Manish Butte

Front Oncol. 2022 Sep 22;12:1007616. doi: 10.3389/fonc.2022.1007616. eCollection 2022.

ABSTRACT

[This corrects the article DOI: 10.3389/fonc.2022.843741.].

PMID:36226071 | PMC:PMC9549773 | DOI:10.3389/fonc.2022.1007616

Front Nutr. 2022 Sep 26;9:948488. doi: 10.3389/fnut.2022.948488. eCollection 2022.

ABSTRACT

Undernutrition remains a major issue in global health. Low protein-energy consumption, results in stunting, wasting and/or underweight, three deleterious forms of malnutrition that affect roughly 200 million children under the age of five years. Undernutrition compromises the immune system with the generation of various degrees of immunodeficiency, which in turn, renders undernourished individuals more sensitive to acute infections. The severity of various infectious diseases including visceral leishmaniasis (VL), influenza, and tuberculosis is associated with undernutrition. Immunosuppression resulting from protein-energy undernutrition severely impacts primary and secondary lymphoid organs involved in the response to related pathogens. The thymus-a primary lymphoid organ responsible for the generation of T lymphocytes-is particularly compromised by both undernutrition and infectious diseases. In this respect, we will discuss herein various intrathymic cellular and molecular interactions seen in undernutrition alone or in combination with acute infections. Many examples illustrated in studies on humans and experimental animals clearly revealed that protein-related undernutrition causes thymic atrophy, with cortical thymocyte depletion. Moreover, the non-lymphoid microenvironmental compartment of the organ undergoes important changes in thymic epithelial cells, including their secretory products such as hormones and extracellular matrix proteins. Of note, deficiencies in vitamins and trace elements also induce thymic atrophy. Interestingly, among the molecular interactions involved in the control of undernutrition-induced thymic atrophy is a hormonal imbalance with a rise in glucocorticoids and a decrease in leptin serum levels. Undernutrition also yields a negative impact of acute infections upon the thymus, frequently with the intrathymic detection of pathogens or their antigens. For instance, undernourished mice infected with Leishmania infantum (that causes VL) undergo drastic thymic atrophy, with significant reduction in thymocyte numbers, and decreased levels of intrathymic chemokines and cytokines, indicating that both lymphoid and microenvironmental compartments of the organ are affected. Lastly, recent data revealed that some probiotic bacteria or probiotic fermented milks improve the thymus status in a model of malnutrition, thus raising a new field for investigation, namely the thymus-gut connection, indicating that probiotics can be envisioned as a further adjuvant therapy in the control of thymic changes in undernutrition accompanied or not by infection.

PMID:36225882 | PMC:PMC9549110 | DOI:10.3389/fnut.2022.948488

Expert Rev Anti Infect Ther. 2022 Oct 12. doi: 10.1080/14787210.2022.2134117. Online ahead of print.

ABSTRACT

INTRODUCTION: Monoclonal antibodies (mAbs) have been authorized for the treatment of COVID-19 in pediatric populations, however, there is a lack of evidence for their use in these populations.

AREAS COVERED: We outline the evidence of mAbs for COVID-19, discuss their use in the treatment of COVID-19 infection for pediatric patients, and consider alternative treatment options and challenges to COVID-19 drug approvals.

EXPERT OPINION: Limited evidence exists for the safety and efficacy of mAbs to treat COVID-19 in children as new variants emerge. In rare pediatric outpatient settings, such as profound immunodeficiency or severe pulmonary disease, the benefits of antiviral treatment for COVID-19 likely outweigh the relatively small risks. However, for the great majority of pediatric patients, mAb treatment is likely not indicated. Small molecule antiviral therapies are another potential treatment for COVID-19 in children in an outpatient setting, though neither mAb nor small molecule antiviral treatments have significant supporting evidence in children and developing a strong evidence base for these decisions will be challenging if not impractical. Ultimately, these decisions are likely to be made at the level of individual cases using expert opinion as the primary guiding principle.

PMID:36225144 | DOI:10.1080/14787210.2022.2134117

Pediatr Infect Dis J. 2022 Nov 1;41(11):e489-e494. doi: 10.1097/INF.0000000000003655. Epub 2022 Oct 11.

ABSTRACT

Q fever osteomyelitis has been rarely reported in children. This infection has an unclear pathophysiology and the optimal therapy is unknown. We report a 2-year-old girl with Coxiella burnetti recurrent multifocal osteomyelitis: femur, metatarsal, cuneiform, and calcaneus. We highlight the complicated diagnosis and management of this case and the importance of considering Q fever in children with chronic-recurrent multifocal osteomyelitis.

PMID:36223236 | DOI:10.1097/INF.0000000000003655

J Clin Immunol. 2022 Oct 12. doi: 10.1007/s10875-022-01345-y. Online ahead of print.

ABSTRACT

BACKGROUND: Due to the absence of curative treatments for inborn errors of immunity (IEI), children born with IEI require long-term follow-up for disease manifestations and related complications that occur over the lifespan. Effective transition from pediatric to adult services is known to significantly improve adherence to treatment and long-term outcomes. It is currently not known what transition services are available for young people with IEI in Europe.

OBJECTIVE: To understand the prevalence and practice of transition services in Europe for young people with IEI, encompassing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID).

METHODS: A survey was generated by the European Reference Network on immunodeficiency, autoinflammatory, and autoimmune diseases Transition Working Group and electronically circulated, through professional networks, to pediatric centers across Europe looking after children with IEI.

RESULTS: Seventy-six responses were received from 52 centers, in 45 cities across 17 different countries. All services transitioned patients to adult services, mainly to specialist PID or AID centers, typically transferring up to ten patients to adult care each year. The transition process started at a median age of 16-18 years with transfer to the adult center occurring at a median age of 18-20 years. 75% of PID and 68% of AID centers held at least one joint appointment with pediatric and adult services prior to the transfer of care. Approximately 75% of PID and AID services reported having a defined transition process, but few centers reported national disease-specific transition guidelines to refer to.

CONCLUSIONS: Transition services for children with IEI in Europe are available in many countries but lack standardized guidelines to promote best practice.

PMID:36222999 | DOI:10.1007/s10875-022-01345-y

J Allergy Clin Immunol. 2022 Oct 8:S0091-6749(22)01335-5. doi: 10.1016/j.jaci.2022.09.029. Online ahead of print.

ABSTRACT

BACKGROUND: A substantial proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown aetiology. However, due to histological similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism.

OBJECTIVE: Herein we aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic and microbial signatures of duodenal biopsies in CVID.

METHODS: Total RNA and protein were isolated from snap-frozen pieces of duodenal biopsies from CVID (with and without duodenal inflammation), healthy controls and celiac disease (untreated). RNA-sequencing, mass spectrometry-based proteomics and 16S rRNA sequencing (bacteria) were then performed.

RESULTS: CVID separated from controls in regulation of transcriptional response to lipopolysaccharide and cellular immune responses. These differences were independent of mucosal inflammation. Instead, CVID patients with duodenal inflammation displayed alterations in transcription of genes involved in response to viral infections. Four proteins were differently regulated between CVID patients and healthy controls: DBNL, TRMT11, GCHFR, and IGHA2, independently of duodenal inflammation. Despite similar histology, there were major differences in CVID with duodenal inflammation and celiac disease both at RNA and protein level. No significant difference was observed in the bacterial gut microbial signature between CVID, celiac and healthy controls.

CONCLUSION: Our findings suggest altered functions of the duodenal epithelium, particularly in response to lipopolysaccharide and viruses. The latter finding was related to duodenal inflammation, suggesting that viruses, and not gluten sensitivity, could be related to duodenal inflammation in CVID.

PMID:36220400 | DOI:10.1016/j.jaci.2022.09.029

Acta Endocrinol (Buchar). 2022 Apr-Jun;18(2):238-240. doi: 10.4183/aeb.2022.238.

ABSTRACT

Hematopoietic stem cell transplantation (HSCT) is an effective treatment for various types of hereditary hematologic disease, hematological malignancy, primary immunodeficiency and metabolic disease. Thyroid dysfunction is a common complication of HSCT, which situation is mainly manifested as hypothyroidism and rarely as hyperthyroidism. This report presents a 28-year-old man who developed hyperthyroidism 9 years after sibling allogeneic HSCT, which was most likely caused by chronic GVHD. In the meantime, the patient also suffered from liver dysfunction and pancytopenia, for which he was inappropriate to take antithyroid drugs (ATD) for treatment of hyperthyroidism. The patient was orally administered 259 MBq ¹³¹I, an individualized dose. The symptoms of hyperthyroidism were mitigated by ¹³¹I treatment.

PMID:36212265 | PMC:PMC9512369 | DOI:10.4183/aeb.2022.238

Front Immunol. 2022 Sep 23;13:987895. doi: 10.3389/fimmu.2022.987895. eCollection 2022.

ABSTRACT

RATIONALE: Eosinophilic gastrointestinal disorders (EGID), including eosinophilic esophagitis (EoE), are inflammatory disorders of the gastrointestinal mucosa mediated by complex immune mechanisms. Although there have been initial reports of EGID in patients with inborn errors of immunity (IEI), little is known about the presentation of EGID in immunodeficient individuals.

METHODS: We queried the U.S. Immunodeficiency Network (USIDNET) for patient records including the terms eosinophilic esophagitis, gastritis, enteritis, or colitis. We analyzed 74 patient records from the database, including diagnoses, demographics, infectious history, laboratory findings, genetic studies, therapeutic interventions, and clinical outcomes.

RESULTS: We examined 74 patient records. A total of 61 patients had isolated EoE, and 13 had distal gastrointestinal involvement consistent with EGID. The most common IEI were common variable immunodeficiency (43.2%), some form of combined immunodeficiency (21.6%), chronic granulomatous disease (8.1%), hyper-IgE syndrome (6.8%), and autoimmune lymphoproliferative syndrome (6.8%). The median age at presentation with IEI was 0.5 years (IQR 1.725, max 39 years) and 56.76% were male. Approximately 20% of the patients in the cohort received a hematopoietic stem cell transplantation for treatment of IEI, but the timing of the HSCT in relationship to the EGID diagnosis was unknown.

CONCLUSIONS: Here, we report EGID in a diverse cohort of IEI patients, suggesting that both non-EoE EGID and EoE can be seen as comorbid conditions with a variety of IEI. Our data suggests that EGID may be more common in patients with IEI than would be expected based on estimates of EGID in the general population.

PMID:36211419 | PMC:PMC9539548 | DOI:10.3389/fimmu.2022.987895

Front Immunol. 2022 Sep 22;13:922752. doi: 10.3389/fimmu.2022.922752. eCollection 2022.

ABSTRACT

Tremendous progress has been made in the recognition of primary immune deficiencies (PIDs) in Bulgaria since in 2005 we have joined the J Project Central-Eastern European collaborative program. Ten years later an Expert Centre (ExpC) for Rare Diseases – Primary Immune Deficiencies at the University Hospital “Alexandrovska”- Sofia was established. In May 2017 The National Register of Patients with Rare Diseases also became operational as a database containing clinical and genetic information for Bulgarian patients with PID. The transfer of data and information on Bulgarian PID patients to the European Primary Immunodeficiency Database, managed by the European Society for Primary Immunodeficiency (ESID) has started in 2020. The total number of registered patients now is 191 (100 men and 91 women), with more than half of them being children (106; 55.5%). Regular updating of the information in the register showed that 5.2% of patients are deceased and the majority (94.8%) is a subject to continuous monitoring as it has been reported for other European countries as well. With the establishment of the ExpC, the dynamics in the diagnosis and registration of patients with PID significantly intensified. For a period of 5 years (2016-2021) 101 patients were evaluated and registered in comparison with previous period – before ExpC establishment when only 89 patients were diagnosed. The most common pathology was humoral immune deficiency (85 patients; 44.5%). Ninety-six (50.3%) of the patients underwent genetic testing, and 66. 7% had genetically confirmed diagnosis. Three of the variants have not been reported in population databases. Following genetic investigation confirmation of the initial phenotypic diagnosis was achieved in 82.8% of cases and change in the diagnosis – in 17%. Sixty-two patients were on regular replacement or specific therapy, and the rest received symptomatic and supportive treatment. In summary, we present the first epidemiological report of PIDs in Bulgaria, based on the National PID register. Data on the clinical, phenotypic and genetic characteristics of PID patients provided important information about the nature of primary immunodeficiency diseases in our country.

PMID:36211402 | PMC:PMC9535737 | DOI:10.3389/fimmu.2022.922752

Front Immunol. 2022 Sep 23;13:984376. doi: 10.3389/fimmu.2022.984376. eCollection 2022.

ABSTRACT

BACKGROUND: Individuals with primary and secondary immunodeficiency (PID/SID) were shown to be at risk of poor outcomes during the early stages of the SARS-CoV-2 pandemic. SARS-CoV-2 vaccines demonstrate reduced immunogenicity in these patients.

OBJECTIVES: To understand whether the risk of severe COVID-19 in individuals with PID or SID has changed following the deployment of vaccination and therapeutics in the context of the emergence of novel viral variants of concern.

METHODS: The outcomes of two cohorts of patients with PID and SID were compared: the first, infected between March and July 2020, prior to vaccination and treatments, the second after these intervention became available between January 2021 and April 2022.

RESULTS: 22.7% of immunodeficient patients have been infected at least once with SARS-CoV-2 since the start of the pandemic, compared to over 70% of the general population. Immunodeficient patients were typically infected later in the pandemic when the B.1.1.529 (Omicron) variant was dominant. This delay was associated with receipt of more vaccine doses and higher pre-infection seroprevalence. Compared to March-July 2020, hospitalization rates (53.3% vs 17.9%, p<0.0001) and mortality (Infection fatality rate 20.0% vs 3.4%, p=0.0003) have significantly reduced for patients with PID but remain elevated compared to the general population. The presence of a serological response to vaccination was associated with a reduced duration of viral detection by PCR in the nasopharynx. Early outpatient treatment with antivirals or monoclonal antibodies reduced hospitalization during the Omicron wave.

CONCLUSIONS: Most individuals with immunodeficiency in the United Kingdom remain SARS-CoV-2 infection naïve. Vaccination, widespread availability of outpatient treatments and, possibly, the emergence of the B.1.1.529 variant have led to significant improvements in morbidity and mortality followings SARS-CoV-2 infection since the start of the pandemic. However, individuals with PID and SID remain at significantly increased risk of poor outcomes compared to the general population; mitigation, vaccination and treatment strategies must be optimized to minimize the ongoing burden of the pandemic in these vulnerable cohorts.

PMID:36211396 | PMC:PMC9539662 | DOI:10.3389/fimmu.2022.984376