Characteristics and outcomes of older patients hospitalised for COVID-19 in the first and second wave of the pandemic in The Netherlands: the COVID-OLD study.

BACKGROUND: as the coronavirus disease of 2019 (COVID-19) pandemic progressed diagnostics and treatment changed. OBJECTIVE: to investigate differences in characteristics, disease presentation and outcomes of older hospitalised COVID-19 patients between the first and second pandemic wave in The Netherlands. METHODS: this was a multicentre retrospective cohort study in 16 hospitals in The Netherlands including patients aged ≥ 70 years, hospitalised for COVID-19 in Spring 2020 (first wave) and Autumn 2020 (second wave). Data included Charlson comorbidity index (CCI), disease severity and Clinical Frailty Scale (CFS). Main outcome was in-hospital mortality. RESULTS: a total of 1,376 patients in the first wave (median age 78 years, 60% male) and 946 patients in the second wave (median age 79 years, 61% male) were included. There was no relevant difference in presence of comorbidity (median CCI 2) or frailty (median CFS 4). Patients in the second wave were admitted earlier in the disease course (median 6 versus 7 symptomatic days; P < 0.001). In-hospital mortality was lower in the second wave (38.1% first wave versus 27.0% second wave; P < 0.001). Mortality risk was 40% lower in the second wave compared with the first wave (95% confidence interval: 28-51%) after adjustment for differences in patient characteristics, comorbidity, symptomatic days until admission, disease severity and frailty. CONCLUSIONS: compared with older patients hospitalised in the first COVID-19 wave, patients in the second wave had lower in-hospital mortality, independent of risk factors for mortality.The better prognosis likely reflects earlier diagnosis, the effect of improvement in treatment and is relevant for future guidelines and treatment decisions.

TLR2, TLR4 and TLR9 genotypes and haplotypes in the susceptibility to and clinical course of Chlamydia trachomatis infections in Dutch women.

Chlamydia trachomatis infections demonstrate remarkable differences in clinical course that are approximately 40% based on host genetic variation. Here, we study the single nucleotide polymorphisms (SNPs) and their haplotypes in TLR2, TLR4 and TLR9 (TLR2 +2477G>A; TLR2 -16934T>A; TLR4+896A>G; TLR9 -1237T>C and TLR9 +2848G>A) in relation to the susceptibility to, and severity of C. trachomatis infections. We analysed the five SNPs in a cohort of 770 Dutch Caucasian women either attending a sexually transmitted diseases outpatient clinic (n = 731) or having complaints of subfertility (n = 39). Haplotype analyses showed a trend for TLR2 haplotype I (-16934T/+2477G) to protect against the development of symptoms and tubal pathology (Ptrend = 0.03) after Chlamydia infection. In the susceptibility cohort, TLR9 haplotype III (-1237C/+2848A) showed a significant decreasing trend in the development of symptoms after C. trachomatis infection (P = 0.02, OR: 0.55, 95%CI: 0.33-0.91). Logistic regression of the TLR2 haplotypes, TLR4+896A>G, and TLR9 haplotypes showed that the TLR2 haplotype combinations AG-TA and AG-TG confer risk (OR 3.4 (P = 0.01) and 1.6 (P = 0.03)), while the TLR9 haplotype combination TG-TA protects against C. trachomatis infections (OR: 0.4, P = 0.004). Our study shows that both TLR2 and TLR9 genes and SNP combinations do influence the clinical course of Chlamydia infections.

Heterogeneous imaging characteristics of JC virus granule cell neuronopathy (GCN): a case series and review of the literature.

Granule cell neuronopathy (GCN) is a rare JC virus (JCV)-related disease in immunocompromised patients, characterized by lytic infection of the cerebellar granule cell layer. To enable early diagnosis and intervention, we identify features of GCN and describe possible aspects of disease heterogeneity. We report on two new cases of GCN in HIV-infected patients of whom we retrospectively assessed clinical and radiologic data. In addition, we carried out a literature search and review of clinical, radiologic and histopathologic findings of all published GCN cases. Including the two new cases reported here, a total of 18 GCN cases were included in this study. HIV infection, present in 12 of the cases, was the most common underlying condition, followed by monoclonal antibody treatment which was present in three cases. Cerebellar atrophy was detected in all except two cases. In 12 patients a heterogeneous distribution pattern of white matter changes in the cerebellum and brainstem was observed. Imaging findings in GCN are remarkably heterogeneous; exhibiting cerebellar atrophy, as well as white matter pathology, particularly in the adjacent infratentorial white matter. This suggests an overlap of GCN with other JCV-related diseases, such as progressive multifocal leukoencephalopathy.

Interruption of CXCL13-CXCR5 axis increases upper genital tract pathology and activation of NKT cells following chlamydial genital infection.

BACKGROUND: Regulation of immune responses is critical for controlling inflammation and disruption of this process can lead to tissue damage. We reported that CXCL13 was induced in fallopian tube tissue following C. trachomatis infection. Here, we examined the influence of the CXCL13-CXCR5 axis in chlamydial genital infection. METHODOLOGY AND PRINCIPAL FINDINGS: Disruption of the CXCL13-CXCR5 axis by injecting anti-CXCL13 Ab to BALB/c mice or using Cxcr5-/- mice increased chronic inflammation in the upper genital tract (UGT; uterine horns and oviducts) after Chlamydia muridarum genital infection (GT). Further studies in Cxcr5-/- mice showed an elevation in bacterial burden in the GT and increased numbers of neutrophils, activated DCs and activated NKT cells early after infection. After resolution, we noted increased fibrosis and the accumulation of a variety of T cells subsets (CD4-IFNγ, CD4-IL-17, CD4-IL-10 & CD8-TNFα) in the oviducts. NKT cell depletion in vitro reduced IL-17α and various cytokines and chemokines, suggesting that activated NKT cells modulate neutrophils and DCs through cytokine/chemokine secretion. Further, chlamydial glycolipids directly activated two distinct types of NKT cell hybridomas in a cell-free CD1d presentation assay and genital infection of Cd1d-/- mice showed reduced oviduct inflammation compared to WT mice. CXCR5 involvement in pathology was also noted using single-nucleotide polymorphism analysis in C. trachomatis infected women attending a sub-fertility clinic. Women who developed tubal pathology after a C. trachomatis infection had a decrease in the frequency of CXCR5 SNP +10950 T>C (rs3922). CONCLUSIONS/SIGNIFICANCE: These experiments indicate that disruption of the CXCL13-CXCR5 axis permits increased activation of NKT cells by type I and type II glycolipids of Chlamydia muridarum and results in UGT pathology potentially through increased numbers of neutrophils and T cell subsets associated with UGT pathology. In addition, CXCR5 appears to contribute to inter-individual differences in human tubal pathology following C. trachomatis infection.

Distribution of peroxisome proliferator-activated receptor-gamma polymorphisms in Chinese and Dutch patients with inflammatory bowel disease.

BACKGROUND: As peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is frequently expressed in colon, its genetic polymorphism may play a role in the etiology of inflammatory bowel disease (IBD). The aims of the present study were to determine the distribution of PPAR-gamma polymorphisms Pro12Ala and C161T and to explore the association between the PPAR-gamma genotypes and phenotypes of IBD patients. METHODS: A total of 244 IBD patients [212 ulcerative colitis (UC) and 32 Crohn's disease (CD)] and 220 controls in the Chinese population and 603 IBD patients (302 UC and 301 CD) and 180 controls in the white Dutch population were enrolled in the study. The phenotypes of Chinese IBD patients were grouped according to disease location. The PPAR-gamma polymorphisms Pro12Ala and C161T were genotyped by PCR-based methods. RESULTS: In the Chinese population, T carriers of the PPAR-gamma C161T polymorphism were more common in UC patients than in the controls [37.7% vs. 25.5%, odds ratio 1.77, 95% confidence interval 1.18-2.68, P = 0.007], whereas Ala carriers of the Pro12Ala polymorphism showed no significant association in UC patients, but there was a significant association of Ala carriers with more extensive disease among the UC patients (P = 0.002); Pro12Ala and C161T genotypes did not show any associations with CD patients. No associations were found for the PPAR-gamma C161T SNP studied in the Dutch IBD population. CONCLUSIONS: Our study showed the potential association between the PPAR-gamma C161T polymorphism and UC patients in the central Chinese population. This finding was not replicated in the Dutch population. Further studies are necessary to explore the functional implication of the PPAR-gamma C161T polymorphism in Chinese UC patients.

Chlamydia trachomatis: identification of susceptibility markers for ocular and sexually transmitted infection by immunogenetics.

The aim of this review is to present a concise overview of all data available on the immunogenetics of Chlamydia trachomatis infections, both sexually transmitted urogenital and ocular infections. Currently, candidate gene approaches are used to identify genes related to the susceptibility to and severity of C. trachomatis infections. The main focus in the review will be on data obtained by the study of human cohorts.

Indications and challenges of probiotics, prebiotics, and synbiotics in the management of arthralgias and spondyloarthropathies in inflammatory bowel disease.

Arthralgia and spondyloarthropathy of the peripheral and the axial joints are common in patients with inflammatory bowel diseases. Evidence for this association has been provided by clinical, epidemiologic, and immunologic studies confirming the presence of shared inflammatory pathways in gut and joint. Bacterial gut infections such as Salmonella typhimurium, Yersinia enterocolitica, Shigella, Campylobacter jejuni may induce reactive peripheral arthritis and 20% of these patients may develop chronic spondyloarthropathy. It is not certain that arthralgias in inflammatory bowel diseases are more frequent than in the general population but clinical articular manifestations compatible with spondyloarthropathy are present in 10% to 40% of patients with inflammatory bowel diseases. These enteropathic peripheral arthropathies without axial involvement are subdivided into a pauciarticular of large joints and a bilateral symmetrical polyarthropathy. The rationale and the challenges of using prebiotics, probiotics, and synbiotics in the management of patients with inflammatory bowel diseases with arthralgias and spondyloarthropathy are briefly reviewed. The rationale is based on the modulation of the ubiquitous intestinal flora by bacteria and their products that have been proven to be safe. The challenge is to find the "window of opportunity" to treat the evolutionary stage of joint inflammation. It seems to us that the major aim is not to treat patients who have a self-limited inflammatory joint disorder, but those patients with persistent arthralgias in an early phase of the disease. Seronegative and seropositive patients with early arthritis, before damage may occur, could be managed by this approach to improve the quality of life and to positively influence the natural course of the disease.

Probiotics (VSL#3) in arthralgia in patients with ulcerative colitis and Crohn's disease: a pilot study.

Arthralgia is a common extraintestinal manifestation of inflammatory bowel disease (IBD). Alterations of the immunologic regulation in the gut may contribute to the pathogenesis of arthralgia. Probiotics (VSL#3) have proven effective in the treatment of pouchitis in patients with ileal pouch anal anastomosis after panproctocolectomy for ulcerative colitis both in maintaining remission and in preventing a flare-up without side effects. The aim of this study was to determine the safety and efficacy of VSL#3 in patients with quiescent IBD who suffered from arthralgia for more than two weeks. An open-label trial was conducted using VSL#3. Pre- and post-treatment joint pain intensity were measured on the Ritchie Articular Index and visual analog scale. Disease activity of the bowel was assessed by the Truelove-Witts and the Harvey-Bradshaw scores. Sixteen of 29 patients completed the trial; in 10 of the 16 patients a statistically significant improvement was documented by the Ritchie Articular Index. No one of the patients had a relapse of intestinal disease while on probiotics. These preliminary results suggest that the probiotic mixture VSL#3 may be an alternative treatment for arthralgia in patients with IBD without inducing exacerbation of the disease. Because probiotics may be effective in the treatment of IBD as well, our results suggest that patients with active disease and arthralgia may also derive benefit from this treatment. Proper randomized controlled studies are indicated.