natural killer cells, and a heterogeneous population of T-cells with a normal CD4 to CD8 ratio. Hence, myelodysplastic syndrome was ruled out. Results (if a Case Study enter NA) NA Conclusion This case report provides valuable insights into the limited knowledge of congenital neutropenia with ELANE mutation on G-CSF therapy. It highlights the importance of ruling out Myelodysplastic syndrome in patients with severe congenital neutropenia and ELANE gene mutation treated with G-CSF therapy.

1166 Thymoma and Good's Syndrome: Analysing the Role of Surgery in a Case Series

Abstract Background Good’s syndrome is a rare paraneoplastic phenomenon with unknown pathogenesis in patients with thymoma. The incidence is 0.15 cases per 100,000 population per year. Patients typically have hypogammaglobulinemia, reduced B cell and CD4+ T cell count, and present with recurrent infections and autoimmune manifestations. Case Summary This case series highlights two patients with Good’s syndrome who underwent thymectomy in a United Kingdom Thoracic Surgery Unit. Patient 1, a 57-year-old female, presented with a history of recurrent infections (including Pneumocystis jiroveci), dysphagia, and dyspnoea. The subsequent discovery of a thymoma led to a diagnosis of Good Syndrome. Patient 2, a 61-year-old male, exhibited recurrent infections and immunological abnormalities, eventually leading to the identification of a thymoma. Both patients were diagnosed in their 5th decade, and shared similar clinical profiles with absent B cells, reduced NK cells, hypogammaglobulinemia, and an anterior thymoma. Preoperatively, they received IVIG transfusions. The surgical intervention involved robotic-assisted thymectomy for both patients. Histopathological assessments classified Patient 1 as T1bNxMxR1 and Patient 2 as T1aNXMXR1 providing insights into the extent of the thymomas. Post-operatively they continue to have prophylactic antibiotics and IVIG and have been reportedly well. Conclusions Patients with Good Syndrome are at significant risk of opportunistic infections and may present repeatedly to medical specialties. Thymoma and its associated symptoms can precede immunodeficiency. Consequently, thorough consideration of this diagnosis, interdisciplinary collaboration, and preoperative planning is vital for the effective management of this extremely rare syndrome. Successful outcomes are achievable through timely IVIG and full surgical resection.

Management of first branchial anomalies in children: 20 years of experience.

Branchial cleft anomalies (BCAs) are common pediatric head and neck lesions; however, only 1-4% involve the first branchial cleft. The rare occurrence of first BCAs, their presentation at a young age, and the possible facial nerve involvement make diagnosis and treatment challenging. A retrospective chart review was conducted for children diagnosed with their first BCA between 2000 and 2020. Data on demographics, presenting symptoms, physical findings, imaging features, previous surgery, and treatment outcomes were collected and analyzed. The cohort included 17 patients with a median age of 5 years at presentation. Seven (41%) had undergone previous surgical intervention before definitive surgery. Eight were classified as Work Type II anomalies, and nine as Work Type I. Sixteen patients (94%) underwent definitive surgical excision at a median age of 6.9. A parotid approach was used in 10 (62%), with dissection of the mass from the facial nerve, and a retro-auricular or end-aural approach was used in 6 (38%). Complete excision was achieved in 14/16 patients (88%). Three patients had transient facial nerve paresis postoperatively. Recurrence was noted in 3/16 patients (18%). Enhancement in imaging was positively correlated with post-operative complications (R = 0.463, P = 0.018). First, BCA poses a diagnostic and surgical challenge; thus, definitive surgical treatment is often delayed. The surgical approach should be tailored to the type of anomaly (Work type I or II) and possible facial nerve involvement. Risk factors for post-operative complications are a history of recurrent infections and previous surgical interventions. The presence of contrast enhancement in preoperative imaging should alert surgeons to perioperative challenges and the risk of post-operative complications.

CVID With Unusual Peripheral Mononeuropathy and Associated IL-7 Receptor Mutation.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. It is characterized by hypogammaglobulinemia and can present with a broad range of symptoms including recurrent bacterial infections, autoimmunity, and malignancy. Rarely, it has been implicated with peripheral neuropathy. We present a case of CVID with peripheral neuropathy and a pathogenic heterozygous variant of IL-7 receptor gene. The patient is a 38-year-old female with a history of recurrent infections since childhood including pneumonia and sinus infections status post tonsillectomy and sinus surgery. She subsequently developed severe left leg and lower back pain that progressed to left foot drop and decreased sensation over the left leg. She was found to have severe hypogammaglobulinemia and poor polysaccharide and protein response, thus meeting criteria for CVID. Mononeuropathy is a rare finding in CVID. Genetic panel was performed and was significant for a single pathogenic variant in IL-7 receptor. Disruptions in the IL-7 and IL-7 receptor signaling pathway have been associated with autoimmunity such as rheumatoid arthritis and multiple sclerosis. Further investigation is indicated to determine the clinical significance of this variant.

Navigating the management complexity in long-term asymptomatic immunodeficiency

Background: Common variable immunodeficiency disorder (CVID) is a condition associated with recurrent infections and non-infectious outcomes, including lung disease like bronchiectasis and granulomatous and lymphocytic interstitial lung diseases (GLILD), autoimmune disease, enteropathy, and lymphoma. Treatment involves initiation of replacement immunoglobulin (Ig), which is a lifelong commitment. Prior to Ig replacement, life expectancy for patients with CVID was less than 15 years. With replacement Ig, it has improved to over 50 years. In most cases, patients present to a clinician with a history of recurrent infections, and treatment is indicated. However, in patients with asymptomatic disease, the best timing to start treatment can be difficult to determine. Case: We present a case of an otherwise healthy male who had an incidental diagnosis of CVID. Results: Workup revealed hypogammaglobulinemia for over 30 year. Discussion: Though successful in reducing infections, Ig replacement can come with many side effects, as well as a heavy medical burden to the patient and the healthcare system. It is also a big life adjustment, and can greatly affect a patient's quality of life. In the military, a diagnosis of an immunodeficiency, and the need for monthly intravenous immunoglobulin (IVIG) can be detrimental to deployment readiness, and a patient's military career. Risks and benefits need to be weighed prior to initiating Ig therapy.

Severe congenital neutropenia caused by the elane gene mutation in a 4-year-old vietnamese girl

ABSTRACT Severe congenital neutropenia (SCN) is an exceptionally rare genetic disorder associated with life-threatening bacterial infections. Among the several genetic variations related to SCN, heterozygous mutations in the ELANE gene encoding neutrophil elastase account for approximately 40 - 55% of the genetic causes. Herein, we present the first documented case of SCN in a Vietnamese girl from the Central region of Vietnam. The diagnosis was confirmed through genetic analysis of the ELANE gene, a known causative gene in SCN. The patient exhibited severe neutropenia and a history of recurrent infections that did not respond well to treatment. Treatment involved the administration of granulocyte-stimulating factor (G-CSF) and antibiotics, resulting in a successful increase in neutrophil counts. This report contributes to the understanding of SCN’s clinical presentation, diagnosis, and management, particularly in regions with limited documented cases.

Aplastic anaemia treated using eltrombopag in a dog

AbstractA 2‐year‐old, neutered, female beagle was presented to a referral hospital for investigation of pancytopenia. The patient had a history of recurrent infections and, on previous blood tests, anaemia, leukopenia and thrombocytopenia were detected. At the time of presentation, the patient had been treated for 2 weeks with omeprazole, amoxicillin‐clavulanic acid, marbofloxacin and gabapentin, and for 3 months with prednisolone, in decreasing doses. A bone marrow aspirate and core biopsy were performed. Hypoplastic bone marrow was observed. Once underlying infectious diseases and exposure to toxins were ruled out, a diagnosis of aplastic anaemia was made. The patient was treated with eltrombopag, a thrombopoietin receptor agonist that stimulates primitive haematopoietic stem cells, used for the treatment of aplastic anaemia in humans. One week after starting eltrombopag treatment, all the affected cellular lines were recovered. The patient continued in remission 7 months after treatment.

Physiologic postoperative presepsin kinetics following primary cementless total hip arthroplasty: A prospective observational study.

Presepsin is an emerging biomarker in the diagnosis of sepsis. In the field of orthopaedics, it could be useful in diagnosing and managing periprosthetic joint infections. To define the normal postoperative presepsin plasmatic curve, in patients undergoing primary cementless total hip arthroplasty (THA). Patients undergoing primary cementless THA at our Institute were recruited. Inclusion criteria were: Primary osteoarthritis of the hip; urinary catheter time of permanence < 24 h; peripheral venous cannulation time of permanence < 24 h; no postoperative homologous blood transfusion administration and hospital stay ≤ 8 d. Exclusion criteria were: The presence of other articular prosthetic replacement or bone fixation devices; chronic inflammatory diseases; chronic kidney diseases; history of recurrent infections or malignant neoplasms; previous surgery in the preceding 12 mo; diabetes mellitus; immunosuppressive drug or corticosteroid assumption. All the patients received the same antibiotic prophylaxis. All the THA were performed by the same surgical and anaesthesia team; total operative time was defined as the time taken from skin incision to completion of skin closure. At enrollment, anthropometric data, smocking status, osteoarthritis stage according to Kellgren and Lawrence, Harris Hip Score, drugs assumption and comorbidities were recorded. All the patients underwent serial blood tests, including complete blood count, presepsin (PS) and C-reactive protein 24 h before arthroplasty and at 24, 48, 72 and 96 h postoperatively and at 3, 6 and 12-mo follow-up. A total of 96 patients (51 female; 45 male; mean age = 65.74 ± 5.58) were recruited. The mean PS values were: 137.54 pg/mL at baseline, 192.08 pg/mL at 24 h post-op; 254.85 pg/mL at 48 h post-op; 259 pg/mL at 72 h post-op; 248.6 pg/mL at 96-h post-op; 140.52 pg/mL at 3-mo follow-up; 135.55 pg/mL at 6-mo follow-up and 130.11 pg/mL at 12-mo follow-up. In two patients (2.08%) a soft-tissue infection was observed; in these patients, higher levels (> 350 pg/mL) were recorded at 3-mo follow-up. The dosage of plasmatic PS concentration is highly recommended in patients undergoing THA before surgery to exclude the presence of an unknown infection. The PS plasmatic concentration should be also assessed at 72 h post-operatively, evaluate the maximum postoperative PS value, and at 96 h post-operatively when a decrease of presepsin should be found. The lack of a presepsin decrease at 96 h post-operatively could be a predictive factor of infection.

Impaired Response to Polysaccharide Vaccine in Selective IgE Deficiency.

Immunoglobulin E deficiency (IgED) (defined as IgE < 2IU/mL) is enriched in patients with primary antibody deficiency (PAD). We hypothesized that selective IgED (sIgED) is a more sensitive predictor of the development of PAD than declining IgG, as IgE production typically requires two class switch recombination (CSR) events in contrast to IgG. Thus, the inability of patients with sIgED to mount an appropriate antibody response to a T-cell independent antigen or evidence of aberrant induction of ɛ germ line (ɛGL) or IgE heavy chain (IgEHC) transcripts in vitro would support the concept that sIgED is a biomarker for emerging PAD. We compared pre- and post-polysaccharide vaccination titers in healthy patients with sIgED without a history of recurrent infections or autoimmunity (n = 20) and in healthy controls (HCs) (n = 17). Subsequently, we assessed in vitro induction of εGL and IgEHC transcripts in patients with sIgED and HC (n = 6) in response to IL-4 + CD40L stimulation. Thirty percent of patients with sIgED did not have a robust vaccine response compared to 0% of HCs (p = 0.017). Individuals with sIgED with an abnormal vaccine response demonstrated persistent germline mRNA expression in their B-cells at day 5, with lower levels of IgEHC, compared to both HCs and sIgED participants with a normal vaccine response. Patients with sIgED are more likely to have abnormal antibody responses to a T cell-independent antigen and may have dysregulated CSR machinery. Following individuals with sIgED longitudinally may be beneficial in the early identification of PAD.

Heterozygous TCF3-Related Disease Presenting as X-linked Agammaglobulinemia Mimicry in a Male Toddler with B-cell Aplasia, Agammaglobulinemia, and Severe Neutropenia

IntroductionDisease associated with TCF3 variants are rare and associated with autosomal dominant inheritance agammaglobulinemia. Patients present with profound reduction in CD19+ cells and a block in B cell development at the common lymphoid precursor to pro–B cell phase of differentiation. Severe neutropenia is frequently described in X-linked agammaglobulinemia (XLA) patients but not yet described as a presenting finding in TCF3-related disease. Case ReportThis case describes a 13-month-old full term male with a history of reactive airway disease and recurrent infections including multiple bouts of acute otitis media, hand -foot-mouth, and viral upper respiratory illnesses who presented with fever and persistent severe neutropenia (absolute neutrophil count <100 cell/uL) necessitating hospital admission. Given his infectious history and severe neutropenia, he underwent evaluation for an underlying inborn error of immunity with the following pertinent findings: undetectable IgG (<16 mg/dL), IgM (<10 mg/dL), IgA (<2 mg/dL) and IgE (<2 kU/L), negative pneumococcal, tetanus and diphtheria vaccine titers despite vaccination, lymphocyte subsets with normal CD3, CD4, CD8, and CD16/56 absolute values but extremely low CD19 level (38 cells/cmm), and negative anti-neutrophil antibodies. Patient Bruton tyrosine kinase (Btk) protein flow cytometry results in monocytes were similar to an experimental control, while B-cell subset analysis was unable to be obtained given low B-cell numbers. Comprehensive genetic testing subsequently identified a heterozygous pathogenic TCF3 variant, c.1663G>A, p. (Glu555Lys). Following initiation of intravenous immunoglobulin (IVIG) replacement, our patient's neutropenia resolved quickly and completely. He continues to receive monthly IVIG with goal IgG troughs >800 mg/dL and resultant significant improvement in infections. ConclusionAs in XLA, our patient's severe neutropenia rapidly resolved with initiation of immunoglobulin replacement. While it has been shown that neutrophil development is somewhat dependent on the Btk protein, further study into the importance of the TCF3 protein and additionally adequate immunoglobulin levels in neutrophil expansion is needed. Finally, germline inborn errors of immunity, including TCF3 variants, should be considered in children with a history of recurrent infections and persistent neutropenia.

Delayed onset ADA-SCID presenting as secondary HLH in a patient with normal newborn screening

Severe combined immunodeficiency (SCID) is a rare genetic syndrome caused by aberrant immune cell development or function and is fatal without early identification and treatment. The Centers for Disease Control estimates the annual incidence of SCID to be one case per 40,000 to 100,000 live births. Newborn screening using T-cell receptor excision circles (TREC) allows for early detection and timely treatment of SCID. Adenosine deaminase (ADA) is a vital enzyme in the purine salvage pathway, and its deficiency results in disruption of T, B and NK cell development, accounting for 10–20% of SCID cases. The timing of ADA-SCID presentation ranges from birth to delayed onset disease. Importantly, without early recognition and treatment, delayed onset ADA-SCID results in accumulation of toxic metabolites causing immune dysfunction, recurrent infections, and subsequent organ damage. Recently, some groups have questioned whether traditional TREC newborn screening adequately identifies ADA-SCID, especially those cases with delayed onset. We present the case of a 2-year-old male with normal newborn screening but a history of recurrent otitis media and respiratory infections who developed multisystem organ failure and septicemia with Escherichia coli, candida, adenovirus and enterovirus despite broad-spectrum antimicrobials. The patient also had features of a hyperinflammatory syndrome with fever, pancytopenia, hypertriglyceridemia, and hyperferritinemia and was treated for hemophagocytic lymphohistiocytosis (HLH) with dexamethasone and plasma exchange followed by anakinra, etoposide, and emapalumab. The patient was maximally supported with mechanical ventilation, extracorporeal membrane oxygenation, and renal replacement therapy but had progressive clinical deterioration and ultimately expired. Autopsy was notable for thymic aplasia and erythrophagocytosis in the bone marrow and lymph nodes. Genetic testing revealed a heterozygous missense pathogenic variant in exon 7 in the ADA gene as well as novel heterozygous intronic variant of unknown significance in the ADA gene. Postmortem data suggests this patient had ADA-SCID with multi-pathogen infections and secondary HLH. This case potentially identifies a novel pathogenic variant in ADA missed by traditional TREC newborn screening and highlights the need to retain a high clinical suspicion of SCID in patients with a history of recurrent infections despite normal TREC screening.

A case of primary ovarian failure with Nijmegen Breakage a chromosomal instability syndrome

Abstract Introduction Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive chromosomal instability syndrome, characterized by dysmorphic facial features, intrauterine growth retardation and short stature, recurrent sinopulmonary infections, combined immune deficiency, radiosensitivity, increased risk for cancer, as well as premature ovarian failure. Nibrin gene mutation is responsible for the pathogenesis of the disease. The mechanism of gonadal failure in NBS is thought to be meiotic arrest in gametocytes. Clinical Case A 23-year-old female was admitted to the Marmara University endocrinology outpatient clinic because of secondary amenorrhea. Her first menarche occurred spontaneously at the age of 13, but she has never bled again afterwards. In physical examination, blood pressure was 109/68 mmHg, pulse was 80/min, and temperature was 36°C. Her height was 163 cm, and weight was 67 kg, BMI: 25.6 kg/m2. Midfacial prominent appearance, micrognathia, microcephaly was observed. Breast was assessed for II stage in Tanner scale. Ferriman–Gallwey score was 5. Psychomotor development was natural, cognitive dysfunction was not observed. Her three siblings and aunt had a history of infertility, also her parents were third degree consanguineous. The patient stated that she had recurrent sinopulmonary infections and used several antibiotics since childhood. However, there was no hospitalization due to infection by now. Her two older sisters died due to cancer when they were 10 and 21 years old. The patient had primary ovarian insufficiency according to elevated serum gonadotropins concentration and low serum estradiol concentration (Table 1). The uterus was 50 mm in size, its contours were smooth, and the echo of myometrium was diffusely homogeneous. Bilateral ovaries were not observed in the suprapubic pelvic US examination. Karyotype analysis was performed that was found 46, XX. When considering her family history, facial dysmorphic appearance, and findings of primary ovarian failure, genetic analysis revealed NM_001024688.2 c.625C&amp;gt;T(p.Q209*) homozygous mutation. The patient was started on hormone replacement therapy (estrogen 2 mg once daily, dydrogesterone 10 mg once daily) after the diagnosis. Genetic counseling, immunodeficiency and malignancy screenings were performed. Interestingly, despite the history of recurrent infection, total Ig levels and vaccine responses were normal. Although no malignancy was observed in our case, it is noteworthy that two older sisters died due to cancer. It was recommended to continue the annual screenings. Conclusion Family history should be thoroughly questioned in patients presenting with hypogonadism. NBS should be kept in mind as a rare cause in the presence of a typical phenotypic appearance, recurrent infections, and a family history of infertility and malignancy.

Cesarean section in Swyer-James-Macleod syndrome: Anesthesia implications.

Dear Editor, Swyer-James-MacLeod Syndrome (SJMS) is a rare, acquired postinfectious condition characterized by bronchiectasis or emphysematous changes.[1,2] These patients have a high risk of perioperative pulmonary complications. A 28-year-old primigravida, at 24 weeks of gestation, came with dyspnea on exertion (grade-3) for the 3 months with no history of recurrent infections. On examination, there was diminished breath sounds on the left side. Chest radiograph (done with abdominal shield) showed left hyperlucent lung with reduced vascular markings and slight mediastinal shift. Rest of the investigations were normal. The patient was referred to chest physician for optimization and a diagnosis of Swyer-James syndrome with left lung bulla/pneumothorax was made. The patient was managed with bronchodilators (Metered-Dose Inhaler levosalbutamol and Tiotropium bromide) and breathing exercises (pursed-lip breathing, diaphragmatic breathing). Spirometry was not done since the patient was in the second trimester of pregnancy. The patient got symptomatically better and an elective cesarean section was planned. Blood gas analysis performed a day before surgery showed PH: 7.441, PCO2:25.6, PO2 = 70.6, Bicarbonate = 17, Base excess = 7.21, Oxygen saturation = 94.4%. High-risk written consent was taken and expected complications were explained. On the day of surgery, the patient was taken in the operation theatre after giving inhalational bronchodilators. Ondansetron 4 mg and ranitidine hydrochloride 50 mg were given intravenously 30 min prior to surgery. A 20-G intravenous cannula was secured, Ringer lactate was started and vital parameters were monitored. Spinal anesthesia with 10 mg of heavy bupivacaine and 25 micrograms of fentanyl in the right lateral position was given. The intraoperative period was uneventful. SJMS was first described in 1953 by Swyer and James, and later explained in detail by MacLeod. A chest radiograph demonstrates lobar or unilateral hyperlucent lung and normal or reduced volume of the affected lung. Patients can present with a multitude of symptoms ranging from asymptomatic with incidental radiographical diagnosis to severe symptoms such as dyspnea and repeated pulmonary infections.[1,2] This syndrome is usually diagnosed in childhood after an evaluation for recurrent respiratory infections, but sometimes they are asymptomatic and may be diagnosed in adulthood.[3,4] In a case series by S. S. Hadice et al.,[3] three out of four patients had no history of airway infection in childhood and were diagnosed in adulthood. The clinical incidence of SJMS in pregnancy is 1:2500.[2] The management focuses on early diagnosis, prevention, and treatment of recurrent pulmonary infections and vaccine administration.[2–4] Severe cases of SJMS may require anesthetic care cautiously tailored to significant obstructive pulmonary physiology.[5] Regional anesthesia should be preferred whenever feasible. Chopra S et al.,[2] reported the successful delivery in a case of SJMS under spinal anesthesia in emergency. Labor epidural anesthesia can also be used in electively scheduled patients and supplemented with low-dose spinal anesthesia before surgery, if required. General anesthesia is associated with risk of bulla rupture, worsening of pneumothorax, and other pulmonary complications. Drugs that can cause histamine release and bronchoconstriction should be avoided. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient and her father have given their consent for his images and other clinical information to be reported in the journal. The patient and father understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Clinical and laboratory evaluation of Turkish children with IgG subclass deficiency.

IgG subclass deficiency is a laboratory diagnosis and becomes important with recurrent infections. This study aimed to examine the demographic, clinical, and laboratory results of pediatric cases with IgG subclass deficiency and to improve the understanding of the clinical significance of IgG subclass deficiency. In this study, the clinical and laboratory features of 111 pediatric patients, with at least one whose serum IgG subclasses was measured as lower than 2 standard deviation of healthy aged-matched control values, were evaluated. The clinical and laboratory features of the cases with isolated IgG subclass deficiency (Group 1) and those with low serum levels of any of IgG, IgA, and IgM in addition to the IgG subclass deficiency (Group 2) were compared. A total of 55 (49.54%) and 56 (50.45%) patients were included in Groups 1 and 2, respectively. Among our studied cases, 20 (18.1%) had a history of hospitalization in the neonatal period, 61 (54.95%) had at least one hospitalization due to infection, and 55 (49.54%) had a history of recurrent infection. The frequencies of these three conditions were statistically significantly higher in Group 2 (p<0.05). The frequencies of infections in the last year in Groups 1 and 2 were 4.4±1.2 and 5.4±1.9, respectively (p<0.05). As a result of recurrent infections, 43.24% (n=48) of our patients received antibiotic prophylaxis, and 21.62% (n=24) had immunoglobulin replacement therapy. Furthermore, the numbers of patients who needed these treatments were higher in Group 2 (p<0.05). In cases with IgG subclass deficiencies, concomitant main-group immunoglobulin deficiencies may increase the number and severity of infections, leading to hospitalizations, antibiotic prophylaxis, and immunoglobulin therapy. More attention should be paid to cases of immunoglobulin main-group deficiencies in the follow-up of these cases.

Selective immunoglobulin A deficiency in children with diabetes mellitus: Data from a medical center in Ukraine.

The aim of this study was to estimate the prevalence of selective immunoglobulin A deficiency (SIgAD) among children with type 1 diabetes mellitus (DM) in Ternopil region (western Ukraine). Serum IgA levels were measured in 240 patients aged 4-17 years with DM and in 324 children of a control group of the same age. Normal IgA level was observed in 210 (87.5%) patients, increased-in 18 (7.5%), decreased (lower than the age reference value)-in 12 (5.0%) patients with DM. The mean IgA level in patients with DM was 152.11±73.78 mg/dL. SIgAD criteria were met by 7 (2.9%) children with DM, but none of the children of the control group met the SIgAD criteria. Female / male ratio among the patients with SIgAD was 1/6. There was no history of recurrent infections in these patients. No correlation between IgA and HbA1c levels was detected. Autoimmune thyroiditis was observed in 42.9% of patients with DM and SIgAD, and in 3.5% of patients with DM and normal or increased IgA levels. Thus, the prevalence of selective IgA deficiency in children with DM in Ternopil region (Ukraine) is 2.9% (1:34). This study shows that patients with low IgA levels need further re-examination of IgA levels to exclude SIgAD. Children with SIgAD and DM should be monitored for autoimmune manifestations that may affect the course and consequences of the disease.

RARE MUTATION IN AIRE GENE IDENTIFIED IN PATIENT WITH VERY EARLY ONSET IBD

<h3>Introduction</h3> The etiology of very early-onset inflammatory bowel disease (VEO IBD) is thought to have a greater likelihood of being due to a monogenic inborn error of immunity than later-onset IBD. <h3>Case Description</h3> We present the case of a 6-year-old female with VEO IBD who was found to have a variant of unknown significance (VUS) in the AIRE gene. She was diagnosed with VEO IBD at 2 years old after she was found to have failure to thrive, diarrhea, and blood in stool. She was initially treated with mesalamine, azathioprine, and steroids, but never went into remission. She does not have history of recurrent infections or other symptoms of autoimmune disease. There is no significant known family history of autoimmune disease. Labs were notable for normal antibody responses to Hep A, Hep B, and VZV vaccines, but low S. pneumoniae titers despite vaccination with Prevnar. She had normal T and B-cell counts, including T-cell subsets, and a normal oxidative burst test. Invitae PID panel was notable for a rare heterozygous VUS in AIRE gene. Given mutations in AIRE gene are associated with the autoimmune disease APECED, plan was made to test family for VUS in AIRE and evaluate for immunologic defects seen in AIRE, such as low Tregs and IL-17, as well as elevated ANA and autoantibodies to GAD65 and thyroid. <h3>Discussion</h3> While various organs are affected in APECED, the intestinal tract is not usually affected. Nonetheless, given early onset of IBD, strong suspicion remains for monogenic disorder, either in AIRE or other genes.

CARD11 MUTATION IN A PATIENT WITH VERY EARLY ONSET IBD AND IMMUNODEFICIENCY

<h3>Background</h3> Caspase activation and recruitment domain 11 (CARD11) is a lymphocyte-specific scaffolding protein which plays are role in signaling through both the NF-κB and mTOR signaling cascades important in B- and T-cell function. Various mutations in the <i>CARD11</i> gene cause several different phenotypes. Heterozygous dominant negative (DN) mutations can result in variable immune deficiency, with associated predisposition for atopy. Gain-of-function mutations causes BENTA (B-cell Expansion with NF-κB and T-cell Anergy) disease. While most patients with <i>CARD11</i> mutations are diagnosed in childhood, some milder phenotypes can result delayed diagnosis. <h3>Case Description</h3> A 4-year-old female was diagnosed with VEO-IBD (ulcerative colitis). She had a history of recurrent infections since 8-months-old including infantile pneumonia, otitis media, MRSA skin abscesses, molluscum contagiosum and cutaneous warts, as well as eczema, allergic rhinitis and asthma. Immunologic workup revealed inadequate response to polysaccharide vaccine . Lymphocyte proliferation was decreased to <i>Candida</i> and Tetanus antigens. Despite IVIG infusions, with control of sinopulmonary infections but her viral cutaneous infections worsened. Her IBD was unresponsive to anti-TNF therapy, but improved with vedolizumab. Primary immunodeficiency diseases panel (426 gene) revealed a heterozygous <i>CARD11</i> VUS (c.223C>T, p.Arg75Trp). The same variant was present in her father, who was symptomatic with molluscum contagiousum and aphthous ulcers. <h3>Discussion</h3> We present a unique CARD11 mutation in the coiled-coil domain region of the CARD11 gene is suspected of causing a DN phenotype, including recurrent bacterial sinopulmonary and viral infections, atopic features, and VEO-IBD. In vitro functional studies of this mutation are in process to confirm pathogenicity of this variant.

CANDIDA TROPICALIS FUNGEMIA IN AN ADOLESCENT PATIENT WITH SICKLE CELL DISEASE ON CRIZANLIZUMAB

<h3>Introduction</h3> Crizanlizumab is a monoclonal antibody that blocks P-selectin on vascular endothelial cells and platelets. In sickle cell disease (SCD) P-selectin is upregulated promoting adhesion of endovascular cell clusters in vaso-occlusive crisis. Inhibition of P-selectin with crizanlizumab may decrease SCD vaso-occlusive crises. Given the role of P-selectin in neutrophil recruitment, we theorize P-selectin blockade with crizanlizuamb may pose an increased susceptibility to infection. We present a patient who developed fungemia and bacteremia while undergoing treatment with crizanlizumab. <h3>Case Description</h3> An adolescent patient with SCD and chronic pain, but no history of recurrent infections, was admitted for pain crisis. The patient was receiving intermittent crizanlizumab for 15 months, last given 7 weeks prior to admission. While hospitalized the patient developed fever and respiratory failure requiring intubation. Blood cultures grew <i>Candida tropicalis</i> and the patient was treated with micafungin. Over the course of a 2-month hospitalization, subsequent blood cultures grew multiple organisms including <i>Klebsiella pneumoniae, Lactobacillus, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus warneri,</i> and <i>Candida glabrata</i>. The patient improved with antimicrobials and was discharged. <h3>Discussion</h3> <i>Candida tropicalis</i> fungemia is most common in patients with risk factors such as neutropenia, indwelling central lines, or malignancy, and not commonly associated with SCD thus representing an unusual infection for this patient without risk factors. Given a non-revealing and thorough immunological evaluation, we hypothesize that crizanlizumab may have led to a functional neutrophil defect, predisposing the patient to fungemia and bacteremia. Since stopping crizanlizumab, this patient has had pain-crises but has not suffered ongoing infectious complications.

COMMON VARIABLE IMMUNODEFICIENCY WITH UNUSUAL PERIPHERAL NEUROPATHY AND ASSOCIATED IL-7 RECEPTOR MUTATION

<h3>Introduction</h3> Common variable immunodeficiency is the most common symptomatic primary immunodeficiency, characterized by hypogammaglobulinemia and presenting with a broad range of symptoms including recurrent bacterial infections, autoimmunity, and neoplastic conditions. We present a case of common variable immunodeficiency associated with peripheral neuropathy and a pathogenic heterozygous variant of interleukin-7 receptor (IL7R) gene. <h3>Case Description</h3> The patient is a thirty-eight-year-old female with a history of recurrent infections since childhood including pneumonia and sinus infections status post-tonsillectomy and sinus surgery. She subsequently developed severe left leg and lower back pain which progressed to left foot drop and decreased sensation over the leg with accompanied paresthesia. Labs showed profound hypogammaglobulinemia with scarce levels of IgG (55mg/dl) and IgM (21mg/dl) and lack of IgA (2mg/dl) and IgE (<0.3 IU/ml). Further workup included normal lymphocyte proliferation with deficient polysaccharide and protein response. The patient's lack of IgG antibody production is an important criterion for the diagnosis of common variable immunodeficiency. Genetic panel was performed and significant for a single pathogenic variant in IL7R. <h3>Discussion</h3> We present a case of recurrent sinopulmonary infections with associated peripheral neuropathy prompting further evaluation, revealing the diagnosis of common variable immunodeficiency. Mononeuropathy is a rare finding in common variable immunodeficiency, although should elicit further evaluation if the etiology is unclear. Additional workup was significant for a single pathogenic variant in IL7R. This gene is associated with autosomal recessive severe combined immunodeficiency when homozygous. Further genetic testing is indicated to determine the clinical significance of this variant.

An Unusual Association of Hyper-IgE Syndrome with Celiac Disease: A Case Report

Hyper-IgE syndrome (HIES) is a primary immunodeficiency disorder characterized by eczema, cold abscesses, pneumonia, eosinophilia, and a very high serum IgE concentration. An association with celiac disease is rare. Immunodeficiency and autoimmunity are two manifestations of immune system dysfunction that can be associated with common pathophysiological links. We present the case of a 3-year-old child with psychomotor retardation and a history of recurrent infections who had generalized eczema, failure to thrive, and abdominal distension with hepatosplenomegaly. The patient improved after receiving a monthly intravenous immunoglobulin infusion and a gluten-free diet.