Manish Butte

J Pers Med. 2023 Apr 23;13(5):707. doi: 10.3390/jpm13050707.

ABSTRACT

Nasal polyps (NPs) are rarely reported in childhood and usually represent red flags for systemic diseases, such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and immunodeficiencies. The European Position Paper released in 2020 (EPOS 2020) provided a detailed classification and defined the correct diagnostic and therapeutic approaches. We report a one-year experience of a multidisciplinary team, made up of otorhinolaryngologists, allergists, pediatricians, pneumologists and geneticists, with the aim of ensuring a personalized diagnostic and therapeutic management of the pathology. In 16 months of activity, 53 patients were admitted (25 children with chronic rhinosinusitis with polyposis and 28 with antro-choanal polyp). All patients underwent phenotypic and endo-typic assessment, using proper classification tools for nasal pathology (both endoscopic and radiological), as well as adequate cytological definition. An immuno-allergic evaluation was carried out. Pneumologists evaluated any lower airway respiratory disease. Genetic investigations concluded the diagnostic investigation. Our experience enhanced the complexity of children’s NPs. A multidisciplinary assessment is mandatory for a targeted diagnostic and therapeutic pathway.

PMID:37240876 | DOI:10.3390/jpm13050707

J Clin Med. 2023 May 17;12(10):3516. doi: 10.3390/jcm12103516.

ABSTRACT

Primary immunodeficiencies (PIs) are a group of diseases that increase susceptibility to infectious diseases. Few studies have examined the relationship between PI and COVID-19 outcomes. In this study, we used Premier Healthcare Database, which contains information on inpatient discharges, to analyze COVID-19 outcomes among 853 adult PI and 1,197,430 non-PI patients who visited the emergency department. Hospitalization, intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and death had higher odds in PI patients than in non-PI patients (hospitalization aOR: 2.36, 95% CI: 1.87-2.98; ICU admission aOR: 1.53, 95% CI: 1.19-1.96; IMV aOR: 1.41, 95% CI: 1.15-1.72; death aOR: 1.37, 95% CI: 1.08-1.74), and PI patients spent on average 1.91 more days in the hospital than non-PI patients when adjusted for age, sex, race/ethnicity, and chronic conditions associated with severe COVID-19. Of the largest four PI groups, selective deficiency of the immunoglobulin G subclass had the highest hospitalization frequency (75.2%). This large study of United States PI patients provides real-world evidence that PI is a risk factor for adverse COVID-19 outcomes.

PMID:37240621 | DOI:10.3390/jcm12103516

J Clin Med. 2023 May 11;12(10):3401. doi: 10.3390/jcm12103401.

ABSTRACT

BACKGROUND AND OBJECTIVES: Inborn errors of immunity (IEI) refer to genetically determined disorders presenting with recurrent infections, autoimmunity, allergies, and malignancies. IEI is now commonly used, replacing the previously used term primary immunodeficiencies (PID). The 10 warning signs of IEI are widely used in the identification patients with IEI. The aim of the study was to determine and compare the utility of the 10 and 14 warning signs in IEI diagnosing.

METHODS: A retrospective analysis of 2851 patients was performed (98.17% were subjects under 18 years old and 1.83% were adults). All patients were questioned about the 10 warning signs and four additional signs: severe eczema, allergies, hemato-oncologic disorders and autoimmunity. Sensitivity, specificity, positive and negative predictive values, and odds ratio were calculated for the 10 and 14 warning signs.

RESULTS: IEI were diagnosed in a total of 896 (31.4%) patients and excluded in 1955 (68.6%). The strongest predictors of IEI were hemato-oncologic disorders (OR = 11.25; p < 0.001) and autoimmunity (OR = 7.74; p < 0.001). The strongest predictors of severe IEI were hemato-oncologic disorders (OR = 89.26; p < 0.001), positive family history (OR = 25.23; p < 0.001), and autoimmunity (OR = 16.89; p < 0.001). There were 20.4% and 14% of IEI patients without any signs from the 10 and 14 warnings signs, respectively (p < 0.001). 20.3% and 6.8% of patients with severe PIDs had no presence of any signs from 10 and 14 signs, respectively (p = 0.012).

CONCLUSIONS: The 10 warning signs have limited usefulness in identifying IEI. The modified list of 14 warning signs seems to represent an effective diagnostic method for the detection of IEI patients, especially those with severe PIDs.

PMID:37240507 | DOI:10.3390/jcm12103401

Biology (Basel). 2023 Apr 24;12(5):644. doi: 10.3390/biology12050644.

ABSTRACT

Cutaneous manifestations are one of the most common presentations among patients with inborn errors of immunity (IEI). These skin manifestations are often among the first presenting features in the majority of patients preceding the IEI diagnosis. We studied 521 available monogenic patients with IEI listed in the Iranian IEI registry up to November 2022. We extracted each patient’s demographic information, detailed clinical history of cutaneous manifestations, and immunologic evaluations. The patients were then categorized and compared based on their phenotypical classifications provided by the International Union of Immunological Societies. Most patients were categorized into syndromic combined immunodeficiency (25.1%), non-syndromic combined immunodeficiency (24.4%), predominantly antibody deficiency (20.7%), and diseases of immune dysregulation (20.5%). In total, 227 patients developed skin manifestations at a median (IQR) age of 2.0 (0.5-5.2) years; a total of 66 (40.7%) of these patients initially presented with these manifestations. Patients with cutaneous involvement were generally older at the time of diagnosis [5.0 (1.6-8.0) vs. 3.0 (1.0-7.0) years; p = 0.022]. Consanguinity was more common among patients who developed skin disorders (81.4% vs. 65.2%, p < 0.001). The overall skin infection rate and the type of dominant pathogens were significantly different among the IEI patients in different phenotypical classifications (p < 0.001). Atopic presentation, including urticaria, was highly prevalent among patients with congenital defects of phagocytes (p = 0.020). The frequency of eczema was also significantly higher among cases with both syndromic and non-syndromic combined immunodeficiency (p = 0.009). In contrast, autoimmune cutaneous manifestations, including alopecia and psoriasis, were most common in patients with immune dysregulation (p = 0.001) and defects in intrinsic or innate immunity (p = 0.031), respectively. The presence of autoimmune cutaneous complications significantly improved the survival rate of IEI patients (p = 0.21). In conclusion, cutaneous manifestations were observed in nearly 44% of Iranian patients with monogenic IEI. A considerable number of patients with cutaneous involvements developed these disorders as their first manifestation of the disease, which was particularly noticeable in patients with non-syndromic combined immunodeficiency and phagocytic defects. The neglected skin disorders in IEI patients might delay diagnosis, which is generally established within a 3-year interval from the development of skin-related problems. Cutaneous disorders, especially autoimmune features, might indicate a mild prognosis in IEI patients.

PMID:37237458 | DOI:10.3390/biology12050644

iScience. 2023 May 5;26(6):106818. doi: 10.1016/j.isci.2023.106818. eCollection 2023 Jun 16.

ABSTRACT

Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.

PMID:37235056 | PMC:PMC10206195 | DOI:10.1016/j.isci.2023.106818

Front Immunol. 2023 May 9;14:1146500. doi: 10.3389/fimmu.2023.1146500. eCollection 2023.

ABSTRACT

Primary antibody deficiencies, such as common variable immunodeficiency (CVID), are heterogenous disease entities consisting of primary hypogammaglobulinemia and impaired antibody responses to vaccination and natural infection. CVID is the most common primary immunodeficiency in adults, presenting with recurrent bacterial infections, enteropathy, autoimmune disorders, interstitial lung diseases and increased risk of malignancies. Patients with CVID are recommended to be vaccinated against SARS-CoV-2, but there are relatively few studies investigating humoral and cellular responses to immunization. We studied the dynamics of humoral and cell-mediated immunity responses up to 22 months in 28 patients with primary immunodeficiency and three patients with secondary immunodeficiency receiving ChAdOx1, BNT162b2 and mRNA-1273 COVID-19 vaccines. Despite inadequate humoral response to immunization, we demonstrate a robust T cell activation likely protecting from severe COVID-19.

PMID:37234151 | PMC:PMC10206403 | DOI:10.3389/fimmu.2023.1146500

Front Immunol. 2023 May 10;14:1212029. doi: 10.3389/fimmu.2023.1212029. eCollection 2023.

ABSTRACT

[This corrects the article DOI: 10.3389/fimmu.2021.767188.].

PMID:37234149 | PMC:PMC10207328 | DOI:10.3389/fimmu.2023.1212029

J Clin Immunol. 2023 May 26. doi: 10.1007/s10875-023-01514-7. Online ahead of print.

ABSTRACT

PURPOSE: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID).

METHODS: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed.

RESULTS: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines.

CONCLUSION: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.

PMID:37231290 | DOI:10.1007/s10875-023-01514-7

JAAPA. 2023 Jun 1;36(6):23-26. doi: 10.1097/01.JAA.0000923544.76902.f9.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder that results in decreased immunity and increased infection risk. This multisystem disorder often presents as recurrent, prolonged respiratory tract infections. Other manifestations include chronic lung disease, systemic granulomatous disease, malignancies, enteropathy, splenomegaly, and autoimmune disease including cytopenias. Diagnosis often is delayed, affecting patient quality of life, morbidity, and mortality. This article reviews the presentation, diagnosis, and management of patients with CVID.

PMID:37229582 | DOI:10.1097/01.JAA.0000923544.76902.f9

Eye (Lond). 2023 May 24. doi: 10.1038/s41433-023-02581-1. Online ahead of print.

ABSTRACT

PURPOSE: To characterize the retinal phenotype in RNU4ATAC-associated Roifman syndrome.

METHODS: Ten patients (including 8 males) with molecularly confirmed Roifman syndrome underwent detailed ophthalmologic evaluation including fundus imaging, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT), and electroretinography (ERG). Six patients had follow-up eye exams. All patients also underwent comprehensive examination for features of extra-retinal Roifman syndrome.

RESULTS: All patients had biallelic RNU4ATAC variants. Nyctalopia was common (7/10). Visual acuity at presentation ranged from 20/20 to 20/200 (Age Range: 5-41 years). Retinal exam revealed features of generalized retinopathy with mid-peripheral pigment epithelial changes. A para or peri-foveal ring of hyper-autofluorescence was the commonest FAF abnormality noted (6/8). The SD-OCT demonstrated relative preservation of the foveal ellipsoid zone in six cases; associated features included cystoid changes (5/10) and posterior staphyloma (3/10). The ERG was abnormal in all patients; nine showed generalized rod-cone dystrophy, whilst one patient with sectoral retinal involvement only had isolated rod dystrophy (20 years old). On follow-up examination (Mean duration: 8.16 years), progressive loss of visual acuity (2/6), mid-peripheral retinal atrophy (3/6) or shortening of ellipsoid zone width (1/6) were observed.

CONCLUSION: This study has characterized the retinal phenotype in RNU4ATAC-associated Roifman syndrome. Retinal involvement is universal, early-onset, and overall, the retinal and FAF features are consistent with rod-cone degeneration that is slowly progressive over time. The sub-foveal retinal ultrastructure is relatively preserved in majority of patients. Phenotypic variability independent of age exists, and more study of allelic- and sex-based determinants of disease severity are necessary.

PMID:37225827 | DOI:10.1038/s41433-023-02581-1