Manish Butte

J Allergy Clin Immunol Pract. 2021 Jun 25:S2213-2198(21)00702-9. doi: 10.1016/j.jaip.2021.06.019. Online ahead of print.

ABSTRACT

COVID-19 has had a calamitous effect on the global community. In spite of intense study, the immunological response to the infection is only partially understood. In addition to older age and ethnicity, patients with co-morbidities including obesity, diabetes, hypertension, coronary artery disease, malignancy, renal and pulmonary disease, may experience severe outcomes. Some patients with primary and secondary immunodeficiencies also appear to be at increased risk from COVID-19. In addition to their vulnerability to SARS-CoV-2, patients with primary immunodeficiencies (PIDs) often suffer from chronic pulmonary disease and may not respond to vaccines, exacerbating their long-term risks. Patients with Common Variable Immunodeficiency disorders (CVID), the most frequent symptomatic PID in adults and children, have a spectrum of B and T cell defects. It may be possible to stratify their risk of severe COVID-19 based on age, ethnicity, the severity of their T cell defect as well as the presence of other co-morbidities. Patients with CVID and other immunodeficiencies are at risk of chronic COVID-19, a dangerous stalemate between a suboptimal immune response and SARS-CoV-2. Intra-host viral evolution could result in the rapid emergence of vaccine resistant mutants and is a public health emergency. Vaccination and prevention of Chronic COVID-19 in immunodeficient patients is therefore of the highest priority. Having a reliable diagnostic assay for T cell immunity to SARS-CoV-2 is critical for evaluating responses to vaccines in these patients. New treatments such as NZACE2-Pātari for COVID-19, are likely to be of particular benefit to immunodeficient patients, especially those who fail to mount a robust T cell response to vaccines.

PMID:34182162 | DOI:10.1016/j.jaip.2021.06.019

Pediatr Allergy Immunol. 2021 Jun 28. doi: 10.1111/pai.13589. Online ahead of print.

ABSTRACT

Predominantly antibody deficiencies (PADs) encompass a heterogeneous group of disorders characterized by low immunoglobulin serum levels in the presence or absence of peripheral B cells. Clinical presentation of affected patients may include recurrent respiratory and gastrointestinal infections, invasive infections, autoimmune manifestations, allergic reactions, lymphoproliferation and increased susceptibility to malignant transformation. In the last decades, several genetic alterations affecting B cell development/maturation have been identified as causative of several forms of PADs, adding important information on the genetic background of PADs which in turn should lead to a better understanding of these disorders and precise clinical management of affected patients. This review aims to present a comprehensive overview of the known and potentially involved molecules in the etiology of PADs to elucidate the pathogenesis of these disorders and eventually offer a better prognosis for affected patients.

PMID:34181780 | DOI:10.1111/pai.13589

Front Immunol. 2021 Jun 10;12:689472. doi: 10.3389/fimmu.2021.689472. eCollection 2021.

ABSTRACT

Since the first clinical report in 2013, inhibitors of the intracellular kinase BTK (BTKi) have profoundly altered the treatment paradigm of B cell malignancies, replacing chemotherapy with targeted agents in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia. There are over 20 BTKi, both irreversible and reversible, in clinical development. While loss-of-function (LoF) mutations in the BTK gene cause the immunodeficiency X-linked agammaglobulinemia, neither inherited, nor somatic BTK driver mutations are known. Instead, BTKi-sensitive malignancies are addicted to BTK. BTK is activated by upstream surface receptors, especially the B cell receptor (BCR) but also by chemokine receptors, and adhesion molecules regulating B cell homing. Consequently, BTKi therapy abrogates BCR-driven proliferation and the tissue homing capacity of the malignant cells, which are being redistributed into peripheral blood. BTKi resistance can develop over time, especially in MCL and high-risk CLL patients. Frequently, resistance mutations affect the BTKi binding-site, cysteine 481, thereby reducing drug binding. Less common are gain-of-function (GoF) mutations in downstream signaling components, including phospholipase Cγ2 (PLCγ2). In a subset of patients, mechanisms outside of the BCR pathway, related e.g. to resistance to apoptosis were described. BCR signaling depends on many proteins including SYK, BTK, PI3K; still based on the resistance pattern, BTKi therapy only selects GoF alterations in the NF-κB arm, whereas an inhibitor of the p110δ subunit of PI3K instead selects resistance mutations in the RAS-MAP kinase pathway. BTK and PLCγ2 resistance mutations highlight BTK’s non-redundant role in BCR-mediated NF-κB activation. Of note, mutations affecting BTK tend to generate clone sizes larger than alterations in PLCγ2. This infers that BTK signaling may go beyond the PLCγ2-regulated NF-κB and NFAT arms. Collectively, when comparing the primary and acquired mutation spectrum in BTKi-sensitive malignancies with the phenotype of the corresponding germline alterations, we find that certain observations do not readily fit with the existing models of BCR signaling.

PMID:34177947 | PMC:PMC8222783 | DOI:10.3389/fimmu.2021.689472

Pediatr Dev Pathol. 2021 Jun 28:10935266211022528. doi: 10.1177/10935266211022528. Online ahead of print.

ABSTRACT

BACKGROUND: Granulomatous lymphocytic interstitial lung disease (GLILD) has been increasingly recognized in children affected with primary immunodeficiencies (PIDs). In this study, we aimed to better characterize the spectrum of pediatric PIDs coexisting with GLILD including clinical and immunological predictors, thoracic imaging findings, and histopathologic features.

METHODS: We respectively reviewed records of six representative cases of children, three of them affected with common variable immunodeficiency (CVID) and three with syndromic immunodeficiencies, in whom a diagnosis of GLILD was established based on clinical, radiological, and histopathologic findings. Clinical and immunological predictors for GLILD were also analyzed in the patients studied.

RESULTS: All the children with GLILD had a history of autoimmune phenomena, organ-specific immunopathology, and immune dysregulation. Defective B-cell maturation and deficiency of memory B cells were found in all the children with GLILD. The radiological and histopathological features consistent with the diagnosis of GLILD, granulomatous disease, and lymphoid hyperplasia, were accompanied by chronic airway disease with bronchiectasis in children with CVID and syndromic PIDs.

CONCLUSIONS: Our study shows that both CVID and syndromic PIDs may be complicated with GLILD. Further studies are required to understand the predictive value of coexisting autoimmunity and immune dysregulation in the recognition of GLILD in children with PIDs.

PMID:34176349 | DOI:10.1177/10935266211022528

Blood Cells Mol Dis. 2021 Jun 2;90:102587. doi: 10.1016/j.bcmd.2021.102587. Online ahead of print.

ABSTRACT

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe bacterial and fungal infections. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide and subsequently formed other reactive oxygen species (ROS) are instrumental in killing phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91^phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients in Europe and in about 20% in countries with a high ratio of parental consanguinity. This article lists all mutations identified in CYBB and should therefore help in genetic counseling of X-CGD patients’ families. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of disease-causing mutations. In addition, we also include some mutations in G6PD, the gene on the X chromosome that encodes glucose-6-phosphate dehydrogenase, because inactivity of this enzyme may lead to shortage of NADPH and thus to insufficient activity of NADPH oxidase. Severe G6PD deficiency can induce CGD-like symptoms.

PMID:34175765 | DOI:10.1016/j.bcmd.2021.102587

Prog Mol Biol Transl Sci. 2021;182:111-151. doi: 10.1016/bs.pmbts.2021.03.001. Epub 2021 Apr 7.

ABSTRACT

Primary immunodeficiencies (PID) are a growing list of unique disorders that result in a failure of the innate/adaptive immune systems to fully respond to disease or infection. PIDs are classified into five broad categories; B cell disorders, combined B and T cell disorders, phagocytic disorders, complement disorders, and disorders with recurrent fevers and inflammation. Many of these disorders, such as X-SCID, WAS, and CGD lead to early death in children if intervention is not implemented. At present, the predominant method of curative therapy remains an allogeneic transplant from a healthy donor, however many complications and limitations exist with his therapy such as availability of donors, graft vs host disease, graft rejection, and infection. More recently, gene therapy using viral based complementation vectors have successfully been implemented to functionally correct patient cells in an autologous transplant, but these methods carry significant risks, including insertional mutagenesis, and provide non-physiological gene expression. For these reasons, gene-editing reagents such as targeted nucleases, base editors (BE), and prime editors (PE) are being explored. The BE and PE tools, sometimes referred to as digital editors, are of very high interest as they provide both enhanced molecular specificity and do not rely on DNA repair pathways after DSBs to change individual base pairs or directly replace DNA sequences responsible for pathogenic phenotypes. With this in mind the purpose of this chapter is to highlight some of the most common PIDs found within the human population, discuss successes and shortcomings of previous intervention strategies, and highlight how the next generation of gene-editing tools may be deployed to directly repair the underlying genetic causes of this class of disease.

PMID:34175040 | DOI:10.1016/bs.pmbts.2021.03.001

Hematol Oncol Clin North Am. 2021 Aug;35(4):827-845. doi: 10.1016/j.hoc.2021.03.010. Epub 2021 May 26.

ABSTRACT

Reversing or preventing immunodeficiency in patients with chronic lymphocytic leukemia (CLL) is of the highest priority. The past decade of research has met the challenge of treating CLL for most patients. Patients continue to struggle, however, with infections and second primary malignancies related to immunodeficiency. Strategies addressing this need currently are limited to vaccinations, with suboptimal efficacy, and immunoglobulin replacement. Correlative studies have provided insights into immunologic alterations on treatment. Understanding vulnerabilities in the immune system may help identify potential interventions to boost immunity. An emphasis on systematically testing such interventions is required to restore immunocompetence in patients with CLL.

PMID:34174988 | DOI:10.1016/j.hoc.2021.03.010

J Clin Immunol. 2021 Jun 23. doi: 10.1007/s10875-021-01066-8. Online ahead of print.

ABSTRACT

PURPOSE: There is still scarce data on SARS-CoV-2 infection in patients with Inborn Errors of Immunity (IEI) and many unresolved questions. We aimed to describe the clinical outcome of SARS-CoV-2 infection in Brazilian IEI patients and identify factors influencing the infection.

METHODS: We did a cross-sectional, multicenter study that included patients of any age affected by IEI and SARS-CoV-2 infection. The variables studied were sex, age, type of IEI, comorbidities (number and type), treatment in use for IEI, clinical manifestations and severity of SARS-CoV-2 infection.

RESULTS: 121 patients were included: 55.4% female, ages from six months to 74 yo (median age = 25.1 yo). Most patients had predominantly antibody deficiency (n = 53). The infection was mostly asymptomatic (n = 21) and mild (n = 66), and one child had multisystem inflammatory syndrome (MIS-C). We could not observe sex-related susceptibility, and there was a weak correlation between age and severity of infection. The number of comorbidities was higher in severe cases, particularly bronchiectasis and cardiopathy. There were no severe cases in hereditary angioedema patients. Six patients aged 2 to 74 years died, three of them with antibody deficiency.

CONCLUSION: The outcome was mild in most patients, but the Case Fatality Ratio was higher than in the general population. However, the type of IEI was not a determining factor for severity, except for complement deficiencies linked to milder COVID-19. The severity of SARS-CoV-2 infection seems to be more related to older age, a higher number of comorbidities and type of comorbidities (bronchiectasis and cardiopathy).

PMID:34164762 | DOI:10.1007/s10875-021-01066-8

Cureus. 2021 Jun 19;13(6):e15760. doi: 10.7759/cureus.15760.

ABSTRACT

The objective of this retrospective study was to present a series of cases involving the rare ocular disease of microsporidia keratitis treated at a private practice clinic and describe the details regarding specific water exposure, clinical course, voriconazole treatment, and increased prevalence of this infection in Augusta, Georgia, USA. Our analysis was based on the accumulated data from all patients (n=15) diagnosed with microsporidia keratitis at our private practice clinic; the clinical course of three cases is discussed in detail in this article. Specific environmental exposures were documented in 10 patients. All patients self-reported that they had no acquired immunodeficiency. In all cases, patients had complete resolution of active symptoms after receiving treatment with 1-2% topical voriconazole, with an approximate average primary treatment duration of 40.1 ± 17.1 days (median: 40 days, range: 14-70 days). None of the patients reported any clinically significant adverse effects from therapy. There have been increasing reports about this emerging infectious pathogen, particularly in Asia. However, there is limited data in the literature on the etiology, pathogenesis, and treatment of microsporidia-caused ophthalmic diseases. In this case series, we highlight the strong correlation of our patients’ condition with specific types of water exposure in the USA as well as the complete resolution of active disease in all our patients as a result of monotherapy with topical voriconazole.

PMID:34164251 | PMC:PMC8214417 | DOI:10.7759/cureus.15760

Wiad Lek. 2021;74(6):1510-1514.

ABSTRACT

OBJECTIVE: The aim: To present data on the possibility of occurrence and active progression of generalized periodontitis in persons with secretory immunoglobulin A deficiency and possible methods of its correction.

PATIENTS AND METHODS: Мaterials and methods: Analytical elaboration of scientific and medical literature based on the immunological aspect of generalized periodontitis.

CONCLUSION: Conclusions: The deficiency of secretory immunoglobulin A may occur in cases of primary or secondary insufficiency of the immune system. Selective IgA deficiency is an example of primary insufficiency of the immune system. Secondary immunodeficiency disorders is a clinical and immunological syndrome that develops against the background of a previously normally functioning immune system, characterized by a steady decrease in quantitative or functional indicators of specific or(and) nonspecific factors of immunoresistance. Insufficient awareness of dentists about certain aspects of the etiology and pathogenesis of generalized periodontitis leads to deterioration of treatment results.

PMID:34159947