Manish Butte

J Allergy Clin Immunol Pract. 2022 Apr 11:S2213-2198(22)00340-3. doi: 10.1016/j.jaip.2022.03.028. Online ahead of print.

ABSTRACT

BACKGROUND: Few published studies address eye disease in primary immunodeficiency (PID) despite ocular infections and autoimmune disease being known manifestations of immunodeficient states.

OBJECTIVE: Data from the USIDNET Registry provide a resource to study ocular ailments in subjects with PID.

METHODS: Ocular manifestations and patient characteristics were determined using data from 4,624 PID patients enrolled in the US Immunodeficiency Network (USIDNET) Registry.

RESULTS: 519 (11.2%) of patients had recorded ocular diseases. Those with auto-inflammatory disorders (n=4 of 7, 57.1%), intrinsic and innate immunity defects (n=9 of 44, 20.5%), and immune dysregulation (n=27 of 142, 19.0%) had the highest percentage of ocular diseases for PID diagnosis category. Of the 67.6% with infections, 85.5% had conjunctivitis. Bacteria (56.2%) and viruses (27.4%) were the most common microorganisms reported with Staphylococcus (31.7%), Haemophilus (26.8%), and Streptococcus (22.0%) being the most common bacteria isolated. Those with a history of eye infections had lower immunoglobulin levels, lower CD19 B cell percentages, and a lower number of protective pneumococcal titers. In patients with noninfectious ocular complications, 30.8% had vision changes, with retina (n=20, 8.0%), cataract (n=16, 6.4%), and nerve diseases (n=16, 6.4%) also being common. Many patients with ocular disease had serious sequelae with 12.7% undergoing eye surgery and 10.6% having a vision-based disability.

CONCLUSIONS: Vision loss and conjunctivitis were the most commonly reported ocular complications and pose large quality of life issues. Learning more about ocular disease in PID will increase awareness about the importance of addressing and evaluating for these ailments.

PMID:35421605 | DOI:10.1016/j.jaip.2022.03.028

J Allergy Clin Immunol. 2022 Apr 11:S0091-6749(22)00449-3. doi: 10.1016/j.jaci.2022.04.002. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients.

OBJECTIVES: We studied humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult IEI patients.

METHODS: In a prospective, controlled, multicenter study 505 IEI patients (common variable immunodeficiency (CVID), isolated or undefined antibody deficiencies, X-linked agammaglobulinemia (XLA), combined immunodeficiency (CID), phagocyte defects) and 192 controls were included. All participants received two doses of the mRNA-1273 COVID-19 vaccine. Levels of SARS-CoV-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first and 28 days after second vaccination.

RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to healthy controls, but seroconversion rates in patients with more severe IEI, like CVID and CID, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to controls in all IEI cohorts, with the exception of CVID patients. The presence of non-infectious complications and the use of immunosuppressive drugs in CVID patients were negatively correlated with the antibody response.

CONCLUSION: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with CID and CVID. Lowest response was detected in XLA and in CVID patients with non-infectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision-making for additional vaccinations.

PMID:35421449 | DOI:10.1016/j.jaci.2022.04.002

J Clin Immunol. 2022 Apr 14. doi: 10.1007/s10875-022-01231-7. Online ahead of print.

ABSTRACT

BACKGROUND: Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood.

OBJECTIVES: COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination.

METHODS: Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs.

RESULTS: A total of 5.6% (n = 320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n = 168) compared with 100% of healthy controls (n = 205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p = 0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p = 0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine.

CONCLUSION: SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.

PMID:35420363 | DOI:10.1007/s10875-022-01231-7

Neurohospitalist. 2022 Apr;12(2):361-365. doi: 10.1177/19418744211050215. Epub 2021 Dec 31.

ABSTRACT

The role of the adaptive immune system in mediating COVID-19 is largely unknown. Therefore, it is difficult to predict the clinical course in patients with common variable immunodeficiency (CVID), a disease characterized by dysfunctional lymphocytes and impaired antibody production. We report a case of SARS-CoV-2 infection presenting as isolated neurological symptoms in a patient with CVID. The patient subsequently improved following steroids, intravenous immunoglobulin, and convalescent plasma (CP). The latter has been shown to be safe and efficacious in treating COVID-19 in patients with primary immunodeficiency. Recent data suggest that the mechanism of CNS injury in COVID-19 may be due to immunological dysregulation rather than direct viral-mediated injury. This case exemplifies the complex interaction between the brain, the immune system, and the SARS-CoV-2 virus.

PMID:35419133 | PMC:PMC8995593 | DOI:10.1177/19418744211050215

Cureus. 2022 Mar 9;14(3):e23002. doi: 10.7759/cureus.23002. eCollection 2022 Mar.

ABSTRACT

The purpose of this case report was to present a case of cytomegalovirus (CMV) retinitis in a patient with diffuse large B-cell lymphoma (DLBCL) post-CD19 chimeric antigen receptor (CAR) T-cell therapy. A 43-year-old female patient who was complaining of metamorphopsia and sudden blurring in the vision of her left eye was referred to the ophthalmology department. The patient had DLBCL and was started on systemic chemotherapy, which showed no response to therapy and disease progression. Therefore, she was diagnosed with primary refractory DLBCL and treated with CAR T-cell therapy. The visual acuity of the left eye was 20/25 in the left eye on the Snellen visual acuity chart. The dilated fundus examination of the left eye demonstrated a diffuse yellowish retinal infiltration radiating from the optic disc involving the inferior macula and inferotemporal arcade. A color fundus image of the left eye showed a creamy infiltrate involving the inferior half of the macula sparing the fovea with subtle small white lesions in the midperiphery. Horizontal cross-section optical coherence tomography (OCT) of the macula of the left eye showed islands of destruction of all the retinal layers, which are replaced with moderately hyperreflective material; these infiltrates spare the fovea but with subfoveal fluid. Further systemic evaluation indicated CMV viremia reactivation and an absolute CD4+ cells count of 13 cells/mcL. Thus, she was diagnosed with CMV retinitis. After three days of the initial presentation, she received the first intravitreal ganciclovir injection; 17 days after presentation, she received five intravitreal ganciclovir injections. The patient responded well to intravitreal ganciclovir therapy. She regained very good vision, and the visual acuity was 20/20 in both eyes. Early recognition and initiation of proper treatment are crucial. Thus, any visual complaints in patients with immunodeficiency should be taken seriously and should be further assessed. As the right eye had retinal scaring indicating previous retinitis, prophylactic treatment with ganciclovir could have been used to reduce the risk of retinitis development in the left eye.

PMID:35415043 | PMC:PMC8993130 | DOI:10.7759/cureus.23002

Internist (Berl). 2022 Apr 12. doi: 10.1007/s00108-022-01326-8. Online ahead of print.

ABSTRACT

Infections are an important warning sign for a weakened immune system. In the internal medical practice acquired (secondary), particularly drug-induced immunodeficiencies, are much more frequent than congenital (primary) immunodeficiencies. The management starts as early as the planning phase before initiation of immunosuppression. The risk of infection should be individually stratified and protective vaccinations should be completed. Depending on the immunosuppressive treatment, there can be a necessity for preventive treatment, e.g. for latent tuberculosis infection or hepatitis B. The serological results on varicella zoster virus and JC polyomavirus must also be considered. The basic immunological diagnostics include differential blood count and the determination of immunoglobulins (IgG, IgA, IgM) prior to and during immunosuppressive treatment. Relevant conspicuous laboratory results before initiation of treatment should prompt advanced immunological work-up for the identification of primary immunodeficiencies, which are often accompanied by clinical signs of immune dysregulation. Depending on the type of pathogen, localization, frequency and duration as well as the severity of the infection, prophylactic antibiotic treatment may be required. Patients with chronic severe lymphocytopenia, in particular with CD4 positive T (helper) cells < 200/µl, are at increased risk for opportunistic infections so that an antibiotic prophylaxis is recommended. In patients with significantly increased proneness to infections and detection of a relevant quantitative (IgG < 4 g/l) and/or qualitative antibody deficiency (impaired vaccine response), additional immunoglobulin replacement therapy may be necessary and can be administered intravenously (IVIG) or subcutaneously (SCIG) as home treatment. In accordance with the localization of the infection, multidisciplinary clarification and management is warranted.

PMID:35412057 | DOI:10.1007/s00108-022-01326-8

J Clin Med. 2022 Apr 5;11(7):2025. doi: 10.3390/jcm11072025.

ABSTRACT

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized by a broad and heterogeneous clinical presentation associated with various degrees of T-cell deficiency. We report the clinical, immunologic, and genetic findings of a cohort of eight patients presenting with a clinical phenotype that is highly suggestive of this syndrome but without the 22q11.2 deletion. The cardinal features of 22q11.2DS, such as congenital heart defects, hypoparathyroidism, and facial dysmorphisms, were observed in the majority of the patient cohort. The unusual features are described in detail. The immunologic assessment showed various degrees of immunodeficiency of the T-cell compartment, notably a reduction in the thymic output. Half of the patient cohort exhibited a reduction in total dendritic cells. Array comparative genomic hybridization (CGH) revealed six patients harboring copy number variations (CNVs) never reported in normal subjects. The gene content of these CNVs was carefully analyzed to understand the mechanisms leading to 22q11.2DS phenocopies. According to these results, we suggested that array-CGH should be used as a first-tier tool for patients resembling 22q11.2DS.

PMID:35407632 | DOI:10.3390/jcm11072025

Transplant Cell Ther. 2022 Apr 8:S2666-6367(22)01196-4. doi: 10.1016/j.jtct.2022.04.002. Online ahead of print.

ABSTRACT

BACKGROUND: . Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a valuable alternative for children with non-malignant disease and ex-vivo negative selection of TCR αβ⁺-cells is an emerging graft manipulation option that carries several potential advantages in terms of reduced risk of Graft versus Host Disease (GvHD) and improved immune reconstitution.

METHODS: . We reported all consecutive patients with a diagnosis of non-malignant disease who received a TCR-αβ⁺ and CD19⁺depleted haplo-HSCT at “IRCCS Istituto Giannina Gaslini” from 2013 to 2019; the conditioning regimen was myeloablative or non-myeloablative, depending on underlying disease; all patients received anti-thymocyte globulin and rituximab. No post-transplant GvHD prophylaxis was given in presence of a TCR-αβ⁺ cell-dose in the graft lower than the threshold of 1 × 10⁵/kg of the recipient’s weight.

RESULTS: . Among 20 HSCTs, engraftment occurred in 17 (85%) after a median of 14 and 12 days from graft infusion for neutrophils and platelets respectively. Primary graft failure was diagnosed in 3 (15%) patients, two (10%) experienced secondary rejection; all of these underwent a second HSCT. The cumulative incidence of a-GvHD and c-GvHD was 15% (2 grade 1, 1 grade 4) at 90 days and 5% (1 grade 1) at 7 months, respectively. Cytomegalovirus reactivation requiring pre-emptive treatment was observed in 9 patients (45%). One patient developed a JC virus-related progressive multifocal leukoencephalopathy, successfully managed with donor-derived virus-specific T-cell infusions. A complete immunological recovery was reached in most patients within 6 months. After a median follow-up of 4 years, 18 patients are alive, with a cumulative survival probability of 90%.

CONCLUSION: . Haplo-HSCT after ex-vivo TCR-αβ⁺/CD19⁺ negative selection may be considered a good option for children with non-malignant diseases since it ensures a high engraftment rate with an acceptable risk of graft failure, very low incidence of significant GvHD, and good immune reconstitution with low frequency of severe virus-related disease. However, the control of viral infection/reactivation should be kept high in order to promptly provide pre-emptive treatments and approaches of antiviral adoptive immunotherapy.

PMID:35405368 | DOI:10.1016/j.jtct.2022.04.002

Front Pediatr. 2022 Mar 23;10:861692. doi: 10.3389/fped.2022.861692. eCollection 2022.

ABSTRACT

We report a child with Fanconi anemia who, after hematopoietic stem cell transplantation (HSCT) complicated by acute graft-versus-host disease (GVHD), underwent orthotopic liver transplantation (OLT). Approximately 1 month after OLT, the presence of third-party genetic material from the liver donor was noted and in the next few weeks, the chimerism assessment revealed 100% liver donor leukocytes in the peripheral blood. The rapidly progressing GVHD with gut involvement resulted in patient’s death 6 months after OLT. The liver can act as a clinically significant source of hematopoietic stem cells, and the liver donor’s young age must be emphasized as potentially predisposing to this phenomenon. Transfer of OLT hematopoietic stem cells may not have clinical significance unless the patient is not immunocompetent or develops liver-transplantation associated GVHD, that can result in lymphocyte mediated elimination of original hematopoiesis. Patients with preexisting immunity disorder (such as primary or secondary immunodeficiency) might require intensified immunosuppressive therapy in peritransplant period as a prevention of liver-transplantation associated GVHD. Close monitoring of hematopoietic chimerism after OLT is warranted in patients at risk, because cytopenia or OLT hematopoiesis can reflect subclinical GVHD and further studies are necessary to elucidate this phenomenon.

PMID:35402365 | PMC:PMC8984257 | DOI:10.3389/fped.2022.861692

Front Pediatr. 2022 Mar 23;10:855200. doi: 10.3389/fped.2022.855200. eCollection 2022.

ABSTRACT

Infections and infectious complications are hallmarks of common variable immunodeficiency (CVID) and the leading cause of morbidity and mortality in affected patients at any age. However, the pediatric CVID is no longer perceived as a primary immunodeficiency associated solely with infectious manifestations; autoimmune, allergic, lymphoproliferative, and malignant disorders and organ-specific immunopathology also characterize the spectrum of non-infectious complications. In this study, we sought to determine the role of immune dysregulation and frequency of non-infectious sequelae in children affected with CVID. We also aimed at providing an insight into the pathogenesis of non-infectious complications and at delineating the diagnostic approach to pediatric CVID with immune dysregulation. An in-depth retrospective analysis of clinical manifestations and their correlations with selected immune parameters was performed in a group of 39 CVID children, followed by our pediatric immunology department. Whereas recurrent sinopulmonary infections were present in all (100%) of the children studied, an unexpectedly high rate of non-infectious disorders and immune dysregulation phenotypes were observed in as many as 32 (82.05%) patients, compared with infection-only phenotypes limited to 7 (17.95%) male patients. The most common inflammatory comorbidity was asthma, diagnosed in 21 (53.85%) patients. The second most frequent immune dysregulation group was autoimmune disorders, present in 18 (46.15%) of the children studied with a high rate of autoimmune thyroiditis in as many as 10 (25.64%) of the CVID-affected children. Lymphoproliferation was seen in 14 children (35.90%), and, among them, lymphadenopathy occurred in nine (23.08%) cases and granulomatous lymphocytic interstitial lung disease in seven (17.95%) cases. Finally, malignancies occurred in two female patients (5.13%), papillary thyroid cancer in the first one and T-cell lymphoblastic leukemia in the other one. The most prominent abnormalities in the B- and T-cell compartment contributing to complex immune deficiency and immune dysregulation phenotypes were seen in the autoimmunity group, showing significant reductions in the switched memory B cell, naive T helper cell, and regulatory T-cell subsets. Herein, we document the previously unreported high rate of immune dysregulation in pediatric CVID as a clinical and diagnostic challenge with the variability of defects in the humoral and cellular immune responses.

PMID:35402361 | PMC:PMC8983883 | DOI:10.3389/fped.2022.855200