Manish Butte

Iran J Allergy Asthma Immunol. 2023 Sep 3;22(4):398-404. doi: 10.18502/ijaai.v22i4.13612.

ABSTRACT

Primary immunodeficiencies are a diverse group of rare genetic disorders, among which phagocytic dysfunction impairs neutrophil function in a wide range of inherited disorders. Due to the heterogeneity of the disorders a multidisciplinary approach is often required for early diagnosis and initiation of appropriate treatments. The aim of this study was to evaluate the imaging findings in children admitted with phagocytic primary immunodeficiencies. Thirty-five children who fulfilled the inclusion criteria for phagocytic dysfunction were enrolled in this study. The patients were under close observation and monitoring from January 2011 until data locking in December 2017. The diagnosis of phagocytic immunodeficiency was confirmed by the patient’s clinical course, presentation features, and laboratory data. Among the 35 patients studied, the most frequent condition was chronic granulomatous disease (CGD) (23 patients), followed by different types of neutropenia (8 patients) and Job’s syndrome (4 patients). Mediastinal and hilar lymphadenopathies and consolidation were the most frequent presentations. There was a significant relationship between mediastinal/hilar lymphadenopathies and fungal infections. A meaningful relationship was also found between pulmonary nodules without halo signs in patients with concomitant tuberculosis and fungal infections. A significant correlation was found between CGD, pulmonary fibrotic changes, and mediastinal lymphadenopathies. The most frequent radiological manifestations in children included mediastinal and hilar consolidations. Physicians’ awareness of the radiological and clinical manifestations of these inherited diseases may be helpful in the early diagnosis and timely initiation of specific prophylaxis measures to prevent infections and also to initiate hematopoietic stem cell transplantation as the curative management modality.

PMID:37767682 | DOI:10.18502/ijaai.v22i4.13612

Cureus. 2023 Aug 27;15(8):e44211. doi: 10.7759/cureus.44211. eCollection 2023 Aug.

ABSTRACT

Common variable immune deficiency (CVID) is a primary immunodeficiency disorder, with hypogammaglobulinemia and increased susceptibility to recurrent infections, autoimmune disorders, granulomatous diseases and malignancy. Among the solid organ transplant (SOT) recipient population, those with primary immunodeficiency disorders under chronic immunosuppression therapy can theoretically be at higher risk of atypical infections, autoimmune complications and disease recurrence with suboptimal long term graft survival, but literature is scarce. Here, we report a 27-year-old female with type 1 diabetes mellitus, complicated with nephropathy that progressed to end-stage renal disease (ESRD), who had a history of a chronic inflammatory response dysregulation, with chronic monoarthritis, persistent elevation of inflammation markers, recurrent infections, low immunoglobulin G (IgG) and A (IgA) serum levels, a slightly decreased population of memory B cells at flow cytometric immunophenotyping, and a confirmed pathological heterozygous mutation in the tumor necrosis factor receptor superfamily 13B (TNFRSF13B), with a suspected diagnosis of CVID. Whilst on hemodialysis, she received a simultaneous kidney and pancreas transplant from a standard criteria donor (SCD), and our induction and maintenance immunosuppression protocol and prophylaxis regimen allowed for a successful transplant with immediate pancreatic function, with no evidence of renal graft rejection upon biopsy in the early post-transplant period, and no novel episodes of serious infectious complications were recorded during a follow-up period of six months.

PMID:37767270 | PMC:PMC10521941 | DOI:10.7759/cureus.44211

Vaccines (Basel). 2023 Aug 23;11(9):1403. doi: 10.3390/vaccines11091403.

ABSTRACT

(1) Background: Coronavirus proteins are quite conserved amongst endemic strains (eCoV) and SARS-CoV-2. We aimed to evaluate whether peptide epitopes might serve as useful diagnostic biomarkers to stratify previous infections and COVID-19. (2) Methods: Peptide epitopes were identified at an amino acid resolution that applied a novel statistical approach to generate data sets of potential antibody binding peptides. (3) Results: Data sets from more than 120 COVID-19 or eCoV-infected patients, as well as vaccinated persons, have been used to generate data sets that have been used to search in silico for potential epitopes in proteins of SARS-CoV-2 and eCoV. Peptide epitopes were validated with >300 serum samples in synthetic peptide micro arrays and epitopes specific for different viruses, in addition to the identified cross reactive epitopes. (4) Conclusions: Most patients develop antibodies against non-structural proteins, which are useful general markers for recent infections. However, there are differences in the epitope patterns of COVID-19, and eCoV, and the S-protein vaccine, which can only be explained by a high degree of cross-reactivity between the viruses, a pre-existing immune response against some epitopes, and even an alternate processing of the vaccine proteins.

PMID:37766081 | DOI:10.3390/vaccines11091403

Pathogens. 2023 Sep 12;12(9):1156. doi: 10.3390/pathogens12091156.

ABSTRACT

A 35-year-old man with a late-onset combined immunodeficiency (LOCID) variant of common variable immunodeficiency, severe plaque psoriasis, psoriatic arthritis, and Crohn’s disease was attended in the Regional Hospital of Presidente Prudente and HC-FMUSP, São Paulo, Brazil. Anti-IL-12/IL-23 (ustekinumab) monoclonal antibody was prescribed due to the failure of other treatments (phototherapy, oral acitretin) for psoriasis and a Psoriasis Area Severity Index >10. We evaluated the impact of treatment with ustekinumab on severe infectious diseases in a patient with uncontrolled psoriasis and LOCID followed for 8 years. Four quarterly doses of ustekinumab 90 mg and human immunoglobulin replacement (10,000 mg at 28-day intervals) were administered. Immunophenotyping, cultures of lymphocytes, genetic sequencing, and whole exome sequencing were performed to investigate the primary immunodeficiency. Normal lymphocyte proliferation; pathogenic variants in genetic sequencing, and clinically significant variants in the whole exome for primary immunodeficiencies were not detected. The main infections before and after treatment with ustekinumab were chronic sinusitis and gastroenteritis. The patient was infected with COVID-19, dengue (twice) and influenza and was hospitalized three times for intravenous antibiotic therapy. Ustekinumab did not influence the susceptibility of the patient with LOCID to severe infections and significantly improved psoriasis, psoriatic arthritis, and Crohn’s disease.

PMID:37764964 | DOI:10.3390/pathogens12091156

Microorganisms. 2023 Sep 5;11(9):2233. doi: 10.3390/microorganisms11092233.

ABSTRACT

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by a defect in the phagocytic function of the innate immune system owing to mutations in genes encoding the five subunits of the nicotinamide adenine dinucleotide phosphatase (NADPH) oxidase enzyme complex. This review aimed to provide a comprehensive approach to the pathogens associated with chronic granulomatous disease (CGD) and its management. Patients with CGD, often children, have recurrent life-threatening infections and may develop infectious or inflammatory complications. The most common microorganisms observed in the patients with CGD are Staphylococcus aureus, Aspergillus spp., Candida spp., Nocardia spp., Burkholderia spp., Serratia spp., and Salmonella spp. Antibacterial prophylaxis with trimethoprim-sulfamethoxazole, antifungal prophylaxis usually with itraconazole, and interferon gamma immunotherapy have been successfully used in reducing infection in CGD. Haematopoietic stem cell transplantation (HCT) have been successfully proven to be the treatment of choice in patients with CGD.

PMID:37764077 | DOI:10.3390/microorganisms11092233

Biomedicines. 2023 Sep 17;11(9):2551. doi: 10.3390/biomedicines11092551.

ABSTRACT

Emerging science continues to establish the detrimental effects of malnutrition in acute neurological diseases such as traumatic brain injury, stroke, status epilepticus and anoxic brain injury. The primary pathological pathways responsible for secondary brain injury include neuroinflammation, catabolism, immune suppression and metabolic failure, and these are exacerbated by malnutrition. Given this, there is growing interest in novel nutritional interventions to promote neurological recovery after acute brain injury. In this review, we will describe how malnutrition impacts the biomolecular mechanisms of secondary brain injury in acute neurological disorders, and how nutritional status can be optimized in both pediatric and adult populations. We will further highlight emerging therapeutic approaches, including specialized diets that aim to resolve neuroinflammation, immunodeficiency and metabolic crisis, by providing pre-clinical and clinical evidence that their use promotes neurologic recovery. Using nutrition as a targeted treatment is appealing for several reasons that will be discussed. Given the high mortality and both short- and long-term morbidity associated with acute brain injuries, novel translational and clinical approaches are needed.

PMID:37760993 | DOI:10.3390/biomedicines11092551

Biomedicines. 2023 Sep 16;11(9):2548. doi: 10.3390/biomedicines11092548.

ABSTRACT

The hyperinflammatory response caused by SARS-CoV-2 infection contributes to its severity, and many critically ill patients show features of cytokine storm (CS) syndrome. We investigated, by next-generation sequencing, 24 causative genes of primary immunodeficiencies whose defect predisposes to CS. We studied two cohorts with extreme phenotypes of SARS-CoV-2 infection: critical/severe hyperinflammatory patients (H-P) and asymptomatic patients (AM-risk-P) with a high risk (older age) to severe COVID-19. To explore inborn errors of the immunity, we investigated the presence of pathogenic or rare variants, and to identify COVID-19 severity-associated markers, we compared the allele frequencies of common genetic polymorphisms between our two cohorts. We found: 1 H-P carries the likely pathogenic variant c.887-2 A>C in the IRF7 gene and 5 H-P carries variants in the MEFV gene, whose role in the pathogenicity of the familial Mediterranean fever (FMF) disease is controversial. The common polymorphism analysis showed three potential risk biomarkers for developing the hyperinflammatory response: the homozygous haplotype rs1231123A/A-rs1231122A/A in MEFV gene, the IFNAR2 p.Phe8Ser variant, and the CARMIL2 p.Val181Met variant. The combined analysis showed an increased risk of developing severe COVID-19 in patients that had at least one of our genetic risk markers (odds ratio (OR) = 6.2 (95% CI) (2.430-16.20)).

PMID:37760989 | DOI:10.3390/biomedicines11092548

Biomolecules. 2023 Sep 12;13(9):1380. doi: 10.3390/biom13091380.

ABSTRACT

The development of severe COVID-19, which is a complex multisystem disease, is thought to be associated with many genes whose action is modulated by numerous environmental and genetic factors. In this study, we focused on the ideas of the omnigenic model of heritability of complex traits, which assumes that a small number of core genes and a large pool of peripheral genes expressed in disease-relevant tissues contribute to the genetics of complex traits through interconnected networks. We hypothesized that primary immunodeficiency disease (PID) genes may be considered as core genes in severe COVID-19, and their functional partners (FPs) from protein-protein interaction networks may be considered as peripheral near-core genes. We used whole-exome sequencing data from patients aged ≤ 45 years with severe (n = 9) and non-severe COVID-19 (n = 11), and assessed the cumulative contribution of rare high-impact variants to disease severity. In patients with severe COVID-19, an excess of rare high-impact variants was observed at the whole-exome level, but maximal association signals were detected for PID + FP gene subsets among the genes intolerant to LoF variants, haploinsufficient and essential. Our exploratory study may serve as a model for new directions in the research of host genetics in severe COVID-19.

PMID:37759780 | DOI:10.3390/biom13091380

Clin Respir J. 2023 Sep 27. doi: 10.1111/crj.13702. Online ahead of print.

ABSTRACT

BACKGROUND: Many gaps remain in our understanding of the immune and molecular characteristics that underlie activated phosphoinositide 3-kinase delta syndrome (APDS).

METHODS: We performed RNA sequencing of peripheral blood leukocytes obtained from a child with APDS and his healthy parents and deconvoluted bulk transcriptional data to assess immune cell status.

RESULTS: Pathway enrichment analysis suggested signaling pathways enriched in virus infection as well as the PI3K, mitogen-activated protein kinase (MAPK), natural killer cell-mediated cytotoxicity, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathways. The proportion of B cells memory, T cells CD4 memory resting and dendritic cells activated were reduced, whereas B cells naïve, T cells CD8, NK cells resting, monocytes and macrophages M2 were increased in the child. Top 10 hub genes were screened and showed moderate to strong relatedness with immune cell proportions.

CONCLUSION: Deconvolution of bulk RNA sequencing to assess immune cells status can provide further insight into the alterations in immunological features underlying APDS and other rare diseases.

PMID:37753823 | DOI:10.1111/crj.13702

Immunotherapy. 2023 Sep 27. doi: 10.2217/imt-2023-0127. Online ahead of print.

ABSTRACT

Aim: To investigate the stability of the anti-pneumococcal (PCP) and anti-haemophilus type B (Hib) immunoglobulins (IgGs) in human IgG-depleted serum samples frozen at -20°C. Materials & methods: Modified commercially available immunoassays (ELISAs) were bioanalytically validated. These ELISAs were used to measure levels of the two anti-bacterial IgG in samples kept at -20°C for up to 15 months. Human IgG-depleted serum was spiked with GAMMAGARD Liquid to obtain those samples. Results: Both ELISAs passed the validation test. Anti-PCP IgG and anti-Hib IgG were shown to be stable for at least 15 months at -20°C. Conclusion: These data confirm the stability of anti-bacterial IgG in human IgG-depleted serum and support the common practice of testing frozen samples.

PMID:37753548 | DOI:10.2217/imt-2023-0127