Genomic testing identifies monogenic causes in patients with very early-onset inflammatory bowel disease: a multicenter survey in an Iranian cohort.

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multicenter study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in 1 patient, respectively. In 3 patients (18.7%), no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD.

Pulmonary manifestations in a cohort of patients with inborn errors of immunity: an 8-year follow-up study.

BACKGROUND: Inborn errors of immunity (IEIs) are a group of congenital diseases caused by genetic defects in the development and function of the immune system. The involvement of the respiratory tract is one of the most common presentations in IEIs. METHODS: Overall, 117 patients with diagnosed IEIs were followed-up within 8 years at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD). Demographic, clinical, and laboratory data were collected in a questionnaire. Pulmonary function test (PFT), chest X-ray (CXR), and high-resolution computed tomography (HRCT) scans were obtained where applicable. RESULTS: Our study population consisted of 48 (41%) patients with predominantly antibody deficiencies (PADs), 39 (32%) patients with congenital defects of phagocytes, 14 (11.9%) patients with combined immunodeficiency (CID), and 16 (14%) patients with Mendelian susceptibility to mycobacterial diseases (MSMD). . Recurrent pneumonia was the most common manifestation, while productive cough appeared to be the most common symptom in almost all diseases. PFT showed an obstructive pattern in patients with PAD, a restrictive pattern in patients with CID, and a mixed pattern in patients with CGD. HRCT findings were consistent with bronchiectasis in most PAD patients, whereas consolidation and mediastinal lesions were more common in the other groups. CONCLUSIONS: Pulmonary manifestations vary among different groups of IEIs. The screening for lung complications should be performed regularly to reveal respiratory pathologies in early stages and follow-up on already existing abnormalities.

The Prevalence of Atopic Manifestations in 313 Iranian Patients with Inborn Errors of Immunity.

INTRODUCTION: Inborn errors of immunity (IEIs) are rare inherited disorders with a broad spectrum of manifestations. Here, we aimed to delineate the atopy burden in a cohort of patients with IEIs. METHODS: 313 patients with IEIs were enrolled in the study within a 9-years period, and data were collected via a questionnaire. All statistical analyses were performed using SPSS software (v. 25.0, Chicago, IL, USA). The statistical significance level was set at p < 0.05. RESULTS: Overall, 51 out of 313 (16.3%) patients were identified to have atopic manifestations. Food allergy was detected in 34 (10.2%), atopic dermatitis in 21 (6.7%), as well as allergic asthma and allergic rhinitis each in 4 (1.3%) patients. The allergic disorders were reported as initial manifestations among 14 out of 35 (40.0%) atopic patients. Most of these 51 patients fell within the category of combined immunodeficiency (CID) (n = 38, 74.5%), followed by, severe CID (SCID) (n = 5, 9.8%), common variable immunodeficiency (n = 3, 5.9%), chronic granulomatous disease (n = 3, 5.9%), selective IgA deficiency (n = 1, 2.0%), and leukocyte adhesion defect (n = 1, 2.0%). No patient with Mendelian susceptibility to mycobacteria was found to have atopic manifestation. Atopic dermatitis (p = 0.001) and food allergy (p < 0.001) were both significantly higher in patients with CID than in other IEI groups. Among atopic patients with CID and SCID, food allergy and atopic dermatitis were the most prevalent comorbidities. DISCUSSION/CONCLUSION: Atopic diseases may contribute to the clinical picture of IEIs, particularly in patients with CID. Atopy in association with other warning signs of IEIs increases the possibility of an underlying IEI.

Respiratory pattern complexity in newly-diagnosed asthmatic patients.

BACKGROUND: The intensity of respiratory symptoms and expiratory airflow limitations in asthma fluctuate over time. Some studies have reported variable complexity of the respiratory patterns in asthmatic patients. Thus, we conducted a novel study to assess the correlation between asthma severity and breathing pattern dynamics in newly-diagnosed asthmatic patients. METHODS: A total of 20 newly-diagnosed asthmatic patients (7 male, 13 female) and 20 healthy cases (11 male, 9 female) were included. The respiratory patterns of all participants and the asthma severity for asthmatic patients were measured using a spirometer (before and after a bronchodilator exposure) and airflow recorder, respectively. The peak-to-peak intervals and the amplitude of peaks were considered as the inter-breath interval (IBI) and lung volume (LV) series. The Detrended Fluctuation Analysis (DFA), Sample Entropy (SampEn), Multi-scale Entropy (MSE), short-term (SD1) and long-term (SD2) variability, and IBI and LV Cross-Sample Entropy of the respiratory pattern dynamics were calculated using MATLAB (Mathwork, USA). RESULTS: Asthma patients showed notable increase in the average of sample entropy in both IBI and LV parameters (p = 0.025 and p = 0.018, respectively) and also decreased synchronization between IBI and LV (p = 0.042). The multi-scale sample entropy of both IBI and LV was significantly higher in asthmatic patients (p < 0.05). Furthermore, SD1 and SD2 were higher in the patients with asthma (p < 0.05). Significant correlations were detected between spirometric (forced expiratory flow (FEF) change, pre FEF, pre forced expiratory volume in one second (FEV1) / forced vital capacity (FVC), FVC change) and respiratory pattern (mean-IBI, mean-LV, mean-respiratory rate (RR), coefficient of variation (CV)-IBI, CV-LV, cross-sample entropy) parameters (p < 0.05). Furthermore, we identified a negative correlation between CV of IBI and asthma severity (r = -0.52, p = 0.021). CONCLUSION: Here, we took a novel approach and observed increased irregularity (more complexity) in the breathing pattern of patients newly-diagnosed with asthma. Remarkable correlations were detected between breathing complexity markers and spirometric indices along with disease severity in asthmatic patients. Thus, our data suggests respiratory pattern indices could be utilized as an indicator of asthma and its severity. However, more clinical data are required to support this conclusion.

Novel PGM3 mutation in two siblings with combined immunodeficiency and childhood bullous pemphigoid: a case report and review of the literature.

BACKGROUND: Bullous pemphigoid is the most common autoimmune subepidermal blistering disorder with a low incidence in childhood. Combined immunodeficiencies (CIDs) are a group of monogenic inborn errors of immunity (IEIs) characterized by T- and B-cell dysfunction leading to recurrent infections, lymphoproliferation, predisposition to malignancy, and autoimmunity. Here, we report two Afghan siblings with a diagnosis of CID and extremely rare manifestation of diffuse bullous pemphigoid skin lesions. CASE PRESENTATION: The older sibling (patient 1) was a 32-month-old male with facial dysmorphism, protracted diarrhea, failure to thrive, recurrent oral candidiasis, recurrent otitis media with tympanic membrane perforation, who had been previously diagnosed with CID. While he was under treatment with intravenous immunoglobulin (IVIg), he developed extensive blistering lesions, which were diagnosed as childhood bullous pemphigoid. Methylprednisolone and azathioprine were added to the regimen, which resulted in a remarkable improvement of the skin lesions and also the feeding condition. However,2 weeks later, he was re-admitted to the intensive care unit (ICU) and eventually died due to fulminant sepsis. Later, his 12-month-old sister (patient 2) with similar facial dysmorphism and a history of developmental delay, food allergy, recurrent oral candidiasis, and respiratory tract infections also developed blistering skin lesions. She was under treatment for occasional eczematous lesions, and had been receiving IVIg for 3 months due to low levels of immunoglobulins. Further immunologic workup showed an underlying CID and thus treatment with IVIg continued, gradually improving her clinical condition. The genetic study of both siblings revealed a novel homozygous mutation in exon 7 of the PGM3 gene, c.845 T > C (p.Val282Ala). CONCLUSIONS: Dermatologic disorders may be the presenting sign in patients with CID and mutated PGM3. This case report further extends the spectrum of skin manifestations that could be observed in PGM3 deficiency and emphasizes the importance of considering CIDs during the assessment of skin disorders, particularly if they are extensive, recurrent, refractory to treatment, and/or associated with other signs of IEIs.

Serum level of specific IgG antibody for aspergillus and its association with severity of asthma in asthmatic children.

Aspergillosis is one of the frequent causes of exacerbation of asthma depending on the geographical regions. The specific serum IgG level for aspergillus is a major diagnostic criterion in aspergillosis.Ninety-six asthmatic patients, with mean age of 5.4 ± 3.0 years who were referred to the asthma clinic of the Mofid Children's Hospital, were enrolled in this study. Serum specific IgG for aspergillus was measured and its association with severity of asthma was evaluated.Nineteen asthmatic patients (10 females and 9 males) had aspergillus IgG antibody. Among them, severe persistent asthma and moderate persistent asthma were detected in 5 and 13 cases, respectively, whereas only one patient suffered from mildpersistent asthma. A total of 36.5% of the 96 patients had a history of atopy, while 26% had allergic rhinitis. There was an association between the severity of asthma and the presence of aspergillus IgG antibody. Moreover, the positivity for aspergillus IgG antibody was higher in older patients.Our results indicated an association between aspergillus antibody level and severity of asthma. It could be recommended that the IgG titer for aspergillus is measured in pediatric patients with asthma, whereas co-morbidity of aspergillosis and asthma increases the risk of asthma exacerbation.