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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Immunoglobulin substitution in patients with secondary antibody deficiency in chronic lymphocytic leukemia and multiple myeloma: a representative analysis of guideline adherence and infections.

INTRODUCTION: In secondary immunodeficiency, immunoglobulin replacement therapy (IgRT) is recommended by guidelines (GL) for patients with IgG level < 4 g/l and more than 3 infections or a severe infection. IgRT may be appropriate if IgG level < 4 g/l and/or 1-3 less severe infections (≤ grade 2). METHODS: This was a retrospective sample analysis representative for practices and hospitals in Germany. The treatments and infection data were collected from patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). GL adherence (GLAD) was analyzed. RESULTS: Data from 1086 patients (CLL 490, MM 596) were collected from 86 centers. Of all patients, 34.8% developed IgG deficiency during therapy (CLL 35.5%; MM 34.2%). IgRT was given in 23.5% of CLL and 14.4% of MM patients. GLAD in hypogammaglobulinemia and indication to IgRT was 23.3% of 86 CLL and 22.1% of 77 MM patients. Without GLAD, the hazard ratio (HR) for any infection was 4.49 (95% CI 3.72-5.42; p < 0.001) and for severe infections (grade ≥ 3) 10.64 (95% CI 7.54-15.00; p < 0.001). Significant independent risk factors for infections were a higher Charlson Comorbidity Index, IgG deficiency, and 3rd + line treatment, as well as therapy with BTK inhibitors or chemotherapy in CLL. Multivariable analysis showed a significantly lower risk of severe infections after start of IgRT with a HR of 0.47 (95% CI 0.28-0.77; p = 0.003). CONCLUSIONS: Guideline adherence correlated with fewer and less severe infections but was low in patients with indication to IgRT. Risk factors for infection can be identified. Risk of severe infections was significantly lower in patients with IgRT.

Clinical heterogeneity among pediatric patients with autoimmune type 1 diabetes stratified by immunoglobulin deficiency.

BACKGROUND: Type 1 diabetes (T1D) may coexist with primary immunodeficiencies, indicating a shared genetic background. OBJECTIVE: To evaluate the prevalence and clinical characteristics of immunoglobulin deficiency (IgD) among children with T1D. METHODS: Serum samples and medical history questionnaires were obtained during routine visits from T1D patients aged 4-18 years. IgG, IgA, IgM, and IgE were measured by nephelometry and enzyme-linked immunosorbent assay (ELISA). IgG and IgM deficiency (IgGD, IgMD) were defined as IgG/IgM >2 standard deviations (SD) below age-adjusted mean. IgE deficiency was defined as IgE <2 kIU/L. IgA deficiency (IgAD) was defined as IgA >2 SD below age-adjusted mean irrespective of other immunoglobulin classes (absolute if <0.07 g/L, partial otherwise) and as selective IgAD when IgA >2 SD below age-adjusted mean with normal IgG and IgM (absolute if <0.07 g/L, partial otherwise). RESULTS: Among 395 patients (53.4% boys) with the median age of 11.2 (8.4-13.7) and diabetes duration 3.6 (1.1-6.0) years, 90 (22.8%) were found to have hypogammaglobulinemia. The IgGD and IgAD were the most common each in 40/395 (10.1%). Complex IgD was found in seven patients. Increased odds of infection-related hospitalization (compared to children without any IgD) was related to having any kind of IgD and IgAD; OR (95%CI) = 2.1 (1.2-3.7) and 3.7 (1.8-7.5), respectively. Furthermore, IgAD was associated with having a first-degree relative with T1D OR (95%CI) = 3.3 (1.4-7.6) and suffering from non-autoimmune comorbidities 3.3 (1.4-7.6), especially neurological disorders 3.5 (1.2-10.5). CONCLUSIONS: IgDs frequently coexist with T1D and may be associated with several autoimmune and nonimmune related disorders suggesting their common genetic background.

Fatigue Is Common in Immunoglobulin G Subclass Deficiency and Correlates With Inflammatory Response and Need for Immunoglobulin Replacement Therapy.

Purpose: Individuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study perceived quality of life (QoL) and fatigue in individuals with IgGsd, on and off immunoglobulin replacement therapy (IgRT) were correlated to inflammatory markers in plasma to identify the subgroup that benefits from IgRT. Method: Thirty-five IgGsd-patients were sampled on three occasions: at baseline, after being on IgRT for at least 18 months, and 18 months after discontinuation of IgRT. Short form 36, EQ-5D-5L visual analogue scale and fatigue impact scale questionnaires were used for evaluation of QoL and fatigue. Furthermore, a panel of 92 inflammatory markers were analysed in plasma. Thirty-two gender- and age-matched healthy individuals were included as controls and sampled on one occasion. Results: QoL was lower and perceived fatigue higher in IgGsd compared to the controls. Severe fatigue and low QoL were associated with the need to restart IgRT (which is considered in IgGsd-individuals with a high burden of infections in Sweden). Twenty-five inflammatory factors were dysregulated in IgGsd and the plasma protein patterns were similar regardless of whether IgRT was ongoing or not. Enrichment analysis indicated IL-10 signalling as the most affected pathway. Severe fatigue was associated with decreased levels of the neurotrophic factors VEGFA and CSF-1. Conclusion: Fatigue is a major contributory factor to impaired health-related QoL in IgGsd and is related to the need for IgRT. Low-grade systemic inflammation is a potential driver of fatigue. In addition to the burden of infections, we suggest the degree of fatigue should be considered when the decision to introduce IgRT is made.

Immunoglobulin G Deficiency in Children with Recurrent Respiratory Infections with and Without History of Allergy.

Recurrent respiratory tract infections (RTI) are one of the most common diseases in childhood. Frequent infections adversely affect the development of a child and may lead to suspicion of immunodeficiency. An additional allergy component is thought conducive to infection occurrence. In this study, we retrospectively assessed medical records of 524 children hospitalized with RTI. Patients were divided into two groups: RTI-alone (n = 394) and RTI with a history of allergy (n = 130). Overall, we found that a great majority of children with RTI had the immunoglobulin G within the normal limit, irrespective of allergy. A variable IgG deficiency, most often affecting IgG1, IgG3, and IgG4 subclass, was present in less than one-third of children. Proportions of specific IgG subclass deficiency, varying from about 10% to 40%, were similar in both RTI-alone and RTI-allergy groups. The only significant effect was a modestly smaller proportion of children with IgG4 deficiency in the RTI-allergy group when compared with the RTI-alone group. We also found that IgG deficiencies were age-dependent as their number significantly increased with children's age, irrespective of allergy. The results demonstrate a lack of distinct abnormalities in the immunoglobulin G profile which would be characteristic to a clinical history of allergy accompanying recurrent RTI in children. Thus, we conclude that the assessment of IgGs could hardly be of help in the differential diagnostics of the allergic background of RTI.

COVID-19 complicated by parainfluenza co-infection in a patient with chronic lymphocytic leukemia.

The number of people suffering from the new coronavirus SARS-CoV-2 continues to rise. In SARS-CoV-2, superinfection with bacteria or fungi seems to be associated with increased mortality. The role of co-infections with respiratory viral pathogens has not yet been clarified. Here, we report the course of COVID-19 in a CLL patient with secondary immunodeficiency and viral co-infection with parainfluenza.

Impact of immunoglobulin G2 subclass level on late-onset bacterial infection after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Immunoglobulin (Ig) G2 subclass deficiency is known to be associated with recurrent bacterial respiratory infections caused by capsulated bacteria and is found mostly in pediatric patients. However, its impact after allogeneic hematopoietic stem cell transplantation (HSCT) has not been fully assessed. METHODS: We retrospectively evaluated the relationship between IgG2 subclass levels and bacterial pneumonia in 74 adult patients who survived longer than 2 years after allogeneic HSCT. RESULTS: During the evaluation period, nine patients developed bacterial pneumonia. The median IgG2 level was significantly lower in patients with an infectious episode than in those without (143 mg/dL vs 287 mg/dL; P < 0.01). In multivariate analysis, a history of rituximab therapy and cord blood as a stem cell source were significantly associated with decreased levels of both IgG2 and IgG2/IgG ratios (P < 0.05). CONCLUSIONS: Suboptimal serum IgG2 levels could increase susceptibility to late-onset bacterial pneumonia after allogeneic HSCT. IgG2 levels should be considered carefully, especially in patients receiving cord blood transplantation and/or rituximab treatment.

Lifelong immunoglobulin replacement is not always necessary: A case description of a patient with recurrent infections and hypogammaglobulinemia.

Humoral immunodeficiency with accompanying infections is an indication for human immunoglobulin replacement therapy. Whether treatment will be lifelong or necessary only temporarily depends on the nature of deficiency: primary (persistent) or secondary (persistent or transient). It is not always easy to distinguish between primary and secondary immunodeficiency, especially in adults. The article presents a case of a 39-year-old patient with anamnesis and medical tests results that suggested primary humoral immunodeficiency. The deficiency was diagnosed for the first time at the age of 38, when the patient was pregnant. The patient was qualified for immunoglobulin G replacement therapy. Clinical improvement was achieved. After the end of pregnancy, systematic improvement in immunological parameters was observed, suggesting the resolution of immunodeficiency. A decision was made to discontinue immunoglobulin replacement. Due to the ability to respond to vaccine, confirmed during diagnosis, preventive vaccines were recommended. There was no recurrence of serious infections. The clinical course finally enabled a diagnosis of secondary immunodeficiency. The presented case shows the importance of an active approach to the diagnostic and therapeutic process, constant assessment of clinical course, monitoring of IgG concentrations, and the awareness that in the situation when we do not have a genetic confirmation of the disease, the diagnosis may change.

Gamma globulin replacement therapy in uncontrolled, severe asthma associated with humoral immunodeficiency: A series of five case reports.

We report on five adult cases of the rare association of asthma with humoral immunodeficiency (huID). All patients had uncontrolled asthma related to recurrent respiratory infections. Asthma was diagnosed according to the Global Initiative for Asthma (GINA) guidelines, and bronchiectasis was ruled out by a CT chest scan. Two men (aged 28 and 60) presented with pollen allergies, chronic rhinosinusitis, and IgG deficiency (7.8 and 7.6 g/L, respectively). Both patients underwent surgery for nasal polyposis but relapsed with acute sinusitis and severe asthma exacerbations requiring treatment with oral corticosteroids and antibiotics. The immunoglobulin replacement therapy (IRT) partially relieved the asthma by reducing the number of exacerbations. A 55-year-old woman presented with nonallergic, corticosteroid-dependent asthma (20 mg/day prednisone) and IgG deficiency (5.72 g/L). IRT improved asthma control (fall in the Asthma Control Questionnaire (ACQ)-7 score from 3.5 to 1.7) and enabled withdrawal of the corticosteroids. In a 47-year-old woman with an IgG2 subclass deficiency (1.9 g/L) and asthma, IRT increased the degree of asthma control (fall in the ACQ-7 score from 2.8 to 1.1). A 75-year-old woman presented with corticosteroid-dependent asthma (40 mg/day prednisone), IgM and IgG deficiencies (0.28 g/L and 5.36 g/L, respectively), and recurrent respiratory, skin and urinary infections. Again, IRT improved asthma control (fall in the ACQ-7 score from 2.5 to 1.2), reduced the number of hospitalizations for asthma exacerbations, and enabled a 10-mg reduction in the daily dose of prednisone. These observations suggest that IRT may improve disease control in some patients with asthma and associated huID.

Disorders of Humoral Immunity in Children with IgG Subclass Deficiency and Recurrent Respiratory Infections.

Respiratory tract infections in children are one of the most common causes for medical consultations. When the infections are of recurring nature, they are a major reason for the diagnostics for primary immunodeficiency that is in about 65% of cases underlain by disorders of humoral immunity. This study seeks to retrospectively evaluate the history of recurrent respiratory tract infections in children with humoral disorders and the associations among deficiencies in the immune system components. We evaluated 394 children aged 3 months to 18 years. We found 49.5% (195 cases) of children with IgG deficiencies, all of whom had normal IgE levels. There were 8.4% (33 cases) of IgA deficiency, 7.4% (29 cases) of IgM insufficiency, and 4.1% (16 cases) of CD19+ cells deficiency. The elevated level of CD19+ cells was found in 27.7% (109 out of the 394 children). Immunoglobulin deficiencies often coexisted with a deficiency in another immunoglobulin class above outlined. There was an interdependence between IgA abnormality and IgG, IgG3, and IgG4 abnormalities as well as between IgM abnormality and IgG and IgG1 abnormalities. We conclude that respiratory tract infections in children are often underlain by a convergence of IgG with both IgA and IgM abnormal states. The physiopathological meaning of this convergence for the infection course and resulting functional respiratory changes remains elusive.

[EFFICACY OF IVIG TREATMENT IN BRONCHIECTASIS ASSOCIATED WITH IGG SUBCLASS DEFICIENCY].

INTRODUCTION: Bronchiectasis is characterized by an abnormal dilatation of the bronchi leading to a chronic inflammatory process, airway blockage and impaired clearance of secretions. The damage to the airways is usually progressive and is the result of several pathogenic processes. In the past, healing of infections (especially pulmonary tuberculosis) was the main cause of airway dilatation and progression of chronic inflammation. Today, congenital illnesses, anatomical defects and immune deficiency play an important role in the pathogenesis of bronchiectasis formation. The immunoglobulin repertoire is vital for effective host protection against a wide variety of pathogens. Primary antibody deficiency diseases are defects of the humoral arm of the immune system and involve an absence/reduced levels of one or more immunoglobulin classes/subclasses or defects of specific antibody formation. Immunoglobulin G (IGG) subclass deficiency can occur in a healthy person and could be without clinical significance. However, in recent years there is emerging evidence that in patients with recurrent infections, early diagnosis of antibody deficiency affects the prognosis and prevention of ongoing lung damage. The use of IVIG has contributed significantly to the survival rate in primary antibody deficiencies. There is limited literature on the treatment of IVIG for patients with IGG subclass deficiency. However, all studies presented so far demonstrated that immunoglobulin therapy reduced the rate of bacterial infections, days of antibiotic usage, hospital admissions and significantly increased patients' quality of life. Therefore, in the appropriate clinical setting, ie: a patient with bronchiectasis and recurrent infections, it is justified to test whether there are humoral immune defects such as IGG subclass deficiency. In a patient with proven deficiency, we should recommend to start IVIG treatment until clinical benefit is achieved.

The Pneumocell-study: Vaccination of IgG1- and IgG2-deficient patients with Prevnar13.

BACKGROUND: Patients with IgG-deficiency often suffer from repeated bacterial infections with S. pneumoniae. Since there is a lack of knowledge regarding whether IgG-deficient patients would benefit from conjugate pneumococcal vaccination, we set out to evaluate the effect of Prevnar13 vaccination in IgG1- and/or IgG2-deficient patients. METHOD: We designed a small pilot-study including IgG1- and/or IgG2-deficient patients (n=10) and age- and sex-matched healthy controls (n=10). Serum, plasma and heparin-blood were collected prior to vaccination, as well as 1, 2 and 4weeks post vaccination, and the levels of opsonophagocytic activity (Opa) titers and anti-pneumococcal IgG-antibodies were analyzed. RESULTS: Patients generally had lower Opa-titers than controls for most serotypes, but they exhibited an almost normal vaccine response to serotypes 6A and 6B. Notably, 5/10 patients showed vaccine-response to at least one serotype. Most patients reached the presumably protective levels of Opa-titers ≥8 and anti-pneumococcal IgG levels of 0.35µg/ml by 4weeks post-vaccination for a majority of the serotypes. CONCLUSION: Our results show that vaccination of IgG-deficient patients with Prevnar13 is likely to have a clinical benefit. Our initial findings will provide a framework for future vaccine-trials in this vulnerable patient group. Registered at www.clinicaltrials.gov as NCT01847781.

Immunoglobulin G Subclass Deficiencies in Adult Patients with Chronic Airway Diseases.

Immunoglobulin G subclass deficiency (IgGSCD) is a relatively common primary immunodeficiency disease (PI) in adults. The biological significance of IgGSCD in patients with chronic airway diseases is controversial. We conducted a retrospective study to characterize the clinical features of IgGSCD in this population. This study examined the medical charts from 59 adult patients with IgGSCD who had bronchial asthma or chronic obstructive pulmonary disease (COPD) from January 2007 to December 2012. Subjects were classified according to the 10 warning signs developed by the Jeffrey Modell Foundation (JMF) and divided into two patient groups: group I (n = 17) met ≥ two JMF criteria, whereas group II (n = 42) met none. IgG3 deficiency was the most common subclass deficiency (88.1%), followed by IgG4 (15.3%). The most common infectious complication was pneumonia, followed by recurrent bronchitis, and rhinosinusitis. The numbers of infections, hospitalizations, and exacerbations of asthma or COPD per year were significantly higher in group I than in group II (P < 0.001, P = 0.012, and P < 0.001, respectively). The follow-up mean forced expiratory volume (FEV1) level in group I was significantly lower than it was at baseline despite treatment of asthma or COPD (P = 0.036). In conclusion, IgGSCD is an important PI in the subset of patients with chronic airway diseases who had recurrent upper and lower respiratory infections as they presented with exacerbation-prone phenotypes, decline in lung function, and subsequently poor prognosis.

Afección del sistema nervioso central en la enfermedad relacionada con IgG4: descripción de un caso y revisión de la bibliografía / Central nervous system in IgG4-related disease: case report and literature review

Introducción. La enfermedad relacionada con IgG4 es una entidad clínica multisistémica recientemente descrita y que se presenta con diferentes manifestaciones clínicas. Los órganos que están afectados con mayor frecuencia son el páncreas, la vía biliar y las glándulas salivales, y es menos frecuente la afección del sistema nervioso central. Caso clínico. Mujer de 33 años con alteraciones cognitivas, alucinaciones, cefalea, síndrome convulsivo, sinusitis maxilar con afección ósea y evidencia de paquimeningitis y panhipopituitarismo, con biopsia meníngea que confirmó una enfermedad relacionada con IgG4, tras haberse descartado causas secundarias. Se inició tratamiento con glucocorticoides y azatioprina, sin recaídas después de 12 meses de seguimiento. Conclusiones. Se debe considerar el diagnóstico de enfermedad relacionada con IgG4 en casos de paquimeningitis hipertrófica e hipofisitis, incluso sin que se acompañen de otras manifestaciones sistémicas, siempre que se hayan descartado otras causas más frecuentes. El tratamiento de elección son los glucocorticoides, y puede ser necesario añadir otro inmunosupresor como ahorrador de esteroides y para evitar las recaídas. Se necesitan estudios prospectivos para evaluar las diferentes manifestaciones clínicas y paraclínicas y establecer los resultados del tratamiento a largo plazo (AU)

Introduction. IgG4-related disease is a recently described multisystemic clinical entity that can occur with different clinical manifestations. The most often affected organs are the pancreas, bile duct and salivary glands, with unusual central nervous system affection. Case Report. A 33 year old woman who presented with cognitive impairment, hallucinations, headache, convulsive syndrome, maxillary sinus inflammation with bone involvement and evidence of pachymeningitis and panhypopytuirarism with meningeal biopsy that confirmed IgG4-related disease, after ruling out secondary causes. Treatment was started with steroids and azathioprine without relapses after 12 months follow-up. Conclusions. IgG4-related disease should be considered in cases of hypertrophic pachymeningitis and hypophysitis especially when no other cause has been found, even if they are not accompanied by other systemic disease manifestations, having ruled out other common causes. The treatment of choice is glucocorticoids and it could be needed to add another immuno­suppressant agent as steroid sparing and to prevent relapses. Prospective studies are needed to evaluate the different clinical and paraclinical manifestations and to establish the results of long-term treatment (AU)

Selective Subnormal IgG1 in 54 Adult Index Patients with Frequent or Severe Bacterial Respiratory Tract Infections.

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.

Estenosis traqueal y enfermedad por IgG4 / Tracheal stenosis and IgG4-related disease

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Immunoglobulin G Deficiency-Associated Septic Arthritis Identified Following Corticosteroid Injection and Knee Arthroscopy: A Case Report.

CASE: We present the case of a patient who had worsening pain following intra-articular knee corticosteroid injection and who subsequently underwent arthroscopic partial meniscectomy with positive intraoperative cultures for Staphylococcus lugdunensis. He was treated with multiple irrigation and debridements, and subsequent work-up yielded a diagnosis of immunoglobulin G (IgG) deficiency. We believe that it is critical to maintain a high index of suspicion for underlying immune deficiency when faced with atypical presentations of infections or atypical bacteria in otherwise healthy patients. CONCLUSION: Knee arthroscopy for the treatment of meniscal tears is one of the most common procedures performed by orthopaedic surgeons in the United States. Patients with an antibody deficiency may have a limited or reduced immune response when presented with a pathogen foreign to the body. This may place the patient at an increased risk of infection and should be addressed through referral to the appropriate subspecialists when recurrent or atypical infection presents to the orthopaedic surgeon.

Enfermedad relacionada con IgG4 / IgG4-related disease

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