IntroductionBesides recurrent infections, a proportion of patients with Common Variable Immunodeficiency Disorders (CVID) may suffer from immune dysregulation such as granulomatous-lymphocytic interstitial lung disease (GLILD). The optimal treatment of this complication is currently unknown. Experienced-based expert opinions have been produced, but a systematic review of published treatment studies is lacking.GoalsTo summarize and synthesize the published literature on the efficacy of treatments for GLILD in CVID.MethodsWe performed a systematic review using the PRISMA guidelines. Papers describing treatment and outcomes in CVID patients with radiographic and/or histologic evidence of GLILD were included. Treatment regimens and outcomes of treatment were summarized.Results6124 papers were identified and 42, reporting information about 233 patients in total, were included for review. These papers described case series or small, uncontrolled studies of monotherapy with glucocorticoids or other immunosuppressants, rituximab monotherapy or rituximab plus azathioprine, abatacept, or hematopoietic stem cell transplantation (HSCT). Treatment response rates varied widely. Cross-study comparisons were complicated because different treatment regimens, follow-up periods, and outcome measures were used. There was a trend towards more frequent GLILD relapses in patients treated with corticosteroid monotherapy when compared to rituximab-containing treatment regimens based on qualitative endpoints. HSCT is a promising alternative to pharmacological treatment of GLILD, because it has the potential to not only contain symptoms, but also to resolve the underlying pathology. However, mortality, especially among immunocompromised patients, is high.ConclusionsWe could not draw definitive conclusions regarding optimal pharmacological treatment for GLILD in CVID from the current literature since quantitative, well-controlled evidence was lacking. While HSCT might be considered a treatment option for GLILD in CVID, the risks related to the procedure are high. Our findings highlight the need for further research with uniform, objective and quantifiable endpoints. This should include international registries with standardized data collection including regular pulmonary function tests (with carbon monoxide-diffusion), uniform high-resolution chest CT radiographic scoring, and uniform treatment regimens, to facilitate comparison of treatment outcomes and ultimately randomized clinical trials.
Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.
Granulomatous–lymphocytic interstitial lung disease (GLILD) has been defined as “a distinct clinico-radio-pathological ILD [interstitial lung disease] occurring in patients with CVID [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded… usually seen in the context of multisystem granulomatous/inflammatory involvement” [1]. The immune and inflammatory complications of CVID such as GLILD are important and associated with reduced survival [2]. However, as a rare manifestation of a rare disease, the scientific understanding and evidence basis to inform effective diagnosis and management of GLILD [3] are limited. There are challenges with the definition of GLILD presented above and the terminology more widely of ILD in people with CVID, which requires further consensus. In this manuscript, we use the term GLILD to describe the heterogeneous ILD seen as part of multisystem immune dysregulation in a substantial minority of people with CVID. A recent international survey of clinicians found little uniformity in diagnostic and therapeutic interventions, identifying an urgent need for new evidence to support consensus guidance [4]. In 2019, the European Respiratory Society (ERS) established a Clinical Research Collaboration to address GLILD (eGLILDnet) [5]. eGLILDnet aims to promote the exchange of research ideas among clinicians and scientists in order to plan, conduct, evaluate and publish clinical and translational studies. Better evidence to diagnose and manage GLILD requires new multicentre research and to this end, we have conducted and here report the results of an international research prioritisation exercise in GLILD. This was a partnership between multiprofessional clinicians and people living with GLILD.
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