Clinical heterogeneity in families with multiple cases of inborn errors of immunity.

BACKGROUND: Inborn errors of immunity (IEI) are a diverse range of genetic immune system illnesses affecting the innate and/or adaptive immune systems. Variable expressivity and incomplete penetrance have been reported in IEI patients with similar clinical diagnoses or even the same genetic mutation. METHODS: Among all recorded patients in the national IEI registry, 193 families with multiple cases have been recognized. Clinical, laboratory and genetic variability were compared between 451 patients with different IEI entities. RESULTS: The diagnosis of the first children led to the earlier diagnosis, lower diagnostic delay, timely treatment and improved survival in the second children in the majority of IEI. The highest discordance in familial lymphoproliferation, autoimmunity and malignancy were respectively observed in STK4 deficiency, DNMT3B deficiency and ATM deficiency. Regarding immunological heterogeneity within a unique family with multiple cases of IEI, the highest discordance in CD3+, CD4+, CD19+, IgM and IgA levels was observed in syndromic combined immunodeficiencies (CID), while non-syndromic CID particularly severe combined immunodeficiency (SCID) manifested the highest discordance in IgG levels. Identification of the first ATM-deficient patient can lead to improved care and better survival in the next IEI children from the same family. CONCLUSION: Intrafamilial heterogeneity in immunological and/or clinical features could be observed in families with multiple cases of IEI indicating the indisputable role of appropriate treatment and preventive environmental factors besides specific gene mutations in the variable observed penetrance or expressivity of the disease. This also emphasizes the importance of implementing genetic evaluation in all members of a family with a history of IEI even if there is no suspicion of an underlying IEI as other factors besides the underlying genetic defects might cause a milder phenotype or delay in presentation of clinical features. Thus, affected patients could be timely diagnosed and treated, and their quality of life and survival would improve.

Tic disorder in allergic rhinitis children and adolescents: a case-control study.

BACKGROUND: Allergic rhinitis is the most common allergic disease. It can accompany psychological disorders such as tic disorders due to the prolonged course of the symptoms of allergic rhinitis. This pioneer case-control study aims to investigate tic disorders in children and adolescents under 18 years of age diagnosed with allergic rhinitis. METHOD: The case group in this study consisted of patients who had both allergic rhinitis and tic disorders. Patients with allergic rhinitis without tic disorders were also enrolled as the control group with matched gender and age. Demographic characteristics, tic classifications, and contributing factors for allergic rhinitis and tic disorders were studied among the cases. Tic disorders were evaluated using DSM-5 criteria for the classification of tic disorders. RESULTS: 47 patients in the case group and 47 patients in the control group were included in this study. 53.2% and 46.8% were males and females in the case group, respectively. The mean age of the patients was 10.46 ± 3.97 years old. Sound tics were more common among the patients compared to motor tics. Patients with concomitant AR and tic disorders had more days per week with AR symptoms (P-value ≤ 0.001; OR (every day vs. three days a week = 11.02(2.98, 40.76))). Most patients with sound tick were women (p: 0.026), and most patients with motion tic were in the Provisional tic disorder group (p: 0.001). The history of infantile eczema was seen more in patients without sound tic (p: 0.025), and otitis media was significantly less common among patients with sound tics (p: 0.026). Provisional tic disorder was the most common class among the patients. In the case group (coexistence between allergic rhinitis and tic) compared to the control group, patients had significantly more days with AR symptoms per week. CONCLUSION: This preliminary study indicates that Provisional tic disorder was the most common classification of tic among patients with allergic rhinitis, especially in patients with motor tics. Asthma in motor tics, a history of food allergy in infancy, and a history of infantile eczema were also common among patients with vocal tics. Also, patients with allergic rhinitis and tic had more severe disease (more symptoms per week) than those with rhinitis alone. These findings emphasize the association of tic disorders with immunological pathways.

Exploring the potential and safety of quantum dots in allergy diagnostics.

Biomedical investigations in nanotherapeutics and nanomedicine have recently intensified in pursuit of new therapies with improved efficacy. Quantum dots (QDs) are promising nanomaterials that possess a wide array of advantageous properties, including electronic properties, optical properties, and engineered biocompatibility under physiological conditions. Due to these characteristics, QDs are mainly used for biomedical labeling and theranostic (therapeutic-diagnostic) agents. QDs can be functionalized with ligands to facilitate their interaction with the immune system, specific IgE, and effector cell receptors. However, undesirable side effects such as hypersensitivity and toxicity may occur, requiring further assessment. This review systematically summarizes the potential uses of QDs in the allergy field. An overview of the definition and development of QDs is provided, along with the applications of QDs in allergy studies, including the detection of allergen-specific IgE (sIgE), food allergens, and sIgE in cellular tests. The potential treatment of allergies with QDs is also described, highlighting the toxicity and biocompatibility of these nanodevices. Finally, we discuss the current findings on the immunotoxicity of QDs. Several favorable points regarding the use of QDs for allergy diagnosis and treatment are noted.

Diagnosis and selection of alternative antibiotics in beta-lactams hypersensitivity reactions: Current recommendations and challenges.

Beta-lactam (BLM) antibiotics, including amino-penicillin and cephalosporins, are typically the first-choice treatment for bacterial infections. However, adverse reactions to these antibiotics are frequently reported, causing non-allergist physicians to select alternative broad-spectrum antibiotics that can have harmful consequences. Patients with unclear histories of hypersensitivity reactions to BLMs should undergo an allergy workup to establish a firm diagnosis, particularly when different drugs are prescribed simultaneously. However, finding the safest, most precise, and cost-effective methods for confirming BLMs hypersensitivity and selecting the most appropriate alternative BLM is uncertain, particularly in severe delayed reactions. This review aims to provide data and recommendations on the availability and validity of skin tests (STs), drug provocation test (DPT) protocols, based on the latest published literature and guideline. To make the process more practical, we focused on cross-reactivity between BLMs and diagnostic tests. There are two main novel aspects of this document: 1) For T-cell-mediated reactions, patient stratification into high, moderate, and low-risk groups based on the mortality and morbidity of adverse drug reactions. 2) For IgE-mediated reactions, stratification of individuals with isolated limited urticarial without anaphylaxis in a low-risk group and removal of the extensive limitation.

Assessment of the first presentations of common variable immunodeficiency in a large cohort of patients.

BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency syndrome resulting in recurrent infections, autoimmunity, and granulomatous manifestations. METHODS AND MATERIALS: This retrospective study was conducted on an Iranian national registry of immunodeficient patients from 2010 to 2021. The frequency of first presentations of CVID and its association with sex, age of onset, and family history of CVID was evaluated. RESULTS: A total of 383 patients entered the study, 164 of whom were female, and the rest were male. The mean age of the patients was 25.3 ± 14.5 years. The most frequent first presentations of CVID were pneumonia (36.8%) and diarrhea (19.1%). Patient sex, age of onset, and family history did not make significant differences in first presentations of this disease. CONCLUSION: pneumonia is the most common first presentation of CVID. Family history of CVID, the age of symptom onset, and sex made no differences in the first presentations of CVID.

Systemic aspergillosis in a patient with interferon gamma receptor 1 deficiency; a case report.

BACKGROUND: Interferon-gamma receptor deficiency is a heterogeneous spectrum of disease which involves mutations in IFNGR1, IFNGR2 genes, and the downstream signaling proteins such as STAT1. These mutations are associated with immunodeficiency 27 A and 27B, making the patient prone to mycobacterial infections. Patients with this condition are also at increased risk for affliction with viral and bacterial infections, such as with the Herpesviridae family, Listeria, and Salmonella. Moreover, SH2B3 mutation is associated with autoimmune and lymphoproliferative conditions. CASE PRESENTATION: the patient was a 19-month-old infant girl who presented with a two-week history of fever. She had near-normal flowcytometry with high IgM and IgE. She had pneumonic infiltration in her chest and right hilar and para-aortic lymphadenopathy. PCR of whole blood for Aspergillus fumigatus came back positive. In her Whole Exome Sequencing she had IFNGR1 and SH2B3 mutations. CONCLUSION: systemic fungal infections such as Aspergillosis can occur in patients with interferon-gamma receptor one deficiency. This type of immunodeficiency should be considered in treating patients with systemic Aspergillosis.

Face mask correlation with allergic rhinitis symptoms severity during COVID-19 pandemic: A cross-sectional study.

Background: Face mask is the first line to protect the respiratory mucosa from the coronavirus particles in aerocells and droplets and without this, the exposure of the mucosa to the virus and allergens trigger the immune and inflammatory system. These lead to Allergic Rhinitis (AR) symptoms or virus infection. Aim: This study discusses about the effects of face mask on the severity of AR symptoms using the Sino-Nasal Outcome Test (SNOT-22) in AR cases during the Corona Virus Disease 2019 (COVID-19) pandemic. Method: In this cross-sectional study, 54 cases previously diagnosed as moderate and severe AR based on Allergic Rhinitis and its Impact on Asthma and Visual Analog Scale score referred to the tertiary allergy clinic were involved, while 5 of them were excluded. AR symptoms before and during the pandemic were compared based on the SNOT-22 questionnaire. Demographics, AR severity, and comorbidities were registered. Results: The mean age was 31.4 ± 13.5 years with the male-female ratio of 1.4. The mean SNOT-22 score was 36.1 ± 20.3 before and 29.5 ± 16.8 during the pandemic. Although 36.7% (n: 18) of all participants had severe symptoms before the pandemic, 10.2% (n: 5) had severe AR symptoms during the pandemic. 53.0% (n: 26) of patients had moderate AR symptoms, and 36.7% (n: 18) had mild AR symptoms in the pandemic. There was no significant difference between each paired subgroup in AR symptom changes but the symptom improvement was significant in most of the subgroups when compared to the pre-pandemic period. Smoking had an adverse effect on AR symptoms (p: 0.034). Conclusion: Face mask affects the quality of life in AR patients and improves the severity of AR symptoms during COVID-19 pandemic. Smoking worsens this severity. Age, gender, pet ownership, underlying conditions, and previous COVID-19 infection were not associated with AR symptoms severity and alteration in the AR individuals' quality of life during the COVID-19 pandemic.

The effect of vitamin D add-on therapy on the improvement of quality of life and clinical symptoms of patients with chronic spontaneous urticaria.

BACKGROUND: Chronic urticaria is a common distressing allergic skin disorder. Immune dysregulation, histamine release and mast cell degranulation are suggested as its underlying mechanisms. OBJECTIVE: Add-on therapy of vitamin D was evaluated in patients with chronic spontaneous urticaria to determine the quality of life and urticaria severity score. METHODS: In a prospective, double-blinded study, 80 participants with chronic spontaneous urticaria were randomized to low (4200 IU/week, group 1) and high (28,000 IU/week, group 2) vitamin D3 supplementation groups for 12 weeks. Demographic data; quality of life, urticaria severity and medication scores; 25-hydroxyvitamin D and anti-thyroid peroxidase antibody levels; and autologous serum skin test data were collected. RESULTS: Both groups showed significantly reduced total urticaria severity score; decrement in group 2 score was significant compared to group 1 at week 6 (P = 0.010). Quality of life score was also significantly reduced; decrement in group 2 score was significant compared to group 1 at both weeks 6 (P = 0.005) and 12 (P = 0.007). 25-hydroxyvitamin D levels were elevated significantly over the course of 12 weeks in both groups; however, the elevation in group 2 was significantly higher than group 1 at week 12 (P = 0.002). Medication score was significantly reduced, with no significant difference between groups. No association was observed between positive autologous serum skin test, angioedema and high level of Anti thyroperoxidase antibody with positive response to vitamin D. CONCLUSIONS: Add-on therapy with vitamin D (28,000 IU/week) can be considered as a safe and potentially beneficial treatment in patients with chronic spontaneous urticaria.

Novel DNMT3B Mutation in a Patient with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome and a Bronchopulmonary Collateral Artery.

BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder. ICF1 is caused by bi-allelic mutations in the gene encoding deoxyribonucleic acid methyltransferase-3B (DNMT3B). Herein, we report a novel homozygous DNMT3B mutation in a patient with ICF1. CASE PRESENTATION: An eight-month-old Iranian Caucasian infant of consanguineous 1st-degree cousins presented to our clinic for evaluation of neutropenia. Physical examination was unremarkable except for low-set ears and a systolic cardiac murmur. He had a history of recurrent respiratory infections and oral thrush. Moreover, a collateral artery between the bronchial and pulmonary arteries was observed on the angiogram, mimicking a patent ductus arteriosus on the echocardiogram. Growth percentiles were normal; however, he had a neurodevelopmental delay. Family history was significant for a sibling who deceased at nine months of age after recurrent respiratory infections. Laboratory evaluation revealed a normal white blood cell count with neutropenia and normal bone marrow studies. He had hypogammaglobinemia with normal flow cytometric studies and was treated with prophylactic trimethoprim-sulfamethoxazole and itraconazole. After that, he was re-admitted three times due to recurrent episodes of pneumonia and an episode of pseudomonas aeruginosa meningitis. Currently, he is five years old and doing well on monthly intravenous immunoglobulin. Due to recurrent infections, hypogammaglobulinemia, and neutropenia, as well as a family history of consanguinity and a sibling who deceased during infancy, a primary immune deficiency was suspected. Genetic studies utilizing whole-exome sequencing demonstrated a homozygous missense mutation in DNMT3B (LRG_56t1:c.2008C>T; p.Arg670Trp) in the patient studied. The mutation has not been previously reported. CONCLUSION: We describe a novel homozygous DNMT3B mutation in an Iranian boy with ICF1. It is associated with recurrent infections, hypogammaglobinemia, neutropenia, mild facial anomalies, and a bronchopulmonary collateral artery.

Diversity of malignancies in patients with different types of inborn errors of immunity.

Genetic defects in the development, maturation, and/or function of the immune cells can lead to Inborn errors of immunity (IEI) which may predispose patients to malignancies. The overall risk for cancer in children with IEI ranges from 4 to 25% and the type of malignancy is highly dependent on the specific mutant gene underlying IEI. We investigated 3056 IEI patients registered in the Iranian national registry between the years 1999 and 2020 in this retrospective cohort study. The frequency of malignancy and its association with the type of IEI in these patients were evaluated. A total of 82 IEI patients with malignancy were enrolled in this study. Among them, predominantly lymphoma was the most common type of malignancy (67.1%), followed by leukemia (11%), and cancers of the head and neck (7.3%). Among identified lymphoma cancers, non-Hodgkin's lymphomas were the most frequent type (43.9%) followed by different subtypes of Hodgkin's lymphoma (23.2%). Solid tumors (18.3%) appeared to be very heterogeneous by type and localization. The correlation between the type of malignancy and survival status and the association between the type of malignancy and IEI entities were unremarkable. The awareness of the association between the presence of IEI and cancer highlights the importance of a synergistic effort by oncologists and immunologists in the early diagnosis of malignancy and personalized therapeutic strategies in IEI patients.

A rare case of SRD5A3-CDG in a patient with ataxia and telangiectasia: A case report.

Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is an extremely rare congenital disease. Common manifestations are developmental delay, intellectual disability, ophthalmological abnormalities, cerebellar abnormalities, ataxia, and hypotonia. Here, we discuss a seven-year-old boy with SRD5A3-CDG (homozygous variant c.57G>A [p.Trp19Ter]), featuring the unprecedented finding of telangiectasia.

A Review of Aspirin-exacerbated Respiratory Diseases and Immunological Efficacy of Aspirin Desensitization.

Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease. It is defined by asthma, chronic rhinosinusitis with nasal polyposis, and a hypersensitivity reaction to aspirin or nonsteroidal anti-inflammatory drugs. Aspirin desensitization (AD) has been confirmed as an effective treatment to control AERD inflammation through the modulation of immune responses. We aimed to review AERD with an overview of the epidemiology, pathophysiology, and treatment. We also discussed the effect of AD on immunological markers involved in AERD pathogenesis. A search of electronic databases on AERD was performed. We included five randomized clinical trials (RCTs) on AD. We also searched databases for recent studies that investigated the effect of AD on the immunological mechanisms of AERD. RCTs have demonstrated the therapeutic effectiveness of AD on the patients' quality of life, asthma symptom score, inhaled and oral steroid use, forced expiratory volume in 1 sec (FEV1), and inflammatory mediators. The clinical benefits of AD can occur though the regulation of innate and adaptive immune responses that are involved in the pathogenesis of AERD. In addition to the valuable effects of AD in RCTs, some side effects such as gastrointestinal bleeding, asthma exacerbation, or rash have been reported that should be considered for reaching an optimal protocol for AD.

An unusual case of cystic fibrosis with pancytopenia due to copper deficiency and blindness caused by vitamin A deficiency: A case-report.

Cystic fibrosis (CF) is a multi-systemic autosomal recessive disease which mostly involves the respiratory, digestive, and reproductive systems, but it can present with various clinical presentations, especially in adulthood. We describe a 19-year-old boy, a known case of CF who presented with less known clinical presentations of CF, blindness, liver cirrhosis, vitamin A deficiency, and pancytopenia.

In Silico Evaluation of Nonsynonymous SNPs in Human ADAM33: The Most Common Form of Genetic Association to Asthma Susceptibility.

ADAM33 is a zinc-dependent metalloprotease of the ADAM family, which plays a vital biological role as an activator of Th2 cytokines and growth factors. Moreover, this protein is crucial for the normal development of the lung in the fetus two months after gestation leading to determining lung functions all over life. In this regard, mutations in ADAM33 have been linked with asthma risk factors. Consequently, identifying ADAM33 pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) can be very important in asthma treatment. In the present study, 1055 nsSNPs of human ADAM33 were analyzed using biocomputational software, 31 of which were found to be detrimental mutations. Precise structural and stability analysis revealed D219V, C669G, and C606S as the most destabilizing SNPs. Furthermore, MD simulations disclosed higher overall fluctuation and alteration in intramolecular interactions compared with the wild-type structure. Overall, the results suggest D219V, C669G, and C606S detrimental mutations as a starting point for further case-control studies on the ADAM33 protein as well as an essential source for future targeted mechanisms.

Homozygous Autosomal Recessive DIAPH1 Mutation Associated with Central Nervous System Involvement and Aspergillosis: A Rare Case.

The DIAPH1 gene fulfills critical immune and neurodevelopmental roles. It encodes the mammalian Diaphanous-related formin (mDia1) protein, which acts downstream of Rho GTPases to promote F-actin polymerization and stabilize microtubules. During mitosis, this protein is expressed in human neuronal precursor cells and considerably affects spindle formation and cell division. In humans, dominant gain-of-function DIAPH1 variants cause sensorineural deafness and macrothrombocytopenia (DFNA1), while homozygous DIAPH1 loss leads to seizures, cortical blindness, and microcephaly syndrome (SCBMS). To date, only 16 patients with SCBMS have been reported, none of whom were from Iran. Furthermore, aspergillosis is yet to be reported in patients with homozygous DIAPH1 loss, and the link between SCBMS and immunodeficiency remains elusive. In this study, we shed further light on this matter by reporting the clinical, genetic, and phenotypic characteristics of an Iranian boy with a long history of recurrent infections, diagnosed with SCBMS and immunodeficiency (NM_005219.5 c.3145C > T; p.R1049X variant) following aspergillosis and SARS-CoV-2 coinfection.

COVID-19 in Chronic Granulomatosis Disease: A Case Report.

A novel coronavirus disease known as Coronavirus Disease 2019 (COVID-19) has spread quickly throughout the world, and it was declared a pandemic in March 2022. Chronic granulomatous disease (CGD) is a diverse group of genetic disorders characterized by recurrent bacterial and fungal infections, resulting in granulomas due to the inability of phagocytes to destroy microbes. Even though it is thought that impaired neutrophil activity is a protective mechanism against severe COVID-19-induced cytokine storms and hyper-inflammatory responses, patients with CGD have normal immunity to most viruses. Here, we present two CGD patients who were hospitalized due to severe COVID-19 infections, which suggests that COVID-19 might have a different pathogenesis than other viruses.

Identification of the Most Common Allergens of Acer velutinum Pollen.

Pollens have been identified as potent inducers of allergic diseases worldwide. Acer velutinum (Persian maple) tree is an important source of allergic pollens in Iran. This study aimed to identify the immunoglobulin E (IgE)-reactive components of A. velutinum pollen extract in patients with maple allergy. We aimed to evaluate its allergenic components; using IgE in the serum of patients with maple allergy. Twenty-two patients with a clinical history of reaction and a positive skin-prick test to maple pollen extract were included in this study. Identification of IgE-binding proteins in A. velutinum pollen extract was performed by immunoblotting using sera from sensitive patients. A protein band with a molecular weight of around 70 kDa was the most IgE-reactive allergen in A. velutinum pollen extract detected by this method. Identification of a protein with a molecular weight of about 70kDa, as the most reactive allergen of A. velutinum pollen extract, can be considered as a potential allergen for designing diagnostic kits or as a target for immunotherapy of allergic patients with maple allergy.

Geoclimatic risk factors for childhood asthma hospitalization in southwest of Iran.

BACKGROUND: Asthma is a chronic respiratory disease resulting from a complex interaction between genetic and environmental factors. Among environmental factors, climatic and geographical variations have an important role in increasing asthma hospitalization. The current study aimed to investigate the effect of geoclimatic factors on the occurrence of childhood asthma hospitalization in Fars province, southwest Iran. METHOD: We mapped the addresses of 211 hospitalized patients with childhood asthma (2016-2019) and investigated the effects of different temperature models, mean annual rainfall and humidity, number of frosty and rainy days, evaporation, slope, and land covers on the occurrence of childhood asthma hospitalization using a geographical information system. The Kriging and Spline methods have been used for generating interpolated models. Data were analyzed using logistic regression. RESULTS: In the multivariate model, urban setting was recognized as the most important childhood asthma hospitalization predictor (p < 0.001, odds ration [OR] = 35.044, confidence interval [CI] = 9.096-135.018). The slope was considered the determinant of childhood asthma hospitalization when analyzed independently and its increase was associated with decreased childhood asthma hospitalization (p = 0.01, OR = 0.914, CI = 0.849-0.984). CONCLUSION: In the current study, the urban setting was the most important risk factor associated with increased childhood asthma hospitalization.

Investigating the association of atopy and aeroallergen sensitization and chronic spontaneous urticaria.

Introduction: Chronic spontaneous urticaria (CSU) is a common skin allergic reaction with an unknown mechanism. There is inadequate evidence to support the role of aeroallergen sensitization in CSU. Aim: The present study was conducted to investigate the association between the aeroallergen sensitivity and CSU. Material and methods: In this cross-sectional study, 91 patients with CSU were recruited. Information on demographic characteristics was collected. The skin prick test (SPT) for most prevalent aeroallergens and pulmonary function test (PFT) were performed and the results were clinically matched to investigate the allergic rhinitis (AR) and asthma. Total serum immunoglobulin E (IgE) concentration was analysed in the subjects for the presence of atopy. Results: Ninety one patients (75 of them were females) were enrolled in the study (with a mean age of 36.90 ±12.93 years). SPT result was positive in 75 (82.4%) subjects. Weeds (67 cases, 73.6%), trees (61 cases, 67%), and dust mites (55 cases, 60.4%) were the most common pollens in the positive SPT samples. Thirty-seven (40.7%) of the patients had allergic rhinitis. There was a statistically significant association between the presence of AR and positive SPT result (p = 0.002). Eight patients had allergic asthma and 45 (49.4%) of the patients had a total serum IgE level of more than 100 IU/ml. Conclusions: Our results indicated a clear association between the presence of aeroallergen sensitivity and development of CSU. AR exists as a co-morbidity of CSU.

A Comparative Study of Montelukast and Azelastine add on Therapy in Moderate to Severe Allergic Rhinitis Treatment: A Double-Blind Randomized Clinical Trial.

BACKGROUND: Allergic Rhinitis (AR) is a prevalent chronic inflammatory nasal condition with significant negative effects on the patients' quality of life. This study aimed to investigate the efficacy of Montelukast and intranasal antihistamine in combination with intranasal corticosteroid (INCS) in moderate to severe allergic rhinitis on the patients' quality of life and AR control. METHOD: This double-blind randomized clinical trial study was carried out on 66 moderate to severe AR patients referred to Namazi Hospital, Shiraz, Iran from 2020 to 2021, who were randomly divided into 3 groups. Group one received Montelukast add-on therapy and Budesonide nasal spray. The second group received intranasal antihistamine (Azelastine) add-on therapy and Budesonide nasal spray and the third group as the control group received intranasal Budesonide spray with a placebo tablet.To measure the impact of each medication on the patient's quality of life and AR control, we employed the Sino-Nasal Outcome Test-22 questionnaire (SNOT 22). We evaluated the symptoms and compared them at baseline, one and three months after the start of treatments. Spirometry was performed to investigate the possibility of co-morbid asthma at baseline and end of the study. RESULTS: The patients' mean age was 30.13 ± 12.7 years. Most patients experienced perennial AR (65.2%). Reduction of mean scores SNOT22 was statistically different between groups (P-value < 0.001). Three months after treatment, the mean decrease of SNOT-22 in the Azelastine group was statistically significant compared to both Montelukast (P-value < 0.001) and control groups (P-value < 0.001). No significant difference was observed between the Montelukast and control groups (P-value = 0.142). 23 of 66 patients were diagnosed with asthma and asthma treatment was initiated. The amount of FEV1 change after AR treatment was not statistically significant between the groups in asthmatic patients (P-value = 0.351). CONCLUSION: Based on our findings, we recommend Azelastine in conjunction with an intranasal corticosteroid for the treatment of moderate to severe allergic rhinitis. In moderate to severe AR or even asthma management, Montelukast has no greater impact than INCS.