Cytomegalovirus Infections in Children with Primary and Secondary Immune Deficiencies.

Cytomegalovirus (CMV) is a human herpes virus that causes significant morbidity and mortality in immunosuppressed children. CMV primary infection causes a clinically mild disease in healthy children, usually in early childhood; the virus then utilises several mechanisms to establish host latency, which allows for periodic reactivation, particularly when the host is immunocompromised. It is this reactivation that is responsible for the significant morbidity and mortality in immunocompromised children. We review CMV infection in the primary immunodeficient host, including early identification of these infants by newborn screening to allow for CMV infection prevention strategies. Furthermore, clinical CMV is discussed in the context of children treated with secondary immunodeficiency, particularly paediatric cancer patients and children undergoing haematopoietic stem cell transplant (HSCT). Treatments for CMV are highlighted and include CMV immunotherapy.

The Molecular Evolution of Type 2 Vaccine-Derived Polioviruses in Individuals with Primary Immunodeficiency Diseases.

The oral poliovirus vaccine (OPV), which prevents person-to-person transmission of poliovirus by inducing robust intestinal immunity, has been a crucial tool for global polio eradication. However, polio outbreaks, mainly caused by type 2 circulating vaccine-derived poliovirus (cVDPV2), are increasing worldwide. Meanwhile, immunodeficiency-associated vaccine-derived poliovirus (iVDPV) is considered another risk factor during the final stage of global polio eradication. Patients with primary immunodeficiency diseases are associated with higher risks for long-term iVDPV infections. Although a limited number of chronic iVDPV excretors were reported, the recent identification of a chronic type 2 iVDPV (iVDPV2) excretor in the Philippines highlights the potential risk of inapparent iVDPV infection for expanding cVDPV outbreaks. Further research on the genetic characterizations and molecular evolution of iVDPV2, based on comprehensive iVDPV surveillance, will be critical for elucidating the remaining risk of iVDPV2 during the post-OPV era.

COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience.

BACKGROUND: As of November 2020, severe acute respiratory syndrome coronavirus 2 has resulted in 55 million infections worldwide and more than 1.3 million deaths from coronavirus disease 2019 (COVID-19). Outcomes following severe acute respiratory syndrome coronavirus 2 infection in individuals with primary immunodeficiency (PID) or symptomatic secondary immunodeficiency (SID) remain uncertain. OBJECTIVES: We sought to document the outcomes of individuals with PID or symptomatic SID following COVID-19 in the United Kingdom. METHODS: At the start of the COVID-19 pandemic, the United Kingdom Primary Immunodeficiency Network established a registry of cases to collate the nationwide outcomes of COVID-19 in individuals with PID or symptomatic SID and determine risk factors associated with morbidity and mortality from COVID-19 in these patient groups. RESULTS: A total of 100 patients had been enrolled by July 1, 2020, 60 with PID, 7 with other inborn errors of immunity including autoinflammatory diseases and C1 inhibitor deficiency, and 33 with symptomatic SID. In individuals with PID, 53.3% (32 of 60) were hospitalized, the infection-fatality ratio was 20.0% (12 of 60), the case-fatality ratio was 31.6% (12 of 38), and the inpatient mortality was 37.5% (12 of 32). Individuals with SID had worse outcomes than those with PID; 75.8% (25 of 33) were hospitalized, the infection-fatality ratio was 33.3% (11 of 33), the case-fatality ratio was 39.2% (11 of 28), and inpatient mortality was 44.0% (11 of 25). CONCLUSIONS: In comparison to the general population, adult patients with PID and symptomatic SID display greater morbidity and mortality from COVID-19. This increased risk must be reflected in public health guidelines to adequately protect vulnerable patients from exposure to the virus.

Determinants of neurological syndromes caused by varicella zoster virus (VZV).

Varicella zoster virus (VZV) is a pathogenic human herpes virus which causes varicella as a primary infection, following which it becomes latent in peripheral autonomic, sensory, and cranial nerve ganglionic neurons from where it may reactivate after decades to cause herpes zoster. VZV reactivation may also cause a wide spectrum of neurological syndromes, in particular, acute encephalitis and vasculopathy. While there is potentially a large number of coding viral mutations that might predispose certain individuals to VZV infections, in practice, a variety of host factors are the main determinants of VZV infection, both disseminated and specifically affecting the nervous system. Host factors include increasing age with diminished cell-mediated immunity to VZV, several primary immunodeficiency syndromes, secondary immunodeficiency syndromes, and drug-induced immunosuppression. In some cases, the molecular immunological basis underlying the increased risk of VZV infections has been defined, in particular, the role of POL III mutations, but in other cases, the mechanisms have yet to be determined. The role of immunization in immunosuppressed individuals as well as its possible efficacy in preventing both generalized and CNS-specific infections will require further investigation to clarify in such patients.

Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection.

Epstein-Barr virus (EBV) is an enigma; on one hand, it infects and persists in latent form in the vast majority of the global population, causing relatively benign disease in otherwise healthy individuals. On the other hand, EBV represents the first identified oncogenic virus, capable of causing ≥7 different types of malignancies, usually in immunocompromised individuals. Furthermore, some individuals with defined inborn errors of immunity exhibit extreme susceptibility to EBV-induced disease, developing severe and often fatal infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, and/or EBV+ B-cell lymphoma. Thus, host and pathogen have coevolved to enable viral persistence and survival with minimal collateral damage to the healthy host. However, acquired or genetic disruptions to host defense that tip the balance in favor of EBV can have catastrophic effects. The study of primary immunodeficiencies has provided opportunities to define nonredundant requirements for host defense against EBV infection. This has not only revealed mechanisms underlying EBV-induced disease in these primary immunodeficiencies but also identified molecules and pathways that could be targeted to enhance the efficacy of an EBV-specific vaccine or treat severe EBV infection and pathological consequences in immunodeficient hosts.

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency.

BACKGROUND: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. OBJECTIVE: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients. METHODS: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. RESULTS: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8+ T cells had reduced proliferation, impaired expression of IFN-γ and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8+ T-cell activation and cytotoxicity against EBV-infected B cells in vitro. CONCLUSION: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.

Virus-Specific T Cells: Current and Future Use in Primary Immunodeficiency Disorders.

Viral infections are common and can be potentially fatal in patients with primary immunodeficiency disorders (PIDDs). Because viral susceptibility stems from poor to absent T-cell function in most patients with moderate to severe forms of PIDD, adoptive immunotherapy with virus-specific T cells (VSTs) has been used to combat viral infections in the setting of hematopoietic stem cell transplantation in multiple clinical trials. Most trials to date have targeted cytomegalovirus, EBV, and adenovirus either alone or in combination, although newer trials have expanded the number of targeted pathogens. Use of banked VSTs produced from third-party donors has also been studied as a method of expanding access to this therapy. Here we review the clinical experience with VST therapy for patients with PIDDs as well as future potential targets and approaches for the use of VSTs to improve clinical outcomes for this specific patient population.