A New Approach to Eliminate Hymenoptera Venom Grading Sensitization Test in the North Iran: Cross-Sectional Study.

Background: Anaphylaxis is an allergic reaction which occurs with or without the stimulation of the immune system. Hymenoptera stings are common causes of anaphylaxis in the world. Skin tests are the first-line diagnostic measure for Hymenoptera anaphylaxis. The present study aimed to evaluate the safety of a single-step approach in sensitization testing for Hymenoptera venom. Methods: This cross-sectional study was conducted in 2019 in Golestan province the north of Iran. The sample population consisted of 140,000 individuals covered by 84 rural healthcare centers in the vicinity of Gorgan, Iran. Thirty-three patients agreed to receive the diagnostic test. In this research, in contrast to the 2011 ACAAI guideline, the extracts of venom of three types of Hymenoptera were injected intra-dermally without any dilution at the concentration of 1 µg/ml. Results: The results of the skin test in the patients bitten by honey bee, yellow jacket, and paper wasp were negative in 15.2%, 15.2%, and 21.2% of the cases, respectively. After the test, no allergic reaction was observed, with the exception of a minor skin reaction, which improved within a short time. These preventive measures were taken during the test for the following four hours when the patient was present at the test site and up to 48 hours afterward via follow-up from the healthcare center to the home of the patient. Conclusion: The results of our study showed that the non-diluted single injection of the Hymenoptera sting was accompanied by no side effects.

Investigation of the Relationship between Aspirin-Sensitivity and Poor Response to Medical Management in NSAIDs-exacerbated Respiratory Disease Patients with Sinonasal Polyposis.

Background: NSAID-exacerbated respiratory disease (N-ERD) is a highly heterogeneous disorder with various clinical symptoms. The aspirin challenge test is a gold standard method for its diagnosis, and there are still no reliable in vitro diagnostic biomarkers yet. Oral challenge tests are time-consuming and may be associated with a risk of severe systemic reactions. This study aimed to evaluate whether patients with poor responses to medical management are more susceptible to being aspirin-sensitive. Methods: In this cohort study, after CT scanning of all patients and subject selection, conventional medical treatment was started as follows and continued for three consecutive months: at first, saline nose wash twice per day, intranasal beclomethasone spray one puff in each nostril twice per day, montelukast 10 mg tablet once daily, a ten-day course of oral prednisolone starting with the dose of 25 mg per day and taper and discontinued thereafter. Sinonasal outcome test 22 (SNOT22) was used for the evaluation of symptom severity. Statistical analyses were performed with SPSS version 23, and data were analyzed using an independent samples T-test, paired T-test, and Receiver operating curve analysis. Results: 25 males and 53 females were enrolled in this study, with an average age of 41.56 ± 11.74 years old (18-36). Aspirin challenge test results were positive in 29 (37.2%) patients. The average SNOT22 scores before the treatment were 52.97 ± 17.73 and 47.04 ± 18.30 in aspirin-sensitive and aspirin-tolerant patients, respectively, and decreased to 27.41 ± 16.61 and 24.88 ± 16.72 in aspirin-sensitive and aspirin-tolerant patients after the treatment, respectively. There was no significant difference in SNOT22 scores between the groups. Conclusion: The severity of symptoms before treatment and clinical improvement after treatment are not good predictors of N-ERD.

Genetic Study of Hereditary Angioedema Type I and Type II (First Report from Iranian Patients: Describing Three New Mutations).

BACKGROUND: Hereditary Angioedema (HAE) is a rare autosomal dominant immunodeficiency disease with mutation in C1 inhibitor gene (SERPING1) which deficient and dysfunction of C1-INH protein result in HAE type I or type II, respectively. The present study aimed to define the genetic spectrum of HAE type I and type II among Iranian patients. METHODS: Thirty-four patients with clinical phenotype of recurrent edematous attacks in face, upper and lower limbs, hands, and upper airway entered the study. Mutations in SERPING1 were analyzed using PCR and Sanger Sequencing. In addition, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to discover large deletions or duplications in negative screening samples by Sanger. RESULTS: Twenty-three patients were diagnosed with HAE type I and 11 with HAE type II. Fourteen distinctive pathogenic variations including five frameshift (p.G217Vfs*, p.V454Gfs*18, p.S422Lfs*9, p.S36Ffs*21, p.L243Cfs*9), seven missense (p.A2V, p.G493R, p.V147E, p.G143R, p.L481P, p.P399H, p.R466C), one nonsense (p.R494*), and one splicing defect (C.51 + 2 T˃C), which three of these mutations were identified novel. However, no mutation was found in seven patients by Sanger sequencing and MLPA. CONCLUSION: Final diagnosis with mutation analysis of HAE after clinical evaluation and assessment of C1INH level and function can prevent potential risks and life-threatening manifestations of the disorder. In addition, genetic diagnosis can play a significant role in facilitating early diagnosis, pre-symptomatic diagnosis, early diagnosis of children, asymptomatic cases, and those patients who have the borderline biochemical results of C1-INH deficiency and/or C4.

Phenotyping and follow up of forty-seven Iranian patients with common variable immunodeficiency.

BACKGROUND: Common variable immune deficiency (CVID) is a heterogeneous syndrome with a wide variety of signs and symptoms. This study describes the phenotyping and survival of the CVID patients in the allergy and clinical immunology department of Rasol-E-Akram Hospital of Iran University of Medical Sciences in Tehran. METHOD: We retrospectively reviewed hospital files of CVID patients in our department until January 2014. All patients were diagnosed with standard diagnostic criteria of CVID, treated and visited monthly, during the follow-up period. We divided the patients into four phenotypes; infection only, cytopenia, polyclonal lymphocytic infiltration and unexplained enteropathy. The immunologic, demographic and clinical findings in different phenotypes were analysed. RESULTS: The study included 47 CVID patients with mean age at onset of symptoms and diagnosis of 11.2 and 20.2 years, respectively. Phenotyping of our patients was: only infection (62%), cytopenia (26%) and PLI (19%) and 94% of cases had only one phenotype. We did not find a significant relation between the clinical phenotypes and immunologic or demographic data. Rate of parental consanguinity in our cases was 47%. Parental consanguinity was related to lower age at onset, lower age at diagnosis and higher baseline IgG levels. Patients with malignancy and autoimmunity had significantly higher age at onset. Our patients were followed-up for 6.9 years and the mortality rate during this time was 6%. CONCLUSIONS: Parental consanguinity and age at onset of CVID symptoms may have important roles in CVID manifestations.

Novel Patient with Late-Onset Familial Hemophagocytic Lymphohistiocytosis with STXBP2 Mutations Presenting with Autoimmune Hepatitis, Neurological Manifestations and Infections Associated with Hypogammaglobulinemia.

Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous hyperinflammatory syndrome, caused by an uncontrolled and ineffective proliferation and activation of T-lymphocytes, NK-cells, and macrophages that infiltrate multiple organs. Herein, a patient is presented who suffered from hepatitis and atypical brain lesions. Genetic studies revealed a homozygous mutation in the STXP2 gene; and thus, the diagnosis of FHL5 was confirmed.

The effects of vitamin D supplementation on airway functions in mild to moderate persistent asthma.

BACKGROUND: Vitamin D is hypothesized to have some roles in innate and adaptive immunity, inflammation reduction, and remodeling; therefore, it is supposed to affect the asthma phenotype, severity, and response to inhaled corticosteroid (ICS). OBJECTIVE: To explore the synergistic effects of vitamin D supplementation in addition to asthma controllers (ICS or ICS plus long-acting ß-agonist) on airway functions. METHODS: A randomized clinical trial was conducted in 130 individuals aged 10 to 50 years who lived in Tehran during a 24-week period. Data on age, sex, body mass index, stage of asthma, serum total IgE, history of allergic rhinitis, atopic dermatitis, food allergy, and urticaria were collected. Spirometric parameters (forced expiratory volume in 1 second [FEV1] and ratio of FEV1 to forced vital capacity) and serum vitamin D measurement were obtained before and 8 and 24 weeks after the intervention. Patients were divided in 2 groups randomly. Both groups received asthma controllers (budesonide or budesonide plus formoterol) according to their stage, but the intervention group received vitamin D supplementation (100,000-U bolus intramuscularly plus 50,000 U orally weekly) in addition to asthma controllers. RESULTS: FEV1 improved significantly in both groups after 8 weeks, but no significant difference was found between the 2 groups at baseline (P = .20) or after 8 weeks (P = .99); however, a significant improvement was seen in the intervention group in the last 16 weeks, and FEV1 was significantly better in the intervention group than the other group after 24 weeks (P < .001). CONCLUSION: Vitamin D supplementation associated with asthma controllers could significantly improve FEV1 in mild to moderate persistent asthma after 24 weeks. TRIAL REGISTRATION: irct.ir Identifier: IRCT201302079608N1.

The Uncomplicated Course of COVID-19 in Primary Immunodeficiency Patients: A Report of 14 Common Variable Immunodeficiency Patients.

Coronavirus disease 2019 (COVID-19) affects millions of people worldwide. Clinical manifestations range from asymptomatic to severe viral pneumonia. CVID patients with COVID-19 infection are not adequately studied. In some studies, CVID patients had higher mortality rates, although other studies showed that CVID patients might have an uncomplicated COVID-19 infection. We describe 14 cases of COVID-19 infection in Iranian CVID patients in this study, including clinical manifestations, laboratory findings, and treatment strategies. There were 29% of patients with mild disease, 43% with moderate disease, and 29% with severe disease in this study. A critical case and a death occurred in none of our patients. There were six cases of infection more than two weeks after receiving the second dose of Sinopharm BIBP COVID-19 vaccine; all had mild to moderate disease. Among these patients, Remdesivir was the most frequently prescribed medication. According to this study, most of our patients presented with an uncomplicated disease course.

Neonatal Onset of Hemophagocytic Lymphohistiocytosis Due to Prenatal Varicella-Zoster Infection in a Neonate with Griscelli Syndrome Type 2.

Type 2 Griscelli syndrome (Type2 GS) is a primary inborn error of the immune system, classified in the immune dysregulation group.1,2 There are three different types of the disease, with different genetic causes responsible for the autosomal recessive inheritance pattern. Although hypopigmentation is common in all variants, neurological involvement or immunodeficiency with varying severity is seen in different types. Molecular motor protein myosin 5 an (MYo5A) [Type1GS], guanosine Triphosphate (GTP) binding protein (RAB27A) [Type2GS], and mutation in human melanophilin (MLPH) [Type 3GS] which is limited to hypopigmentation are reported as the known genetic defects in GS.3 Severe, ineffective, and uncontrolled inflammatory reactions are referred to as the pathogenesis of Hemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening condition that can be defined as either primary or secondary. Secondary causes happen in the context of autoimmunity, malignancy, spontaneous, or infections.4 Prenatal infections play an important role in causing long-term complications in the fetus. Some of them include toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and other organisms including syphilis, parvovirus, and Varicella zoster, known as TORCH syndrome (5).TORCH has been well described for a long time but there are limited reports of developing HLH in the context of prenatal infections. We described a type 2GS syndrome with neonatal-onset HLH triggered by a prenatal infection.

Atopy Patch Test in the Diagnosis of Food Allergens in Infants with Allergic Proctocolitis Compared with Elimination/Introduction C.

Allergic proctocolitis is a cell-dependent food allergy that is present in both breast and formula-fed infants. The presence of blood with different amounts in the stool is the main manifestation of the disease. Different results have been published on the accuracy and specificity of the atopic patch test (APT). The purpose of this study was to evaluate the results of the APT and compare them with those obtained in the food elimination/introduction (E/I) challenge, as the gold standard of confirming the allergy. Twenty-eight patients (18 boys, 10 girls, <1 year) with allergic proctocolitis were recruited in this study. The mean age of the disease onset and enrolling the study were 2.23±1.7 and 5.25±2.19 months, respectively. After performing APT with fresh foods, an E/I challenge was done in a patient with positive tests, and results were analyzed. APT was positive in 14/28 (50%) individuals. The most common foods detected by APT in all of the individuals were: milk (10/28), rice (5/28), soy (4/28), and egg white (4/28), while in E/I challenge in the APT-positive individuals were: milk (8/10), rice (3/5), egg white (1/4), and soy (0/4). APT was positive in half of the infants<1 year with allergic proctocolitis and there was no significant correlation between the APT results and the E/I challenge test for all foods. Comparing the results of APT and E/I challenge methods showed a convergence between the milk and rice sensitivity, thus we suppose APT to be a useful tool in identifying these two allergens in cell-mediated food allergies like allergic proctocolitis.

Chronic Eosinophilic Pneumonia: a Case Report.

Chronic eosinophilic pneumonia (CEP) is a rare idiopathic interstitial lung disease, predominantly observed in females. Eosinophilia is present in most cases, and alveolar eosinophilia is a diagnostic criterion in more than 40% of bronchoalveolar lavage (BAL) samples. The current study reported a 27-year-old male patient, non-smoker, with a history of uncontrolled asthma, presented to the emergency room with a complaint of cough, fever, and moderate dyspnea. A 30% eosinophilia was reported in his peripheral blood sample. A chest-X ray examination showed an upper and middle lobe consolidation, especially in the left lung. Broad-spectrum antibiotics were then started with a presumptive diagnosis of pneumonia, but no improvements were evident. The chest computed tomography scan showed air space opacities with septal thickening and predominant involvement of upper and middle lobes. Flexible bronchoscopy was performed, and the BAL sample analysis showed eosinophil infiltration, while negative culture. No parasites were identified. Transbronchial biopsies demonstrated eosinophil accumulation in alveoli and interstitium. CONCLUSION: Early recognition, diagnosis, and prompt treatment with corticosteroids are the main therapeutic approaches to CEP.

Atypical Omenn Syndrome Due to RAG2 Gene Mutation, a Case Report.

Severe Combined Immunodeficiency (SCID), characterized by a profound decrease in both the number and function of T cells, is related to more than 20 different mutations. Recombination-activating gene (RAG) 1 and 2 seem to be two of the most common forms presenting with various manifestations, including typical SCID, Omenn syndrome (OS), atypical SCID (AS), or delayed onset combined immunodeficiency with granulomas. One interesting manifestation in RAG mutation is the change in the immunophenotype over time, even after hematopoietic stem cell transplantation (HSCT). As bone marrow transplantation (BMT) is the only curative treatment of SCID, it is necessary to differentiate between SCID and OS due to the different conditioning regimens (CR). We present a novel case of atypical SCID (SCID manifestations with more than 300 CD3+T cells) caused by RAG 2 gene mutation whose immunophenotype changed to atypical Omenn syndrome (all Omenn syndrome manifestations except rash, eosinophilia, and elevated IgE) over time. Differentiation of leaky SCID, SCID and Omenn syndrome in RAG mutation genes and overlap manifestations is important in treatment plan and prognosis.

Characteristics, Etiology and Treatment of Pediatric and Adult Anaphylaxis in Iran.

Despite the increasing prevalence of anaphylaxis, there is little information about the characteristics and practice of healthcare providers in treating anaphylaxis, so this study was conducted to record the characteristics and therapeutic approaches of anaphylaxis from May 2012 until April 2015, the data of all patients diagnosed with anaphylaxis in the Allergy department of three referral university hospitals in Tehran, Iran were recorded. Thereafter, the demographics, clinical features, triggers and therapeutic approach were evaluated. This study investigated 136 individuals, 64 males (47%) between 6 months and 68 years old, as well as 72 others (52.94%) under 18 years of age (pediatric). The following were the most common organs involved: Skin 86.02% (pediatric 91.66% vs adult 79.68%), respiratory tract 51.47% (pediatric 43.05% vs adult 60.93%), cardiovascular 50.73% (pediatric 54.16% vs adult 46.87%), gastrointestinal 20.58% (pediatric 27.7% vs adult 12.5% ) and neurologic system 5.88% (only in adults). The following were the most identified causing foods 69 (50.37%)[42 pediatric (children) and 27 adults], drugs 34( 25%)[14 pediatric and 20 adults], idiopathic 16( 11.77%)[3 pediatric and 13 adults], insect sting 7( 5.15%)[3 pediatric and 4 adults] , exercise 6( 4.42%) [1 pediatric and 5 adults]. Milk, egg and wheat were the most common causative foods in pediatric cases but sesame, as well as egg and milk were the most common causes in adults. Epinephrine injection, auto injector epinephrine prescription as a discharging plan and referral to an allergist were: 10.78, 1.96 and 7.8 %, respectively. In this case series we found that, cutaneous, respiratory, cardiovascular and gastrointestinal complains were the most common manifestations and food, drug and idiopathic were the most common causes.In this study, the diagnosis of anaphylaxis, epinephrine subscription and referral to an allergist were significantly lower in comparison to other studies.

Frequency and Risk Factors of Penicillin and Amoxicillin Allergy in Suspected Patients with Drug Allergy.

BACKGROUND: Unconfirmed beta-lactam allergy is a significant public health problem because of the limitations it imposes in drug selection. In this study, we aimed to evaluate patients referred for beta-lactam allergy to determine the frequency of confirmed beta-lactam allergy and identify some risk factors. METHODS: In a prospective cohort study, all referred patients to Immunology, Asthma and Allergy Research Institute in Tehran University of Medical Sciences (between 2007 - 2009) who suspected to have beta-lactam allergy were entered into this study based on having the inclusion criteria. Follow-up was performed 6 - 8 years after the final diagnosis. Diagnosis of beta-lactam allergy relies on thorough history and specific IgE measurements (ImmunoCAP), skin prick testing (SPT), intradermal testing (IDT), patch testing, and oral drug challenge test. RESULTS: Fifty-one patients with mean age of 24.5 (±18.5) years were enrolled in this study. Based on workups, beta-lactam allergy was confirmed in 16 (31.4%) patients, suspicious in 22 (43.1%) patients and ruled out in 13 (25.5%) patients.  During the follow-up, 3 patients with suspicious drug allergy consumed the culprit drug with no reaction so allergy was finally ruled out in 16 (31.4%) patients. Age, sex, atopy and family history of drug allergies were not significantly different between the patients with confirmed or ruled-out diagnosis of penicillin and amoxicillin allergy. CONCLUSION: At least up to one-third of patients with a history of beta-lactam allergy are proven to be safe using the drug. Also, a clear protocol consists of serum sIgE assay and SPT can be helpful to the physicians in the health care system.

Cow's Milk Desensitization in Anaphylactic Patients: A New Personalized-dose Method.

Cow's milk allergy (CMA) is the most frequent food allergy in children and oral immunotherapy (OIT) is a promising approach for treatment of patients. The most challenging cases are anaphylactic with coexisting asthma and proposing safe protocols is crucial especially in high risk groups. Considering that CMA varies among patients, an individualized OIT protocol would be beneficial to achieve a safer and more efficient method of desensitization. 18 children more than 3 years of age with IgE-mediated CMA were enrolled. CMA was confirmed by positive skin prick test (SPT) and positive oral food challenge (OFC) and 60% of individuals had a convincing history of persistent asthma. SPT with milk extracts, whole fresh milk and serially diluted milk concentrations were performed.  The dilution of milk that induced 3-5 mm of wheal in each individual was selected as the starting dilution for OIT. Desensitization began by 1 drop of the defined dilution and continued increasingly. Overall, 16 out of 18 children (88.8%) achieved the daily intake of 120 mL of milk. Four out of these 16 children accomplished the protocol without any adverse allergic reactions. 12 patients experienced mild to severe reactions. Wheal and erythema in SPT (p≤0.001), and sIgE (p≤0.003) to most milk allergens were significantly decreased following desensitization. We successfully desensitized 16 of 18 children with IgE-mediated CMA by individualized desensitization protocol. Individualizing the OIT protocol would be helpful to save time and perhaps to relieve the allergic symptoms after ingesting cow's milk intake.

Type I and Type II Hereditary Angioedema: Clinical and Laboratory Findings in Iranian Patients.

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by C1-INH (C1 esterase inhibitor), low serum levels (type I), dysfunction (type II) or normal serum levels and function (type III), which lead to subcutaneous and submucosal edema attacks. The aim of this study was to investigate the demographic, clinical and laboratory findings of Iranian patients with HAE. METHODS: The patients with a history or symptoms of angioedema who were referred to Immunology, Asthma and Allergy Research Institute (IAARI) between Jan 2006 and Jan 2014, were assessed based on a specific questionnaire and laboratory evaluation. The patients with a definite diagnosis of HAE type I and type II were entered into this study. RESULTS: Among 51 patients, 63.3% were diagnosed with HAE type I and 36.7% with HAE type II. Fifteen patients were under 18 years and 36 were adults. The mean age of symptoms onset and diagnosis were 12.33 ± 10.20 years and 24.48 ± 14.64 years, respectively. The mean delay of diagnosis was 11.02 ± 11.60 years. The most commonly involved locations of edema were hands, face and genitalia. Moreover, laryngeal edema was observed in 61.2% of patients, which led to death in two patients during this study. CONCLUSION: Hereditary angioedema is a life threatening disease with considerable morbidity and mortality. The outcomes of this study can be used to inform clinicians and health care providers about HAE, which can help earlier diagnosis and better management of the patients, specifically in life threatening attacks.

Clinical and laboratory findings in Iranian patients with leukocyte adhesion deficiency (study of 15 cases).

Leukocyte adhesion deficiency type I (LAD I) is a rare, inherited, autosomal recessive, immunodeficiency disease caused by the combined loss of expression on the surface of leukocytes of the leukocyte integrins. We describe the clinical and laboratory findings for 15 patients with LAD I. The range of patients' ages was from 10 month to 14 years (median 4 years) and 93.3% of their parents had consanguineous marriages. The most commonly occurred manifestations were: recurrent infections (93.3%), poor wound healing (86%), oral ulcers (86%), and skin abscesses (80%). The most specific laboratory findings were defect in CD18 in all of 15 patients. The most common symptoms in these patients are poor wound healing and oral ulcer, so, the clinical physicians should pay special attention to these symptoms. Furthermore, because of considerable rate of consanguineous marriages in parents of LAD patients, we suggested more genetic studies on this disease and genetic consultation for these families.