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Case Reports Immunol. 2023 May 22;2023:3977739. doi: 10.1155/2023/3977739. eCollection 2023.

ABSTRACT

Patients with primary immunodeficiencies are especially vulnerable to developing severe coronavirus disease 2019 (COVID-19) after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an important regulator of immune responses, and patients who suffer from CTLA4 haploinsufficiency have hyperactivation of effector T cells and infiltration of various organs. Overexpression of CTLA4 has been associated with a more severe disease course in patients with COVID-19, but there have only been a few reports on the disease course of COVID-19 in patients with CTLA4 haploinsufficiency. We report on a 33-year-old female with a history of immune thrombocytopenia, autoimmune haemolytic anaemia, granulomatous-lymphocytic interstitial lung disease, and common variable immunodeficiency who developed COVID-19. She was admitted and discharged from the hospital several times in the months thereafter and remained symptomatic and had a positive SARS-CoV-2 PCR for up to 137 days after the first symptoms. No SARS-CoV-2 antibodies were identified in the patients’ serum. The disease was finally controlled after repeated infusions of convalescent plasma and treatment of concurrent bacterial and fungal infections. Genetic analysis revealed a likely pathogenic variant in CTLA4, and CTLA4 expression on regulatory T-cells was low. This case illustrates that patients with primary immunodeficiencies who have a protracted disease course of COVID-19 could benefit from convalescent plasma therapy.

PMID:37260564 | PMC:PMC10228224 | DOI:10.1155/2023/3977739

Clin Respir J. 2023 May 31. doi: 10.1111/crj.13630. Online ahead of print.

ABSTRACT

INTRODUCTION: The current study aims to investigate the etiology spectrum and the clinical characteristics of bronchiectasis in Chinese children.

METHODS: The study is designed as a multicenter retrospective study. 193 cases were enrolled in 13 centers in China between 2008 and 2017. The inclusive cases must meet the clinical as well as the HRCT criteria. Only if both two radiologists confirmed the diagnosis, the case could be enrolled. The cases that could not provide clinical and imageology data were excluded. The data were entered into the specialized system and then analyzed.

RESULTS: One hundred sixty-nine cases (87%) were found to have the underlying etiology. Post-infective (46%), primary immunodeficiency (14%), and PCD (13%) were the common causes. All cases came from 28 provinces in Mainland China. The median age of symptom onset was 5.8 (2.0, 8.9) years. The median age of diagnosis was 8.4 (4.5, 11.6) years. The main symptoms were cough, sputum expectoration, and fever during the exacerbation. Nineteen percent of patients suffered from limited exercise tolerance. Clubbing was found in 17% of cases. Nearly 30% of patients presented growth limitations. On the HRCT findings, 126 cases had diffused bronchiectasis, and bilateral involvement was found in 94 cases. The lower lobes and right middle lobes were most commonly involved. Approximately 30% of cultures of sputum and bronchoalveolar lavage were positive.

CONCLUSION: A majority of cases could be found the underlying etiology. Post-infective, primary immunodeficiency, and PCD were the most common causes. Some clinical figures might indicate a specific etiology.

PMID:37259267 | DOI:10.1111/crj.13630

J Clin Immunol. 2023 May 29. doi: 10.1007/s10875-023-01511-w. Online ahead of print.

ABSTRACT

BACKGROUND: The human CD19 antigen is expressed throughout B cell ontogeny with the exception of neoplastic plasma cells and a subset of normal plasma cells. CD19 plays a role in propagating signals from the B cell receptor and other receptors such as CXCR4 in mature B cells. Studies of CD19-deficient patients have confirmed its function during the initial stages of B cell activation and the production of memory B cells; however, its role in the later stages of B cell differentiation is unclear.

OBJECTIVE: Using B cells from a newly identified CD19-deficient individual, we investigated the role of CD19 in the generation and function of plasma cells using an in vitro differentiation model.

METHODS: Flow cytometry and long-read nanopore sequencing using locus-specific long-range amplification products were used to screen a patient with suspected primary immunodeficiency. Purified B cells from the patient and healthy controls were activated with CD40L, IL-21, IL-2, and anti-Ig, then transferred to different cytokine conditions to induce plasma cell differentiation. Subsequently, the cells were stimulated with CXCL12 to induce signalling through CXCR4. Phosphorylation of key downstream proteins including ERK and AKT was assessed by Western blotting. RNA-seq was also performed on in vitro differentiating cells.

RESULTS: Long-read nanopore sequencing identified the homozygous pathogenic mutation c.622del (p.Ser208Profs*19) which was corroborated by the lack of CD19 cell surface staining. CD19-deficient B cells that are predominantly naïve generate phenotypically normal plasma cells with expected patterns of differentiation-associated genes and normal levels of CXCR4. Differentiated CD19-deficient cells were capable of responding to CXCL12; however, plasma cells derived from naïve B cells, both CD19-deficient and sufficient, had relatively diminished signaling compared to those generated from total B cells. Additionally, CD19 ligation on normal plasma cells results in AKT phosphorylation.

CONCLUSION: CD19 is not required for generation of antibody-secreting cells or the responses of these populations to CXCL12, but may alter the response other ligands that require CD19 potentially affecting localization, proliferation, or survival. The observed hypogammaglobulinemia in CD19-deficient individuals is therefore likely attributable to the lack of memory B cells.

PMID:37246174 | DOI:10.1007/s10875-023-01511-w

Allergy Asthma Clin Immunol. 2023 May 27;19(1):44. doi: 10.1186/s13223-023-00790-7.

ABSTRACT

BACKGROUND: Primary antibody deficiencies (PAD) are characterized by a heterogeneous clinical presentation and low prevalence, contributing to a median diagnostic delay of 3-10 years. This increases the risk of morbidity and mortality from undiagnosed PAD, which may be prevented with adequate therapy. To reduce the diagnostic delay of PAD, we developed a screening algorithm using primary care electronic health record (EHR) data to identify patients at risk of PAD. This screening algorithm can be used as an aid to notify general practitioners when further laboratory evaluation of immunoglobulins should be considered, thereby facilitating a timely diagnosis of PAD.

METHODS: Candidate components for the algorithm were based on a broad range of presenting signs and symptoms of PAD that are available in primary care EHRs. The decision on inclusion and weight of the components in the algorithm was based on the prevalence of these components among PAD patients and control groups, as well as clinical rationale.

RESULTS: We analyzed the primary care EHRs of 30 PAD patients, 26 primary care immunodeficiency patients and 58,223 control patients. The median diagnostic delay of PAD patients was 9.5 years. Several candidate components showed a clear difference in prevalence between PAD patients and controls, most notably the mean number of antibiotic prescriptions in the 4 years prior to diagnosis (5.14 vs. 0.48). The final algorithm included antibiotic prescriptions, diagnostic codes for respiratory tract and other infections, gastro-intestinal complaints, auto-immune symptoms, malignancies and lymphoproliferative symptoms, as well as laboratory values and visits to the general practitioner.

CONCLUSIONS: In this study, we developed a screening algorithm based on a broad range of presenting signs and symptoms of PAD, which is suitable to implement in primary care. It has the potential to considerably reduce diagnostic delay in PAD, and will be validated in a prospective study. Trial registration The consecutive prospective study is registered at clinicaltrials.gov under NCT05310604.

PMID:37245042 | DOI:10.1186/s13223-023-00790-7

J Allergy Clin Immunol Pract. 2023 May 25:S2213-2198(23)00567-6. doi: 10.1016/j.jaip.2023.05.029. Online ahead of print.

NO ABSTRACT

PMID:37244439 | DOI:10.1016/j.jaip.2023.05.029

Pediatr Blood Cancer. 2023 May 26:e30429. doi: 10.1002/pbc.30429. Online ahead of print.

ABSTRACT

Cytomegalovirus retinitis (CMVR) following hematopoietic stem cell transplantation (HCT) for a primary immunodeficiency is a rare but highly morbid condition with potential irreversible consequences despite optimal antiviral pharmacotherapy. Viral-specific T cells (VSTs) pose a promising and safe approach eradicating intractable viral disease. We describe the case of a 21-month-old male with Wiskott-Aldrich syndrome (WAS) and CMVR post HCT with sustained long-term virologic and clinical response after CMV-specific T-cell therapy. This case highlights the need to consider VST as an adjunct upfront strategy in refractory CMVR and for routine ophthalmologic screening and surveillance in high-risk patients post HCT.

PMID:37243390 | DOI:10.1002/pbc.30429

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