Autoimmune and inflammatory manifestations in pediatric patients with primary immunodeficiencies and their importance as a warning sign

INTRODUCTION AND OBJECTIVES: As well as increased susceptibility to infections, autoimmune and inflammatory manifestations also eventuate due to dysregulation of immune system in a substantial proportion of patients with primary immunodeficiency (PID). Autoimmune and inflammatory manifestations can occur prior or after diagnosis of PID. This study aimed to evaluate autoimmune and inflammatory complications among all types of PID patients in childhood and to emphasize the importance of these findings as a warning sign to diagnose PIDs. METHODS: Medical records of 1036 patients with PID, followed up between 2003 and 2019, were retrospectively screened for occurrence of autoimmunity and inflammation. During this time, demographic features, autoimmune/inflammatory findings and initial time, genetic mutations, laboratory and clinical follow up findings, treatment regimens and outcomes were recorded. RESULTS: Autoimmune and inflammatory manifestations were observed in 83 patients (10.1%). The median age of autoimmunity initial time was 61.3 ± 53 months. Sixty-seven (80.7%) patients presented with autoimmune and inflammatory manifestations, and these findings had occurred during 16 patients' (19.3%) follow-up. The most common autoimmune manifestations were autoimmune hematologic (51.8%) and endocrine diseases (26.5%). Fifty patients (60.2%) had a single autoimmune/inflammatory manifestation, however 23 patients (27.7%) had two, eight patients (9.6%) had three and two patients (2.4%) had four different types of autoimmune/inflammatory manifestations. The frequency of autoimmune and inflammatory manifestations in phagocyte defects (56%), combined immune deficiencies (53%) and immune dysregulation diseases (52%) were observed higher than other forms of PIDs. During follow-up 13 (15.7%) patients died. CONCLUSION: Autoimmune/inflammatory manifestations are associated with high morbidity in patients with PIDs and may precede the diagnosis of PID in childhood. Therefore, physicians must be aware of underlying possible immune deficiency and patients with known PIDs should be evaluated for autoimmune and inflammatory complications

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Adverse reactions and influencing factors in children with primary immunodeficiencies receiving intravenous immunglobulin replacement

OBJECTIVES: We aimed to determine adverse reactions and influencing factors, within the scope of the number of patients and total infusions, in patients with primary immunodeficiencies receiving intravenous immunoglobulin (IVIG) replacement. MATERIALS AND METHODS: Children with primary immunodeficiencies receiving IVIG replacement in Izmir Dr Behcet Uz Children's Hospital, between June 2014 and June 2016, were included in our study. RESULTS: The total number of the patients receiving IVIG replacement was 145 (37 female, 108 male). The number of total IVIG infusions was 1214. Adverse reactions were observed in 44.8% of the patients and 14.2% of the infusions. Common variable immunodeficiency was the most common diagnosis of the patients and adverse reactions most commonly developed in this group (24.2%). In all infusions the most frequent adverse reaction was headache (7.8%); fever was the most frequent immediate side effect (3.9%), whereas headache was the most common delayed adverse effect (5.1%). By logistic regression analyses, history of adverse reaction to IVIG in previous infusions, existence of concomitant infectious disease, past or family history of atopic disease, to receive IVIG infusion at the first time, or being under 10 years old were found associated with adverse reactions. There was no correlation between the concentration of IVIG preparations and the rate of side-effect development. CONCLUSIONS: In our study no severe adverse reaction to IVIG was observed, but many mild or moderate side effects occurred. Therefore, IVIG indications must be well identified. Patients, family of the patients and health care workers must be informed for adverse reactions

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Adverse reactions and influencing factors in children with primary immunodeficiencies receiving intravenous immunglobulin replacement.

OBJECTIVES: We aimed to determine adverse reactions and influencing factors, within the scope of the number of patients and total infusions, in patients with primary immunodeficiencies receiving intravenous immunoglobulin (IVIG) replacement. MATERIALS AND METHODS: Children with primary immunodeficiencies receiving IVIG replacement in Izmir Dr Behcet Uz Children's Hospital, between June 2014 and June 2016, were included in our study. RESULTS: The total number of the patients receiving IVIG replacement was 145 (37 female, 108 male). The number of total IVIG infusions was 1214. Adverse reactions were observed in 44.8% of the patients and 14.2% of the infusions. Common variable immunodeficiency was the most common diagnosis of the patients and adverse reactions most commonly developed in this group (24.2%). In all infusions the most frequent adverse reaction was headache (7.8%); fever was the most frequent immediate side effect (3.9%), whereas headache was the most common delayed adverse effect (5.1%). By logistic regression analyses, history of adverse reaction to IVIG in previous infusions, existence of concomitant infectious disease, past or family history of atopic disease, to receive IVIG infusion at the first time, or being under 10 years old were found associated with adverse reactions. There was no correlation between the concentration of IVIG preparations and the rate of side-effect development. CONCLUSIONS: In our study no severe adverse reaction to IVIG was observed, but many mild or moderate side effects occurred. Therefore, IVIG indications must be well identified. Patients, family of the patients and health care workers must be informed for adverse reactions.

Autoimmune and inflammatory manifestations in pediatric patients with primary immunodeficiencies and their importance as a warning sign.

INTRODUCTION AND OBJECTIVES: As well as increased susceptibility to infections, autoimmune and inflammatory manifestations also eventuate due to dysregulation of immune system in a substantial proportion of patients with primary immunodeficiency (PID). Autoimmune and inflammatory manifestations can occur prior or after diagnosis of PID. This study aimed to evaluate autoimmune and inflammatory complications among all types of PID patients in childhood and to emphasize the importance of these findings as a warning sign to diagnose PIDs. METHODS: Medical records of 1036 patients with PID, followed up between 2003 and 2019, were retrospectively screened for occurrence of autoimmunity and inflammation. During this time, demographic features, autoimmune/inflammatory findings and initial time, genetic mutations, laboratory and clinical follow up findings, treatment regimens and outcomes were recorded. RESULTS: Autoimmune and inflammatory manifestations were observed in 83 patients (10.1%). The median age of autoimmunity initial time was 61.3±53 months. Sixty-seven (80.7%) patients presented with autoimmune and inflammatory manifestations, and these findings had occurred during 16 patients' (19.3%) follow-up. The most common autoimmune manifestations were autoimmune hematologic (51.8%) and endocrine diseases (26.5%). Fifty patients (60.2%) had a single autoimmune/inflammatory manifestation, however 23 patients (27.7%) had two, eight patients (9.6%) had three and two patients (2.4%) had four different types of autoimmune/inflammatory manifestations. The frequency of autoimmune and inflammatory manifestations in phagocyte defects (56%), combined immune deficiencies (53%) and immune dysregulation diseases (52%) were observed higher than other forms of PIDs. During follow-up 13 (15.7%) patients died. CONCLUSION: Autoimmune/inflammatory manifestations are associated with high morbidity in patients with PIDs and may precede the diagnosis of PID in childhood. Therefore, physicians must be aware of underlying possible immune deficiency and patients with known PIDs should be evaluated for autoimmune and inflammatory complications.

Do elevated serum IgM levels have to be included in probable diagnosis criteria of patients with ataxia-telangiectasia?

Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder that is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency. Delay in diagnosis or misdiagnosis is probable due to its wide clinical heterogeneity in infancy. Recurrent sinopulmonary infections are often the only presenting symptom and usually patients have decreased immunoglobulins. A total 10% of patients who present with decreased serum immunoglobulin G and A and with normal or elevated immunoglobulin M levels are often misdiagnosed as hyperimmunoglobulin M syndrome. Definitive diagnosis is made if a patient with progressive cerebellar ataxia has a disease causing mutation on the ATM gene. Ataxia-telangiectasia guideline of the European Society for Immunodeficiencies defines the probable diagnosis criteria. We evaluated twenty ataxia-telangiectasia patients (mean age 13.8±4.1 years) retrospectively who were followed-up for a mean of 38.6±27.0 months. Twelve patients had a family history of consanguinity. A total of 80% patients suffered from various infections. Neoplasms occurred in three of them. Patients showed immunological abnormalities as low IgG (45%), low IgA (65%) and elevated IgM (60%) levels. CD3+CD4+ T lymphocyte frequency was low in 45% patients. The mean AFP concentration at the diagnosis was 191.9±140.1 ng/mL and the raised IgM values did not show any statistically significant relationship with high AFP concentrations. Frequency of the elevated IgM concentrations in (60%) patients raises the concerns about thinking this finding has to be accepted as a probable diagnosis criterium.

Determination of cut-off titers and agreement between immunofluorescence and immunoblotting methods for detecting antinuclear antibodies in children.

Detection of antinuclear antibodies (ANA) is a diagnostic adjunct in patients with suspected autoimmune connective tissue diseases, and various detection methods are in use. The aim of this study was to analyze the agreement between the ANA immunoflourescence (IF) and immunoblotting (IB) methods and determine cut-off for children subjects in a laboratory setting. We evaluated 729 serum samples that were analyzed by both ANA IF and IB. The results were evaluated by chi(2) test and, for agreement, kappa index was used. Frequencies determined for both 1:40-1:100 cut-off titers of ANA IF in relation to IB testing supported the idea that 1:100 starting dilution should be recommended in children subjects for ANA IF method and antigen specific immunoblot testing was needed, especially for some of the ANA IF negative samples. Agreement between the two methods, especially with homogenous, granular, and nucleolar ANA IF patterns, was statistically significant.

Homozygosity for a novel mutation in the C1q C chain gene in a Turkish family with hereditary C1q deficiency.

Hereditary complete deficiency of complement component C1q is associated with a high prevalence of systemic lupus erythematosus and increased susceptibility to severe recurrent infections. An 11-year-old girl was screened for immunodeficiency due to a history of recurrent meningitis and pneumonia. Immunologic studies revealed absence of classic pathway hemolytic activity and undetectable levels of Clq. Exon-specific amplification of genomic DNA by polymerase chain reaction followed by direct sequence analysis revealed a novel homozygous missense mutation at codon 48 in the C1q C gene causing a glycine-to-arginine substitution affecting the collagen-like region of C1q. No changes were seen in the exons of the A and B chains. The mutation affected both the formation and the secretion of C1q variant molecules. We describe a novel mutation in the C1q C chain gene that leads to an interchange in amino acids resulting in absence of C1q in serum.

A novel Y331X nonsense mutation in TNFRSF1A gene in two unrelated Turkish families with periodic fever syndrome.

The autoinflammatory disorders differ in severity, as well as age of onset, duration, and manifestations, but they all share some common features: recurring fever peaks, inflammation of serosal membranes, musculoskeletal involvement, varying types of skin rash, amyloidosis as a sequel of the disease. TRAPS is very rare in Turkish population and we present two unrelated Turkish children with similar clinical phenotypes and laboratory findings related with autoinflammatory disorders and with novel p. Y331X mutation in TNFRSF1A gene. Both of the patients were male and they had recurrent fever without abdominal pain and arthralgia. Full cDNA and exon-intron binding regions of TNFRSF1A, MEFV, MVK, CIAS1 genes were analysed by direct DNA sequencing methods in order to differentiate TRAPS, FMF, HIDS, CINCA/MWS/FCAS respectively. We screened ten exons of TNFRSF1A gene, and detected a heterozygous c.1080C>G nucleotide substitution in exon 10 in both of the unrelated patients, resulting p.Y360X nonsense (protein truncated) mutation. According to classical TNFRSF1A gene nomenclature and the agreement of 30th amino acid as the first one, it is accepted as p.Y331X. It was interesting to determine same mutations in fathers of two patients. In one of the cases, E148Q heterozygous mutation, which is one of the disease-causing mutations of MEFV gene, was detected. No nucleotide substitution was identified in exon and exon-intron splicing regions encoding 396 amino acid of MVK gene in both of the patients. In CIAS1 gene, two different nucleotide substitutions resulting synonymous amino acid mutation were detected in exon 3: c.[732G>A] and c.[786A>G] nucleotide substitutions and compatible p.A242A (according to c.DNA p.A244A) and p.R260R (according to c.DNA p.R262R) synonymous amino acid mutations. These nucleotide substitutions were also detected in parents and were reported to be normal variations in Turkish population. In conclusion, in Turkish patients, with dominantly inherited recurrent fever, TRAPS is a diagnosis worthy of attention and novel mutations have to be reported with phenotype associations.