IgG2 Deficiency Research Articles

The impact of primary immunodeficiency on the severity of chronic rhinosinusitis

BackgroundPrimary immunodeficiency has been associated with chronic rhinosinusitis (CRS). However, limited evidence exists on how primary immunodeficiencies affect the severity of CRS. ObjectiveTo assess how primary IgA and/or IgG immunodeficiency affects the severity of CRS. MethodsAdult patients at the Beth Israel Deaconess Medical Center in Boston with IgA and/or IgG deficiency (group A) or normal IgA and IgG (group B) were queried between January 1, 2016 and December 31, 2022. Other immunodeficiencies were excluded. The groups were analyzed for prevalence of CRS based on ICD-10 codes. The groups were matched based on demographics and comorbidities. Patients with CRS were analyzed for ≥3 acute rhinosinusitis (ARS) episodes, mean lifetime ARS episodes, and mean ARS episodes per year (all with or without antibiotic treatment). Additional analyses included need for functional endoscopic sinus surgery (FESS) and mean lifetime FESS procedures based on CPT codes. A logistic regression analysis was then performed over the same parameters. ResultsA total of 346 patients had IgA and/or IgG deficiency (group A), and 11,438 patients had normal IgA and IgG (group B). CRS prevalence was higher in group A than group B (12 % vs. 5 %; p < 0.001). Group A had more patients with ≥3 ARS episodes, higher mean lifetime ARS episodes, and ARS episodes per year, though none of these findings were statistically significant. There was no difference in need for FESS or mean lifetime FESS procedures. ConclusionCRS prevalence is higher in patients with IgA and/or IgG deficiency, but IgA and/or IgG immunodeficiency does not predispose patients to ARS episodes or predict need for FESS.

Transfusion-related acute lung injury (TRALI) following intravenous immunoglobulin infusion in a rituximab immunosuppressed patient with long-shedding SARS-CoV-2

BackgroundTransfusion-related acute lung injury (TRALI) is a rare life-threatening complication of blood product transfusion. Intravenous immunoglobulin (IVIG)-related TRALI is scarcely reported.Case presentationA 63-year-old male patient suffering from multiple sclerosis treated with half-yearly rituximab infusions, was hospitalized due to dry cough, daily fever and shivering for seven days despite antibiotic therapy. Because of the history of COVID-19 one month prior without the symptoms having improved since, persistent bilateral multifocal areas of ground glass opacities in chest computed tomography and positive SARS-CoV-2 PCR from bronchoalveolar lavage with a cycling time of 30.1 COVID-19 due to long-shedding SARS-CoV-2 under immunosuppression with rituximab was diagnosed. He received treatment with nirmatrelvir und ritonavir and because of diagnosed IgG deficiency additionally a single dose of 20 g IVIG. During the IVIG infusion, the patient acutely developed tachycardia, hypotension, fever, chills, and hypoxemic respiratory failure due to pulmonary edema. TRALI was promptly diagnosed, and the patient was transferred to the intensive care unit for non-invasive ventilation for less than 24 h. The patient was discharged home from regular ward 72 h later in a good general condition and no remaining symptoms of TRALI.ConclusionIVIG-related TRALI is a rare but life-threating condition and prompt recognition is lifesaving. Due to an increased use of IVIG not only in long-shedding SARS-CoV-2, an increase of TRALI incidence is expected.

Isotype deficiencies (IgG subclass and selective IgA, IgM, IgE deficiencies).

Background: Immunoglobulin G (IgG) subclass deficiencies and isolated IgA, IgM, IgE deficiencies have all been described in the literature with variable prevalence. Methods: These isotype deficiencies have a variable presentation from asymptomatic to recurrent infections resistant to prophylactic antibiotics. Results: Atopic disorders and autoimmune diseases are common comorbidities. IgE deficiency has been associated with impaired vaccine response and an increased risk of malignancy, particularly in patients with no allergic comorbidities and those with non-common variable immunodeficiency (CVID) humoral immunodeficiency, IgM deficiency, IgG2 deficiency, and CD4 lymphopenia. Conclusion: Close monitoring for malignancy should be strongly considered for these patients who are at risk. Treatment is variable and may include antimicrobial therapies for illnesses and prophylactic antibiotics in select patients, and immunoglobulin replacement can be considered for patients with refractory, recurrent infections.

Serum immunoglobulin levels in group E of chronic obstructive pulmonary disease: insights for clinical management and immunoglobulin therapy strategies

ObjectiveThe study aimed to characterize serum immunoglobulin (Ig) concentrations and their relationship with clinical and paraclinical features in patients with COPD group E in the stable stage. Additionally, the study focused on evaluating the relationship between serum Ig levels and the risk of exacerbations over the next 12 months, thereby clarifying the role of serum Ig deficiency in affecting the future risk for these patients.MethodsA prospective observational study assessed IgG, IgA, IgM, and IgE levels in 67 COPD patients and 30 healthy controls at Military Hospital 103 from October 2017 to August 2020. Primary outcomes included Ig isotype levels in COPD patients, with secondary outcomes exploring differences compared to controls and associations with clinical variables.ResultsCOPD patients showed significantly lower IgG concentrations and higher IgA levels than controls. IgM and IgE levels did not differ significantly. Subgroup analysis revealed notable decreases in IgG1 and IgG3 concentrations, with 10.4% of patients exhibiting reduced IgG levels and 0.3% diagnosed with common variable immunodeficiency. No significant associations were found between Ig levels and exacerbation risk or clinical variables.ConclusionsSerum IgG and IgM concentrations were significantly reduced in COPD patients compared to normal individuals, with IgG1 and IgG3 concentrations notably low. Serum IgA levels were significantly higher in COPD patients compared with normal controls. However, no significant association was found between Ig concentrations, particularly serum IgG deficiency and its subclasses, with the frequency and risk of exacerbations during 12 months of longitudinal follow-up. Caution is warranted in the use of immunoglobulin therapy in the treatment of COPD patients.Trial registrationAn independent ethics committee approved the study (Ethics Committee of Military Hospital 103 (No. 57/2014/VMMU-IRB), which was performed in accordance with the Declaration of Helsinki, Guidelines for Good Clinical Practice.

Low incidence of primary immunodeficiency-associated cancers in children at a tertiary care pediatric hospital in Pakistan: a blessing in disguise or wet behind the ears?

Scarce data is available regarding primary immunodeficiency-associated cancers in children in low-middle-income countries. This study aimed to determine the incidence, clinical features and outcomes of primary immunodeficiencies (PIDs)-associated cancers in children presenting to Pakistan's largest public-sector specialised pediatric oncology center. Among 5,748 children with cancers registered over 5 years, only eight patients were found to have PID-associated pediatric malignancies with an incidence of 1.4 per 1,000 cases. The median age at the time of diagnosis was 6.5 years with a male-to-female ratio of 7:1. Only four types of PIDs were found to be associated with cancer in children at our center: Ataxia Telangiectasia in 37.5% (n = 3), hyper-IgE syndrome and IgG deficiency in 25% (each n = 2) and one case (12.5%) of common variable immune deficiency. Six different types of pediatric cancers were associated with PID with a predisposition towards hematological malignancies (n = 7, 87.5%). Only two patients (25%) survived. The median survival of the cohort was 3.5 months. Infection-related mortality was the cause of death in four patients (66%), and the type of PID was the only statistically significant factor associated with the outcome. It is concluded that a lesser proportion of PID-associated pediatric cancers are found in our center as compared to the reported data from high-income countries. PID-associated cancers in children have an abysmal prognosis and infection-related mortality is the major cause of treatment failure. Sensitisation of oncologists to look for any underlying PID, the introduction of PID-screening programs in children and consideration of PID-associated malignancies as a high-risk group for treatment may help improve the outcomes.

Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study.

Ataxia-telangiectasia (AT) is a rare genetic disorder leading to neurological defects, telangiectasias, and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze factors associated with mortality. Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included. Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0) and5.0 (3.0-8.0)years, respectively. Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency. IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. Mean survival was 24.2years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT.

Long-term neurocognitive, psychosocial, and physical outcomes after prenatal exposure to radiotherapy: a multicentre cohort study of the International Network on Cancer, Infertility, and Pregnancy

The main data available on the safety of radiation during pregnancy originate from animal studies and from studies of survivors of atomic or nuclear disasters. The effect of radiotherapy to treat maternal cancer on fetal development is uncertain. This report presents a unique cohort and aims to determine the long-term neurocognitive, psychosocial and physical outcomes of offspring of mothers treated with radiotherapy during pregnancy. In this international, multicentre, mixed retrospective-prospective cohort study, we recruited participants between Aug 5, 2006, and Aug 24, 2023, aged between 1·5 and 46 years, at three referral centres in Belgium, the Netherlands, and the USA. Participants were eligible if they were born from mothers treated with radiotherapy during pregnancy. Fetal radiation doses were obtained from medical records and participants were followed up at predefined ages (1·5, 3, 6, 9, 12, 15, and 18 years) and 5-yearly in adulthood, based on age at enrolment, using a neurocognitive test battery (measuring intelligence, attention, and memory), parent-reported executive function and psychosocial questionnaires, and a medical assessment. Results were compared with test-specific normative data. Linear regression models investigated associations between radiotherapy factors (fetal radiation dose, gestational age at the start and end of radiotherapy, and radiotherapy duration) and outcomes. 68 maternal cases of radiotherapy during pregnancy were registered by the three participating centres, of which 61 resulted in a livebirth and were therefore eligible to participate in the child follow-up study. After excluding those who did not give consent, 43 participants born from 42 mothers treated with radiotherapy during pregnancy were included in the study (median age at first assessment 3 years [IQR 2-11]; median age at last assessment 12 years [9-18]; median number of assessments two [1-4]). 18 (42%) of the included participants were female and 25 (58%) male, and 37 (86%) were of White ethnicity. Mean neurocognitive outcomes of the entire cohort were within normal ranges. No associations were found with fetal radiation dose or timing of radiotherapy during pregnancy. Six (16%) of 38 participants with neurocognitive outcomes scored lower than one SD on at least one neurocognitive outcome, three (7%) reported chronic medical conditions (spasmophilia, spastic diplegia, and IgG deficiency), and three (7%) were diagnosed with attention-deficit hyperactivity disorder (of whom two scored lower on attention). Of ten (23%) participants with lower neurocognitive score(s), a chronic medical condition, or attention-deficit hyperactivity disorder, eight were born preterm. The remaining 33 (77%) participants showed no neurocognitive, psychosocial, or chronic physical problems. We show on average normal neurocognitive, psychosocial, and physical outcomes after prenatal exposure to radiotherapy. Differences in outcomes could not be explained by exposure to radiotherapy during pregnancy. These results suggest that extra-abdomino-pelvic radiotherapy exposure during pregnancy in general does not adversely affect outcomes of liveborn children. Further research with a larger sample is necessary to confirm these findings. Kom Op Tegen Kanker, KWF Kankerbestrijding, Stichting Tegen Kanker, Research Foundation Flanders.

Causative mechanisms and clinical impact of immunoglobulin deficiencies in ataxia telangiectasia

BackgroundAtaxia Telangiectasia (AT) is characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased cancer susceptibility, caused by mutations in the ataxia telangiectasia mutated (ATM) gene. The immunodeficiency comprises predominantly immunoglobulin (Ig)-deficiency, mainly IgA and IgG2, with a variable severity. So far, the exact mechanisms underlying the Ig-deficiency, especially the variable severity, remain unelucidated. ObjectiveTo characterize the clinical impact of Ig-deficiencies in AT and to elucidate the mechanisms of Ig-deficiencies in AT. MethodsWe analyzed long-term Ig-levels, immunophenotyping, and survival time in our cohort (n=87, median age 16 years; maximum 64 years). Somatic hypermutation (SHM) and class-switch junctions in B-cells were analyzed by next-generation sequencing. Furthermore, an in vitro class-switching induction assay was performed followed by RNAseq, to assess the effect of ATM-inhibition. ResultsOnly the hyper-IgM AT phenotype significantly worsened survival time, while IgA or IgG2-deficiencies did not. The Ig-levels showed predominantly decreased IgG2 and IgA. Moreover, flowcytometric analysis demonstrated reduced naïve B- and T-lymphocytes and a deficiency of class-switched IgG2 and IgA memory B-cells. SHM frequencies were lowered in IgA and IgG2-deficient patients, indicating a hampered germinal center (GC) reaction. In addition, the microhomology of switch junctions was elongated, suggesting alternative end-joining during class-switch DNA-repair. The in vitro class-switching and proliferation were negatively affected by ATM-inhibition. RNA-sequencing analysis showed that ATM-inhibitor influenced expression of GC reaction genes. ConclusionIg-deficiency in AT is caused by disturbed development of class-switched memory B-cells. This study suggests that ATM-deficiency affects both the GC reaction and the choice of DNA-repair pathways in class-switching.

Clinical and immunological features of 55 adult patients with selective IgG4 subclass deficiencies. Running title: IgG4 deficiency in adults: Clinical &amp; immunological features

Aim: Despite intensive research on elevated IgG4 concentrations in serum, little is known about the importance of selective IgG4 subclass deficiency. We investigated the clinical and immunological characteristics of 55 patients with selective IgG4 subclass deficiency. Materials and methods: IgG subclass analyses performed in our hospital over 3 years were examined. The clinical features of patients with selective IgG4 subclass deficiency were reviewed, and the definitive diagnoses and the reasons for IgG subclass analysis were recorded. Results: Of 1675 IgG subclass analyses performed, 55 were indicative of selective IgG4 subclass deficiency. The final diagnoses associated with selective IgG4 subclass deficiency were variable. The most common clinical finding was recurrent infections (33 patients, 60%), and most had upper respiratory tract infections (18 patients, 54.5%). Allergic diseases were noted in 25 patients (45.4%) and were the second most common conditions. Allergic rhinitis was the most frequent allergic disease. Autoimmune diseases were noted in 18 patients (32.7%), Hashimoto thyroiditis being the most frequent. Conclusion: This is the first study of adult selective IgG4 subclass deficiency at a single tertiary medical center in Turkey. In patients with IgG4 deficiency, while the primary concern is the presence of recurrent infections, consideration should also be given to allergic and autoimmune diseases.

Mycoplasma pneumoniae carriage in children with recurrent respiratory tract infections is associated with a less diverse and altered microbiota

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in school-aged children and can be preceded by asymptomatic carriage. However, its role in recurrent respiratory tract infections is unclear. We studied the prevalence of M.pneumoniae carriage in children with recurrent respiratory infections and identified associated factors. We tested M.pneumoniae carriage by qPCR in children with recurrent infections and their healthy family members in a cross-sectional study. Serum and mucosal total and M.pneumoniae-specific antibody levels were measured by ELISA and nasopharyngeal microbiota composition was characterized by 16S-rRNA sequencing. Prevalence of M.pneumoniae carriage was higher in children with recurrent infections (68%) than their family members without infections (47% in siblings and 27% in parents). M.pneumoniae carriage among family members appeared to be associated with transmission within the household, likely originating from the affected child. In logistic regression corrected for age and multiple comparisons, IgA (OR 0.16 [0.06-0.37]) and total IgG deficiency (OR 0.15 [0.02-0.74]) were less prevalent in M.pneumoniae carriers (n=78) compared to non-carriers (n=36). In multivariable analysis, the nasopharyngeal microbiota of M.pneumoniae carriers had lower alpha diversity (OR 0.27 [0.09-0.67]) and a higher abundance of Haemophilus influenzae (OR 45.01 [2.74-1608.11]) compared to non-carriers. M.pneumoniae carriage is highly prevalent in children with recurrent infections and carriers have a less diverse microbiota with an overrepresentation of disease-associated microbiota members compared to non-carriers. Given the high prevalence of M.pneumoniae carriage and the strong association with H.influenzae, we recommend appropriate antibiotic coverage of M.pneumoniae and H.influenzae in case of suspected pneumonia in children with recurrent respiratory tract infections or their family members. Wilhelmina Children's Hospital Research Fund, 'Christine Bader Stichting Irene KinderZiekenhuis', Sophia Scientific Research Foundation, ESPID Fellowship funded by Seqirus, Hypatia Fellowship funded by Radboudumc and The Netherlands Organisation for Health Research and Development (ZonMW VENI grant to LM Verhagen).

Abstract 14201: Double the Trouble: Extremely Rare Incidental Finding of a Double Interatrial Septum With Atrial Septal Aneurysm and Coexisting Patent Foramen Ovale

Case: A 59-year-old&amp;nbsp;female with a past medical history of hypothyroidism and IgG deficiency presents to cardiology clinic due to palpitations and premature ventricular complexes (PVCs) noted at a recent urgent care visit. In-office vitals, physical exam, labs, and EKG were unremarkable. Ambulatory cardiac monitoring showed predominantly sinus rhythm with a PVC burden of 1.4%. Echocardiogram revealed an extremely rare structural anomaly – a double interatrial septum (DIAS) with atrial septal aneurysm. Cardiac MRI (cMRI) further confirmed the presence of a DIAS enclosing an interatrial space, along with blood flow within the interatrial space and a discontinuity in the anterior right lateral atrial septum suggestive of a patent foramen ovale (PFO). There was no evidence of thrombus within the interatrial or intracardiac spaces. Mild right atrial enlargement was seen. The patient was initiated on aspirin for cardioembolic stroke prophylaxis. Discussion: DIAS is a highly rare congenital cardiac anomaly with limited number of cases in literature. It has been described as a midline third atrium resulting in a “tri-atrial heart”. As of 2018, less than 20 cases have been cited. DIAS is characterized by two parallel interatrial septa along with a clear echo lucent midline space that expands in systole and collapses in diastole. This case is unique as it is one of the few to include additional characterization with cMRI. Patients with DIAS are usually asymptomatic but can experience cardioembolic events as the interatrial space is at risk for thrombus formation. Communication across the DIAS makes these events more likely. Unlike with atrial fibrillation/flutter, no current criteria for anticoagulation (AC) initiation exists for DIAS given the scarcity of cases. While some sources advocate for use of anti-platelet agents, others have indicated a preference for oral AC. Our patient had an interatrial space and a PFO but lacked communication across the DIAS, had low bleeding risk, and no other classic risk factors of Virchow’s triad. We determined her risk for thrombus formation to be relatively low, and thus initiated her on aspirin over oral AC. Percutaneous closure of the interatrial space was deferred as it has been dismissed as a viable treatment option in the literature.

The Association Between Malignancy, Immunodeficiency, and Atopy in IgE-Deficient Patients

Studies show that IgE-deficient patients (IgE <2.5 kU/L) have a high prevalence of malignancy, but relevant clinical and laboratory characteristics associated with this susceptibility have never been well characterized. To evaluate if there is an association between a malignancy diagnosis and other immunological parameters (atopy or other immune abnormalities) in IgE-deficient patients. We retrospectively analyzed medical records of 408 IgE-deficient adults seen at our institution between 2005 and2020. A malignancy diagnosis was found in 23.5% (96 of 408) of IgE-deficient patients. Among those who had allergy skin testing performed for allergic rhinitis-like symptoms, the nonatopic IgE-deficient patients (negative environmental skin tests) were more likely to have a malignancy diagnosis than the atopic group (odds ratio [OR]= 4.36, 95% confidence interval [CI]: 1.11-17.13, P= .03). The IgE-deficient individuals with an additional non-common variable immunodeficiency (non-CVID) humoral abnormality (n= 75; with low IgG, IgA, or IgM without meeting criteria for CVID) were more likely to have a malignancy diagnosis than those with only a selective IgE deficiency (n= 134; with normal IgA, IgM, and IgG) (OR= 2.79, 95% CI: 1.37-5.68, P= .005). Among the IgE-deficient patients, certain less well-defined immune abnormalities such as IgM deficiency (OR= 2.46, 95% CI: 1.13-5.36, P= .02), IgG2 deficiency (OR= 10.14, 95% CI: 1.9-54.1, P= .007), and CD4 lymphopenia (OR= 7.81, 95% CI: 2.21-27.63, P= .001) were associated with higher malignancy odds than those without these abnormalities. The odds of a malignancy diagnosis are not shared equally by all IgE-deficient patients. Prospective studies are needed to determine the utility of performing skin testing and measuring additional immunological parameters in assessing the long-term malignancy risk in IgE-deficient patients.

Cellular immune response to SARS-CoV-2 in patients with primary antibody deficiencies.

Primary antibody deficiencies (PAD) are inborn defects of the immune system that result in increased susceptibility to infections. Despite the reduced response to vaccination, PAD patients still benefit from it by reducing the risk of severe infections and complications. SARS-CoV-2 vaccines are recommended in PAD patients, but their immune effects are poorly studied. Here, we analyze virus-specific T-cell responses in PAD patients after booster vaccination against SARS-CoV-2. The study included 57 adult PAD patients on long-term immunoglobulin replacement therapy (IgRT) diagnosed with X-linked agammaglobulinemia (XLA; n = 4), common variable immunodeficiency (CVID; n = 33), isotype defects or IgG subclass deficiency (n = 6), and unclassified IgG deficiency (n = 14). Of those, 49 patients (86%) received vaccination against SARS-CoV-2 using mRNA vaccine (Pfizer-BioNTech). T-cell responses were assessed at a median of 21 (13 - 30) weeks after the booster dose (mainly the third dose) using commercially available interferon-gamma release assay (IGRA) with recombinant SARS-CoV-2 spike S1 protein. Vaccinated PAD patients showed an increased (3.8-fold, p = 0.004) release of IFN-γ upon S1 stimulation. In this group, we also documented higher serum levels of anti-SARS-CoV-2 IgG (4.1-fold, p = 0.01), although they were not associated with IGRA results. Further subgroup analysis revealed very similar IGRA responses in CVID and unclassified IgG deficiencies that were 2.4-fold increased compared to XLA and 5.4-fold increased compared to patients with isotype defects or IgG subclass deficiencies (e.g., vs. CVID: p = 0.016). As expected, CVID and XLA patients showed decreased serum titers of anti-SARS-CoV-2 antibodies compared to other studied groups (e.g., CVID vs. unclassified IgG deficiency: 4.4-fold, p = 0.006). The results did not depend directly on IgRT mode or dose, number of vaccine doses and time from the last booster dose, and clinical manifestations of PAD. Interestingly, anti-SARS-CoV-2 titers were positively correlated with serum immunoglobulin levels before IgRT (e.g., for IgA: r = 0.45, p<0.001; for IgG: r = 0.34, p = 0.009) and the percentage of peripheral blood NK cells (r = 0.48, p<0.001). Our results documented satisfactory in vitro cellular immune response in PAD patients after booster SARS-CoV-2 vaccination. Therefore, even patients with agammaglobulinemia should benefit from vaccination due to the apparent induction of cell-mediated immunity, which, together with IgRT, grants comprehensive protection against the pathogen.

Transport Functions of Serum Immunoglobulins Among the Residents of the European Arctic of the Russian Federation

The paper presents data on the level of serum immunoglobulins in residents of the North and Arctic of the European territory of the Russian Federation. In people living in the Arctic, the average concentration of IgM, IgA and IgE is 1.4–2.6 times higher, the frequency of elevated concentrations is 2.4–8.8 times higher. A high frequency of IgG deficiency of 72.3% was established, which indicates inhibition of switching of antibody synthesis with a predominant predominance of IgM and IgA. In an unfavorable climate, the spectrum of antigenic structures increases and expands significantly. Activation of antibody production is due to an increased level of antigenic effects on the body and an increase in the content, diversity in the intravascular environment of tissue metabolism products with the properties of autoantigens. It was revealed that the concentration of immunoglobulins is significant in the formation of circulating immune complexes (CIC). In residents of the Arctic of the European territory of the Russian Federation, increased concentrations of IgM and IgA are associated with an increase in the content of neutrophil granulocytes and interferon-gamma cytokine (IFN-γ), which in turn is aimed at ensuring the effectiveness of the clearance of waste products in hypoxia.

Eosinophilic esophagitis despite isolated IgG4 deficiency: The still unsolved conundrum of pathogenesis

Eosinophilic esophagitis despite isolated IgG4 deficiency: The still unsolved conundrum of pathogenesis

Utility of Class-Switched B-Cells in Diagnosing Common Variable Immunodeficiency

Measuring the relative quantity of peripheral blood class-switched CD27 +IgD- B-cells (CSBs) has previously been proposed as useful in the subclassification of CVID diagnoses. Perhaps incautiously, this practice has been adopted widely among clinical immunologists and has even been included as supportive diagnostic criteria for CVID. Existing research has also shown lower numbers of CSBs in CVID than in IgG deficiency; however, the diagnostic utility of CSBs was not evaluated and additional cohorts have not been studied. This study aimed to determine if low peripheral blood CSB numbers accurately differentiate CVID from other forms of humoral immunodeficiency.We performed a retrospective chart review of all patients at Children's Hospital of Colorado with 8-marker comprehensive B-cell panel results from the time of the panel's implementation in 2020. Inclusion criteria included: age ≥5 years and absolute CD19 B-cell measurement within 60 days of B-cell panel results. Subjects were assigned a diagnosis of CVID based on ICON criteria and by expert opinion when the workup was incomplete, such as in cases with borderline serum immunoglobulin levels or where polysaccharide antibody responses were not available. Patients that did not meet CVID criteria but were considered to have a humoral immunodeficiency based on immunoglobulin levels were separately categorized. Of the patients included (n = 64), 3 met all ICON criteria, 10 had a diagnosis by expert opinion, and 24 had a non-CVID immunological defect. Multinomial logistic regression accounting for age and sex demonstrated no significant association between absolute or percent CSB levels and whether the patient had a known or suspected CVID diagnosis; however, binary logistic regression indicated the odds of having any humoral immunodeficiency, including CVID, increased with decreasing CSB percentage (p = 0.026). Additionally, a linear regression between percent CSBs and in vivo serum IgG levels found a statistically significant relationship (p = 0.046), which has not been demonstrated previously. This observation is consistent with peripheral blood CD27+IgD- CSBs reflecting a person's general ability to class-switch to IgG production. Ultimately these findings suggest that CSBs may have utility as a general indicator of humoral immune disruption but are not an adequately specific metric in forming a CVID diagnosis.

Effects of intravenous immunoglobulin on the negatively transformed subpopulations of neutrophilic granulocytes in newborns with congenital pneumonia and neonatal sepsis

Today, the diagnosis and treatment of severe infectious and inflammatory diseases in newborns, e.g., congenital pneumonia (CP) and neonatal sepsis (NS), present difficult problems. Searching sensitive and specific severity markers of bacterial inflammatory process as well as early and effective treatment are crucial for the outcome and prognosis of these life-threatening diseases. The aim of our study was to assess the effects of intravenous immunoglobulin (IVIG) injections on the negatively transformed subpopulations of neutrophilic granulocytes (NG) СD64-CD16+СD32+СD11b+, СD64+CD16+СD32+СD11b+ and evaluation of their functional activity in newborns with CP and NS. We have observed 38 full-term newborn patients. Group 1 included 19 infants with CP, including 11 children who received conventional therapy and IVIG (group 1.1), and 8 children treated at conventional protocols (group 1.2). Group 2 included 19 children with NS, including 12 children who underwent conventional therapy and IVIG treatment (group 2.1), and 7 children who were subject to conventional therapy (group 2.2). The comparison group consisted of 22 healthy full-term newborns. Testing of NG population included the following parameters: counting the numbers of NG subpopulations which simultaneously expressed CD11b CD64, CD32, CD16, as well as their phenotypic patterns, with regard of the receptor expression density (MFI) using flow cytometric techniques. Moreover, we determined phagocytic and microbicidal activity of the granulocytes. We have revealed negative transformation of СD64-CD16+СD32+СD11b+ and СD64+CD16+СD32+СD11b+ subpopulations of neutrophilic granulocytes in newborns with CP and NS, The diagnostic significance of increased СD64+CD16+СD32+СD11b+NG subpopulation was more pronounced with increasing severity of bacterial infection and inflammatory process, i.e., 18.7-fold in CP, 52.3-fold in NS, along with predominant decrease in expression of appropriate membrane receptors. These phenotypic changes were associated with impaired phagocytic and killing activity of NG. The effect of IVIG on the impaired mechanisms of antibacterial immunity is associated not only with alleviation of IgG deficiency, but also with positive remodeling of negatively transformed subpopulations of СD64-CD16+СD32+СD11b+NG and СD64+CD16+СD32+СD11b+NG, improved effector functions of NG, especially in cases of CP. Thus, following IVIG treatment, a reduced number of СD64-CD16+СD32+СD11b+NG subpopulations was fully recovered in CP, while it increased 1.5 times in NS, and the content of diagnostically significant СD64+CD16+СD32+СD11b+NG subpopulation showed a significantly decrease, both in CP (2-fold) and in NS (2.6-fold). However, this index remained higher than the content of this subpopulation in healthy newborns. At the same time, we have noted the restorative or modulatory effects by changing density of trigger molecules in NG subpopulations. Limitation of the negative NG transformation in their functionally significant subpopulations in newborns with CAP and NS was accompanied by positive clinical effects, i.e., optimization of antibiotic therapy, reduced duration of treatment, and improved mortality rates.

Cutaneous polyarteritis nodosa associated with IgG deficiency &amp; inflammatory bowel disease: case report

Cutaneous polyarteritis nodosa associated with IgG deficiency &amp; inflammatory bowel disease: case report

Characterizing Immunodeficiency in Patients with Telomere Biology Disorders

Telomere biology disorders (TBD) are caused by germline mutations in telomere related genes that lead to excessive telomere shortening. Affected genes include TERT and TERC, which encode two components of the telomerase complex. TBDs are multisystem disorders that present with a constellation of findings including bone marrow failure and lung and/or liver disease. Immunodeficiency has been described but is not well characterized in a large cohort of TBD patients. In the present study, we report the clinical incidence and severity of infections, as well as laboratory evidence of immunodeficiency in 83 patients with TBD. The electronic medical record was queried for the clinical history of patients with TBD who were evaluated at the National Institutes of Health Clinical Center from 2002 to present. Laboratory data included immunoglobulins (IgG, IgA, IgM) and peripheral blood lymphocyte subsets (CD4, CD19). Fifteen patients did not have immunoglobulin levels and 29 patients did not have lymphocyte subsets available. A significant infection history was defined as occurrence of infections that were opportunistic, recurrent, and/or required hospitalization. Recurrent infections were defined as two or more severe infections in one year, three or more respiratory infections (e.g. sinusitis, otitis, bronchitis) in one year, or the need for antibiotics for two months per year. Diminished immune function was defined by CD4 T cell counts: patients with CD4 < 200 cells x 106/L were classified as immunodeficient, and CD4 >200 cells x 106/L but < 500 cells x 106/L as immune impaired. Reference ranges for female and male patients were used to determine whether levels are below or within normal limits. Development of lung and/or liver fibrosis were also assessed. Chi-square tests were used to test the association between the two categorical variables. Kaplan-Meier curves and log rank tests were used to estimate overall survival (OS) and test the differences of survival time distributions among infection groups and immune status groups. Patient characteristics are in Table 1. TERT and TERC were the most commonly mutated genes, and others included DKC1, PARN, TINF2, CTC1, RTEL1, and NAF1. Of 49 patients with laboratory data available, the majority (65%) had depressed CD4 counts with 11 immunodeficient patients, 21 immune impaired patients, and 17 patients with normal counts. Median age was similar in the 3 groups. Three (27%) immunodeficient patients and 2 (10%) immune impaired patients had an opportunistic infection. Two (18%) immunodeficient patients and 6 (29%) immune impaired patients reported recurrent infections. Nine (43%) immune impaired patients required hospitalization from infection. No patients with normal CD4 count had opportunistic or recurrent infections, but 4 had required hospitalization for infection. Lower CD4 count was associated with having a significant infection history, and specifically recurrent infections, and being hospitalized for infection (p=0.0417, p=0.0471, p=0.0154 respectively). We observed varied associations between other clinical factors and immune dysfunction or infection. Low levels of CD19 B cells were observed in 14 patients, and associated with development of recurrent infections (P = 0.0003) but not opportunistic or infections requiring hospitalization. Two patients had deficient IgG and IgA levels while 8 had deficient IgM. However, immunoglobulins were not associated with any significant infection history. All immunodeficient and immune impaired patients had concurrent bone marrow failure. Lung fibrosis was recorded in 6 (54%) immunodeficient and 6 (27%) immune impaired patients, and liver fibrosis in 4 (36%) immunodeficient and 4 (19%) immune impaired patients. Of 11 patients with both lung and liver fibrosis, 4 (36%) were immunodeficient, 2 (18%) were immune impaired, and 5 (45%) did not have CD4 counts available. There was no association between gene mutation and development of low CD4 count or clinically significant infections. OS was lower in TBD patients with clinically significant infections (p=0.00011) or low CD4 counts (p=0.016) (Figure 1). Immune dysfunction is common in TBD and patients are at increased risk of clinically significant infections. Low CD4 counts are associated with worse OS. TBD patients should be routinely screened for immunodeficiency to allow appropriate clinical monitoring, antimicrobial prophylaxis, and education. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P.12 A case report of near normalization of serum creatine phosphokinase in a patient with Duchenne muscular dystrophy during acute pancreatitis

Creatine phosphokinase (CPK) is a muscle-specific protein that has served a vital role as a diagnostic biomarker for Duchenne Muscular Dystrophy (DMD). It is also often used to track disease progression in DMD. However, its role as a monitoring, or predictive biomarker is less clear. We describe a 6-year-old boy with DMD caused by duplication of exon 2 of the dystrophin gene as well at IgG deficiency. He presented acutely to the emergency department with brown colored urine in the setting of five days of non-bloody non-bilious emesis, abdominal pain and poor oral intake. His initial examination was notable for signs of moderate dehydration and a soft, non-tender abdomen. His initial laboratory evaluation was notable for anion gap metabolic acidosis, hyponatremia and hypoglycemia. He was ultimately diagnosed with acute pancreatitis after lipase was found to be 2201.0 unit/L (ref 48.0-199.0 unit/L) on day of his admission. He was placed on intravenous fluids and admitted for a total of 3 days with complete recovery. This individual had a baseline CPK of 11,000-21,000 unit/L at previous outpatient visits. Of note, CPK level was obtained on the day of his hospital admission and was found to be 284 unit/L (ref 30-250). The day after admission, CPK was rechecked twice and were 312 and 322 unit/L separately. Fourteen days after admission, CPK was rechecked and had returned to near his previous baseline at 15,496 unit/L. Pancreatitis and other acute inflammatory conditions in DMD are rare. Transient near normalization of CPK has been described previously in one patient with Becker Muscular Dystrophy patient during transient arthritis. To our knowledge, our patient is the first reported case of normalization of CPK level in DMD during acute inflammatory disease. We hypothesize the transient normalization of CPK was secondary to active systemic response during the acute inflammation. Studies to look deeper into reasons that may underlie such a phenomenon may shed light in finding protective mechanisms associated with the inflammation pathway.