Clinical and humoral response after SARS-CoV-2 breakthrough infection in patients receiving immunosuppressant therapy.

BACKGROUND: Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking. OBJECTIVES: We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls. METHODS: As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection. RESULTS: We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases. CONCLUSIONS: Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.

Immune checkpoint inhibitor-mediated polymyalgia rheumatica versus primary polymyalgia rheumatica: comparison of disease characteristics and treatment requirement.

OBJECTIVES: To compare clinical characteristics, imaging findings and treatment requirements of patients with immune checkpoint inhibitor-mediated polymyalgia rheumatica (ICI-PMR) and primary PMR. METHODS: This single centre, retrospective cohort study compared ICI-PMR in patients with cancer (n = 15) to patients with primary PMR (n = 37). A comparison was made between clinical symptoms, laboratory markers, ultrasonography,18F-FDG-PET/CT findings and treatment requirements related to PMR. RESULTS: Patients with ICI-PMR less frequently fulfilled the EULAR/ACR classification criteria for PMR (66.7%) than patients with primary PMR (97.3%). Morning stiffness, weight loss and elevation of the ESR were less frequently seen in patients with ICI-PMR. No differences were observed regarding the presence of inflammatory lesions on ultrasound of the shoulders and hips between the two groups. The Leuven and the Leuven/Groningen 18F-FDG-PET/CT scores were significantly lower in the ICI-PMR group. Finally, the ICI-PMR group could be managed with less glucocorticoids than the primary PMR group. CONCLUSION: Our findings indicate that ICI-PMR may have a milder course with less inflammation than primary PMR on 18F-FDG-PET/CT. ICI-mediated PMR patients can be managed with a relatively low glucocorticoid dose. Our study underscores that ICI-PMR should be regarded as PMR-like syndrome.

Neurological phenotype of adenosine deaminase 2 deficient patients: a cohort study.

BACKGROUND AND PURPOSE: Patients with adenosine deaminase 2 (ADA2) deficiency can present with various neurological manifestations due to vasculopathies and autoinflammation. These include ischaemic and hemorrhagic stroke, but less clearly defined neurological symptoms have also been reported. METHODS: In this cohort study, patients with confirmed ADA2 deficiency from seven university hospitals in the Netherlands were included. The frequency and recurrence rates of neurological manifestations before and after initiation of tumor necrosis factor α (TNF-α) inhibiting therapy were analyzed. RESULTS: Twenty-nine patients were included with a median age at presentation of 5 years (interquartile range 1-17). Neurological manifestations occurred in 19/29 (66%) patients and were the presenting symptom in 9/29 (31%) patients. Transient ischaemic attack (TIA)/ischaemic stroke occurred in 12/29 (41%) patients and was the presenting symptom in 8/29 (28%) patients. In total, 25 TIAs/ischaemic strokes occurred in 12 patients, one after initiation of TNF-α inhibiting therapy and one whilst switching between TNF-α inhibitors. None was large-vessel occlusion stroke. Two hemorrhagic strokes occurred: one aneurysmatic subarachnoid hemorrhage and one spontaneous intracerebral hemorrhage. Most neurological symptoms, including cranial nerve deficits, vertigo, ataxia and seizures, were caused by TIAs/ischaemic strokes and seldom recurred after initiation of TNF-α inhibiting therapy. CONCLUSIONS: Neurological manifestations, especially TIA/ischaemic stroke, are common in patients with ADA2 deficiency and frequently are the presenting symptom. Because it is a treatable cause of young stroke, for which antiplatelet and anticoagulant therapy are considered contraindicated, awareness amongst neurologists and pediatricians is important. Screening for ADA2 deficiency in young patients with small-vessel ischaemic stroke without an identified cause should be considered.

The link between the early surgery-induced inflammatory response and postoperative cognitive dysfunction in older patients.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication in older patients with cancer and is associated with decreased quality of life and increased disability and mortality rates. Systemic inflammation resulting in neuroinflammation is considered important in the pathogenesis of POCD. The aim of this study was to explore the association between the early surgery-induced inflammatory response and POCD within 3 months after surgery in older cancer patients. METHODS: Patients ≥65 years in need of surgery for a solid tumor were included in a prospective cohort study. Plasma levels of C-reactive protein (CRP), interleukin-1 beta (IL-1ß), IL-6, IL-10, and Neutrophil gelatinase-associated lipocalin (NGAL) were measured perioperatively. Cognitive performance was assessed preoperatively and 3 months after surgery. POCD was defined as a decline in cognitive test scores of ≥25% on ≥2 of five tests within the different cognitive domains of memory, executive functioning, and information processing speed. Logistic regression analysis was performed. RESULTS: POCD was observed in 44 (17.7%) of 248 included patients. Age >75, preoperative Mini-Mental State Examination (MMSE) score ≤26 and major surgery were independent significant predictors for POCD. In multivariate logistic regression analysis, no significant associations were shown between the early surgery-induced inflammatory response and either POCD or decline within the different cognitive domains. CONCLUSIONS: This study shows that one out of six older patients with cancer developed POCD within 3 months after surgery. The early surgery-induced inflammatory response was neither associated with POCD, nor with decline in the separate cognitive domains. Further research is necessary for better understanding of the complex etiology of POCD.

Immunogenicity of COVID-19 booster vaccination in IEI patients and their one year clinical follow-up after start of the COVID-19 vaccination program.

Purpose: Previous studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign. Methods: This study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections. Results: After booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer. Conclusion: Our study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.

Baseline Blood CD8+ T Cell Activation Potency Discriminates Responders from Non-Responders to Immune Checkpoint Inhibition Combined with Stereotactic Radiotherapy in Non-Small-Cell Lung Cancer.

BACKGROUND: Tumor-infiltrating immune cells have been correlated with prognosis for patients treated with immune checkpoint inhibitor (ICI) treatment of various cancers. However, no robust biomarker has been described to predict treatment response yet. We hypothesized that the activation potency of circulating T cells may predict response to ICI treatment. METHODS: An exploratory analysis was conducted to investigate the association between the response to immune checkpoint inhibition (ICI) combined with stereotactic radiotherapy (SBRT) and the potency of circulating T cells to be activated. Blood-derived lymphocytes from 14 patients were stimulated ex vivo with, among others, Staphylococcal enterotoxin B (SEB) and compared to healthy controls (HCs). Patients were grouped into responders (>median progression free survival (PFS)) and non-responders (