Manish Butte

Clin Exp Immunol. 2021 Nov 30:uxab019. doi: 10.1093/cei/uxab019. Online ahead of print.

ABSTRACT

This report highlights case of two siblings who developed Haemophagocytic lymphohystiocytosis (HLH) due to distinct genetic abnormalities. Though their presentation was clinically similar, the cases demonstrate that a shared genetic diagnosis among siblings cannot be assumed.

PMID:35020838 | DOI:10.1093/cei/uxab019

Clin Rev Allergy Immunol. 2022 Jan 12. doi: 10.1007/s12016-021-08916-8. Online ahead of print.

ABSTRACT

Over the past 20 years, the rapid evolution in the diagnosis and treatment of primary immunodeficiencies (PI) and the recognition of immune dysregulation as a feature in some have prompted the use of “inborn errors of immunity” (IEI) as a more encompassing term used to describe these disorders [1, 2] . This article aims to review the future of therapy of PI/IEI (referred to IEI throughout this paper). Historically, immune deficiencies have been characterized as monogenic disorders resulting in immune deficiencies affecting T cells, B cells, combination of T and B cells, or innate immune disorders. More recently, immunologists are also recognizing a variety of phenotypes associated with one genotype or similar phenotypes across genotypes and a role for incomplete penetrance or variable expressivity of some genes causing inborn errors of immunity [3]. The IUIS classification of immune deficiencies (IEIs) has evolved over time to include 10 categories, with disorders of immune dysregulation accounting for a new subset, some treatable with small molecule inhibitors or biologics. [1] Until recently, management options were limited to prompt treatment of infections, gammaglobulin replacement, and possibly bone marrow transplant depending on the defect. Available therapies have expanded to include small molecule inhibitors, biologics, gene therapy, and the use of adoptive transfer of virus-specific T cells to fight viral infections in immunocompromised patients. Several significant contributions to the field of clinical immunology have fueled the rapid advancement of therapies over the past two decades. Among these are educational efforts to recruit young immunologists to the field resulting in the growth of a world-wide community of clinicians and investigators interested in rare diseases, efforts to increase awareness of IEI globally contributing to international collaborations, along with advancements in diagnostic genetic testing, newborn screening, molecular biology techniques, gene correction, use of immune modulators, and ex vivo expansion of engineered T cells for therapeutic use. The development and widespread use of newborn screening have helped to identify severe combined immune deficiency (SCID) earlier resulting in better outcomes [4]. Continual improvements and accessibility of genetic sequencing have helped to identify new IEI diseases at an accelerated pace [5]. Advances in gene therapy and bone marrow transplant have made treatments possible in otherwise fatal diseases. Furthermore, the increased awareness of IEI across the world has driven networks of immunologists working together to improve the diagnosis and treatment of these rare diseases. These improvements in the diagnosis and treatment of IEI noted over the past 20 years bring hope for a better future for the IEI community. This paper will review future directions in a few of the newer therapies emerging for IEI. For easy reference, most of the diseases discussed in this paper are briefly described in a summary table, in the order mentioned within the paper (Appendix).

PMID:35020169 | DOI:10.1007/s12016-021-08916-8

Clin Rev Allergy Immunol. 2022 Jan 12. doi: 10.1007/s12016-021-08881-2. Online ahead of print.

ABSTRACT

The field of Immunology is one that has undergone great expansion in recent years. With the advent of new diagnostic modalities including a variety of genetic tests (discussed elsewhere in this journal), the ability to diagnose a patient with a primary immunodeficiency disorder (PIDD) has become a more streamlined process. With increased availability of genetic testing for those with suspected or known PIDD, there has been a significant increase in the number of genes associated with this group of disorders. This is of great importance as a misdiagnosis of these rare diseases can lead to a delay in what can be critical treatment options. At times, those options can include life-saving medications or procedures. Presentation of patients with PIDD can vary greatly based on the specific genetic defect and the part(s) of the immune system that is affected by the variation. PIDD disorders lead to varying levels of increased risk of infection ranging from a mild increase such as with selective IgA deficiency to a profound risk with severe combined immunodeficiency. These diseases can also cause a variety of other clinical findings including autoimmunity and gastrointestinal disease.

PMID:35020168 | DOI:10.1007/s12016-021-08881-2

Cureus. 2021 Dec 8;13(12):e20273. doi: 10.7759/cureus.20273. eCollection 2021 Dec.

ABSTRACT

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. It presents with variable degrees of immunodeficiency resulting in a variety of clinical presentations and complications. This report describes the case of newly diagnosed CVID in a 74-year-old man with no history of recurrent infections or hospitalizations. He presented with chronic productive cough, wheezing, shortness of breath and fatigue. Physical examination showed bilateral rhonchi and scattered wheezes. Pulmonary function tests showed moderate obstructive defect with partial reversibility and decreased diffusion lung capacity for carbon monoxide (DLCO). Chest computed tomography (CT) showed bilateral lower lobe peribronchial thickening and mildly enlarged lymph nodes in the mediastinum and upper abdomen. Bronchoscopy with alveolar lavage was done and respiratory samples grew Moraxella. He had negative acid fast bacillus stain and negative tuberculosis and fungal cultures. He received a course of antibiotics resulting in brief improvement in symptoms followed by another exacerbation. Repeat sputum cultures grew Pseudomonas. Further testing showed severely depressed levels of immunoglobulin. His symptoms ultimately improved with immunoglobulin replacement therapy. A broad differential, including CVID, needs to be considered in working up a patient with a chronic productive cough and recurrent lower respiratory tract infection.

PMID:35018267 | PMC:PMC8741407 | DOI:10.7759/cureus.20273

Int J Mol Sci. 2021 Dec 25;23(1):223. doi: 10.3390/ijms23010223.

ABSTRACT

We describe a sequential multistaining protocol for immunohistochemistry, immunofluorescence and CyTOF imaging for formalin-fixed, paraffin-embedded specimens (FFPE) in the formalin gas-phase (FOLGAS), enabling sequential multistaining, independent from the primary and secondary antibodies and retrieval. Histomorphologic details are preserved, and crossreactivity and loss of signal intensity are not detectable. Combined with a DAB-based hydrophobic masking of metal-labeled primary antibodies, FOLGAS allows the extended use of CyTOF imaging in FFPE sections.

PMID:35008649 | DOI:10.3390/ijms23010223

Int Immunopharmacol. 2022 Jan 7;104:108472. doi: 10.1016/j.intimp.2021.108472. Online ahead of print.

ABSTRACT

A population pharmacokinetic (PK) model for comparing the PK of subcutaneously administered immunoglobulin G (IgG) replacement therapy (SCIG) with Gamunex-C 10% or SCIG 20% formulations in patients with primary immunodeficiency diseases was developed using data from 3 clinical trials (N = 95, 69.5% adults, 30.5% <18 years) of intravenous IG (IVIG) 10% and SCIG 10% or SCIG 20%. Serum IgG exposure following switches from IVIG 10% every 3 or 4 weeks to biweekly SCIG 20% (dose adjustment factor 1.0 or 1.37) and from weekly SCIG 20% to biweekly SCIG 20% or SCIG 20% 2-7 times/week was simulated. The PK of IVIG 10% and SCIG 20% were adequately described by a 2-compartment model with first-order absorption rate constant of exogenous IgG from an SC depot compartment into the central compartment and first-order elimination from the central compartment. Switching from IVIG 10% every 4 weeks to biweekly SCIG 20% produced similar serum IgG exposure, with lower peak and higher trough serum IgG concentrations. Switching from IVIG 10% every 3 or 4 weeks to weekly and biweekly SCIG 20% yielded comparable IgG exposure and clinically effective trough IgG concentrations.

PMID:35008008 | DOI:10.1016/j.intimp.2021.108472

Am J Gastroenterol. 2021 Dec 1;116(Suppl 1):S17. doi: 10.14309/01.ajg.0000798856.73091.69.

ABSTRACT

CASE: Background: CD is an inflammatory disease that predominantly affects the gastrointestinal tract and has a progressive course. Immunodeficiencies can occur by altering different components of innate or adaptive immune responses. Such changes put the patient at greater risk for infectious diseases or non-infectious complications. Among the non-infectious complications are cancer, autoimmune diseases and gastrointestinal diseases, which should be suspected in patients with recurrent infections, with clinical, radiological or histological features of the disease are atypical or in the occurrence of an unsatisfactory response to conventional therapy.

OBJECTIVE: To describe a case report of a CD patient complicated with enteric alterations related to immunodeficiency.

RESULTS: A 31-year-old male patient started presenting abdominal pain, diarrhea, and weight loss in October 2020. He underwent a colonoscopy that showed diffuse involvement of the colon suggestive of CD. He didn`t respond to therapy with prednisone and azathioprine and lost 40kg until January 2021, when he was referred to an IBD center. He had signs of malnutrition (eg, BMI = 15.4, Albumin = 1.8g/dL). The MRI showed diffuse thickening of the walls of the entire length of the ileum, colon and rectum, associated with submucosal edema and more intense enhancement in the inner layer. Findings compatible with nonspecific diffuse ileocolitis. After negative infectious screening, hydrocortisone, azathioprine and infliximab were prescribed, but the patient remained clinical worsening. During the 6 weeks of therapy use, the patient presented oral candidiasis, septic pyoarthritis, DNA testing for Clostridium difficile and PCR for Cytomegalovius were positive. Despite the treatment of infectious diseases, the patient continued to worsen and was considered a primary non-response to anti-TNF, opting for the initiation of Ustekinumab. There was improvement in endoscopic and fecal calprotectin, but continued progression of ileal disease and diarrhea, with no response to enteral or parenteral nutritional therapies. An investigation for immunodeficiencies was carried out and IgM/IgG deficiency was noted, and parenteral immunoglobulin was started. He presented an intestinal subocclusion, requiring a loop ileostomy. In this surgery, it was decided to send a sample of ileal tissue for diagnostic differentiation, where ileitis was observed with intense plasma cell reaction and lymphoid nodular hyperplasia, uncharacteristic of DC, which may correspond to enteropathy secondary to immunodeficiency. Despite the treatment, the patient presented fungal endocarditis, esophageal moniliasis and septic condition of undetermined origin. He remained in hospital for 120 days until complete improvement of the infectious complications. With the slow improvement in nutritional parameters, there was a reduction in the incidence of infections as well as an increase in immunoglobulins. After five months of combined nutrition and anti-interleukin therapy, the patient presented clinical improvement, weight gain and complete normalization of IgG and IgM. Ileal disease is in regression and in the colon, in endoscopic remission.

CONCLUSION: We present a case report of the initial presentation of DC complicated with severe malnutrition where there was depletion of part of immunoglobulins, resulting in infectious and non-infectious complications, where ileal involvement intensified the manifestation of colonic DC.

PMID:35006190 | DOI:10.14309/01.ajg.0000798856.73091.69

Front Immunol. 2021 Dec 20;12:796065. doi: 10.3389/fimmu.2021.796065. eCollection 2021.

ABSTRACT

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.

PMID:35003119 | PMC:PMC8728873 | DOI:10.3389/fimmu.2021.796065

Front Immunol. 2021 Dec 22;12:773853. doi: 10.3389/fimmu.2021.773853. eCollection 2021.

ABSTRACT

Rituximab (RTX) is an anti-CD20 monoclonal antibody that targets B cells-from the immature pre-B-cell stage in the bone marrow to mature circulating B cells-while preserving stem cells and plasma cells. It is used to treat autoimmune diseases, hematological malignancies, or complications after hematopoietic stem cell transplantation (HSCT). Its safety profile is acceptable; however, a subset of patients can develop persistent hypogammaglobulinemia and associated severe complications, especially in pediatric populations. We report the unrelated cases of two young men aged 17 and 22, presenting with persistent hypogammaglobulinemia more than 7 and 10 years after treatment with RTX, respectively, and administered after HSCT for hemolytic anemia and Epstein-Barr virus reactivation, respectively. Both patients’ immunological workups showed low levels of total immunoglobulin, vaccine antibodies, and class switched-memory B cells but an increase in naive B cells, which can also be observed in primary immunodeficiencies such as those making up common variable immunodeficiency. Whole exome sequencing for one of the patients failed to detect a pathogenic variant causing a Mendelian immunological disorder. Annual assessments involving interruption of immunoglobulin replacement therapy each summer failed to demonstrate the recovery of endogenous immunoglobulin production or normal numbers of class switched-memory B cells 7 and 10 years after the patients’ respective treatments with RTX. Although the factors that may lead to prolonged hypogammaglobulinemia after rituximab treatment (if necessary) remain unclear, a comprehensive immunological workup before treatment and long-term follow-up are mandatory to assess long-term complications, especially in children.

PMID:35003091 | PMC:PMC8727997 | DOI:10.3389/fimmu.2021.773853

Front Immunol. 2021 Dec 24;12:767188. doi: 10.3389/fimmu.2021.767188. eCollection 2021.

ABSTRACT

NF-κB1 deficiency is suggested to be the most common cause of common variable immunodeficiency (CVID). NFKB1 encodes for the p105 precursor protein of NF-κB1, which is converted into the active transcriptional subunit p50 through proteasomal processing of its C-terminal half upon stimulation and is implicated in the canonical NF-kB pathway. Rare monoallelic NFKB1 variants have been shown to cause (haplo) insufficiency. Our report describes a novel NFKB1 missense variant (c.691C>T, p.R230C; allele frequency 0.00004953) in a family vulnerable to meningitis, sepsis, and late-onset hypogammaglobulinemia. We investigated the pathogenic relevance of this variant by lymphocyte stimulation, immunophenotyping, overexpression study and immunoblotting. The ectopic expression of p50 for c.691 C>T restricted transcriptionally active p50 in the cytoplasm, and immunoblotting revealed reduced p105/50 expression. This study shows that the deleterious missense variant in NFKB1 adversely affects the transcriptional and translational activity of NFκB1, impairing its function. Patients immunological parameters show a progressive course of hypogammaglobulinemia, which may partially account for the incomplete disease penetrance and suggest the need for closer immunological monitoring of those mutation carriers.

PMID:35003082 | PMC:PMC8738076 | DOI:10.3389/fimmu.2021.767188