Attenuated humoral responses in HIV after SARS-CoV-2 vaccination linked to B cell defects and altered immune profiles.

We assessed a cohort of people living with human immunodeficiency virus (PLWH) (n = 110) and HIV negative controls (n = 64) after 1, 2 or 3 SARS-CoV-2 vaccine doses. At all timepoints, PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs). Improved neutralization breadth was seen against the Omicron variant (BA.1) after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global MBC dysfunction. In contrast, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, individuals with low or absent neutralization had detectable functional T cell responses. These PLWH had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3+CD127+CD8+T cells after two doses of SARS-CoV-2 vaccination.

Attenuated humoral responses in HIV infection after SARS-CoV-2 vaccination are linked to global B cell defects and cellular immune profiles.

People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can have residual immune dysfunction and often display poorer responses to vaccination. We assessed in a cohort of PLWH (n=110) and HIV negative controls (n=64) the humoral and spike-specific B-cell responses following 1, 2 or 3 SARS-CoV-2 vaccine doses. PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls at all studied timepoints. Moreover, their neutralization breadth was reduced with fewer individuals developing a neutralizing response against the Omicron variant (BA.1) relative to controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs) and pronounced B cell dysfunction. Improved neutralization breadth was seen after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global, but not spike-specific, MBC dysfunction. In contrast to the inferior antibody responses, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, a subset of PLWH with low or absent neutralization had detectable functional T cell responses. These individuals had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3 + CD127 + CD8 + T cells after two doses of SARS-CoV-2 vaccination, which may compensate for sub-optimal serological responses in the event of infection. Therefore, normalisation of B cell homeostasis could improve serological responses to vaccines in PLWH and evaluating T cell immunity could provide a more comprehensive immune status profile in these individuals and others with B cell imbalances.

Improving the accuracy of clinical interpretation of serological testing for the diagnosis of acute hepatitis a infection.

BACKGROUND: Hepatitis A (HA) remains a common infection globally that results in a self-limiting hepatitis with gastrointestinal and systemic symptoms. Direct detection of the virus in blood or stool is often not possible once symptomatic. Serological testing is frequently performed to investigate abnormal liver function tests - and interpretation of equivocal and low-level positive anti-hepatitis A virus (HAV) IgM is difficult even in the context of accurate epidemiological and clinical information. OBJECTIVES: The aim of this project was to characterise the association between low-level reactive anti-HAV IgM results and clinical disease. STUDY DESIGN: Anti-HAV serology results recorded over 22 months were analysed. Equivocal and positive Architect anti-HAV IgM results were matched with available clinical and demographical data to identify confirmed and probable cases of acute HAV infection. RESULTS: Reactive anti-HAV IgM results were recorded for 88/7661 (1.15%) samples. Using clinical and laboratory data, 35 patients were confirmed to have acute HAV infection. Acute HA was associated with a mean Architect anti-HAV IgM value of 9.4 (SD 6.8-12.0). Cases of HA had a mean peak ALT value of 1920 (SD 682-3158). All confirmed cases (35/35) of acute HAV were associated with at least one clinical indicator, with 28/31 cases (90%) having a documented jaundice. All 35 (100%) cases of acute HAV infection had anti-HAV IgM > 4.0. A diagnosis other than acute HA was identified in 7/11 (63.6%) of low-level reactive anti-HAV IgM results (clinical data unavailable for further 4/11, 36.3%). Where clinical information was available, acute HA was excluded in all 31 patients with equivocal or low-level reactive anti-HAV IgM results. CONCLUSIONS: The accuracy of reports sent out to the clinician showed room for improvement. An interpretive algorithm is proposed including a clinically significant cut-off value for anti-HAV IgM.

SARS-CoV-2 immunity and vaccine strategies in people with HIV.

Current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines, based on the ancestral Wuhan strain, were developed rapidly to meet the needs of a devastating global pandemic. People living with Human Immunodeficiency Virus (PLWH) have been designated as a priority group for SARS-CoV-2 vaccination in most regions and varying primary courses (two- or three-dose schedule) and additional boosters are recommended depending on current CD4+ T cell count and/or detectable HIV viraemia. From the current published data, licensed vaccines are safe for PLWH, and stimulate robust responses to vaccination in those well controlled on antiretroviral therapy and with high CD4+ T cell counts. Data on vaccine efficacy and immunogenicity remain, however, scarce in PLWH, especially in people with advanced disease. A greater concern is a potentially diminished immune response to the primary course and subsequent boosters, as well as an attenuated magnitude and durability of protective immune responses. A detailed understanding of the breadth and durability of humoral and T cell responses to vaccination, and the boosting effects of natural immunity to SARS-CoV-2, in more diverse populations of PLWH with a spectrum of HIV-related immunosuppression is therefore critical. This article summarizes focused studies of humoral and cellular responses to SARS-CoV-2 infection in PLWH and provides a comprehensive review of the emerging literature on SARS-CoV-2 vaccine responses. Emphasis is placed on the potential effect of HIV-related factors and presence of co-morbidities modulating responses to SARS-CoV-2 vaccination, and the remaining challenges informing the optimal vaccination strategy to elicit enduring responses against existing and emerging variants in PLWH.

A Springboard for physicians returning to practice.

BACKGROUND: Many physicians take time out of training and have decreased confidence and poor performance ratings on their return. Courses employing multiple educational methods have been shown to be effective in easing learners into new clinical roles during transition periods but, to date, there is limited evidence for courses to support trainees returning to practice (RTP). METHODS: A 2-day course, named Springboard, was developed, specifically to address the needs of trainee physicians RTP. It employed a blended, multi-modal approach to learning, including lectures, workshops, case-based sessions, interactive panel discussions, small group teaching, peer-led practical advice sessions and simulation training. Springboard was delivered eight times between 2014 and 2019 with a total of 540 doctors attending. We analysed participant pre-and post-course questionnaire feedback. RESULTS: Reasons for doctors taking time out of training included parental leave, research, fellowships in education and leadership, health-related absence and career breaks. Time out of training ranged between 3 months and 6 years. A significant pre/post-course increase in candidates' self-reported leadership skills and confidence in being prepared to return to practice was demonstrated alongside an appreciation of a multi-modal, 'boot camp' course delivered by expert faculty and a networking experience. DISCUSSION: Dedicated training courses tailored to the needs of physicians RTP provide an opportunity for improving confidence relating to many areas of clinical and non-clinical practice as well as providing an environment for networking and sharing experiences. Further work would be valuable to establish the potential of providing this on a larger scale.

Presentations and outcomes of central nervous system TB in a UK cohort: The high burden of neurological morbidity.

OBJECTIVES: Most data for Central Nervous System Tuberculosis (CNS-TB) derive from high-incidence, resource-limited countries. We sought to determine the presentation, management and outcomes of CNS-TB in a low-incidence setting with accessible healthcare. METHODS: We undertook a retrospective, observational study of CNS-TB in adults at a single tertiary-referral London hospital (2001-2017). Cases were categorised as either TB meningitis (TBM) or TB mass lesions without meningitis (TBML), applying novel criteria for definite, probable, and possible TBML. RESULTS: We identified sixty-two cases of TBM (37% definite; 31% probable; 32% possible) alongside 14 TBML cases (36% definite; 29% probable; and 36% possible). Clinical presentation was highly variable. Among CSF parameters, hypoglycorrhachia proved most discriminatory for "definite" TBM. Neurosurgical intervention was required for mass-effect or hydrocephalus in 16%. Mortality was higher in TBM versus TBML (16% vs. 0%) but overall morbidity was significant; 33% of TBM and 29% of TBML survivors suffered persisting neurological disability at 12-months. In TBM, hydrocephalus, infarct, basal enhancement and low CSF white cell count were independently associated with worse neurological outcomes. CONCLUSION: Although mortality was lower than previously reported in other settings, morbidity was significant, highlighting the need for improved CNS-TB diagnostics, therapeutics and interventions to mitigate neurological sequelae.

Evaluation of training programmes mapped to the new internal medicine curriculum.

In preparation for the internal medicine training (IMT) programme introduced in 2019, the core medical training (CMT) programme in London was made 'IMT-ready' in 2018 by creating new rotations that reflected the compulsory requirements of the first 2 years of the IMT curriculum, including provision of the requisite number of critical care placements. Core medical trainees completed posts within the 'IMT-ready' programme between August 2018 and August 2019, during which time the trainee experience was evaluated. A total of 497 responses were received. Of these, 96% of trainees were on an 'acute unselected take' on-call rota, 79% were able to attend outpatient clinics, 80% had the opportunity to practise procedural skills and 88% had the opportunity to apply palliative care skills. Clear areas for improvement were identified that predominantly focused on the need to optimise trainee attendance of outpatient clinics and the number of patients seen during an acute take. With respect to future career intentions, only 63% of trainees planned on applying to a group 1 (with general medicine) higher medical specialty. Thematic analysis of trainees in critical care placements highlighted an appreciation of the level of senior support, feeling well integrated into the team, a positive experience of induction and excellent opportunities for performing procedures.

Abdominal tuberculosis: Diagnosis and demographics, a 10-year retrospective review from a single centre.

AIM: To review all cases of abdominal tuberculosis (ATB) for demographic details, diagnostic work up and evidence of vitamin D deficiency. METHODS: This was a retrospective analysis of all patients diagnosed with ATB from June 2003 to August 2013 at St George's Hospital, London. Demographic data was available from the local tuberculosis database. Further clinical information was collected from electronic patient records, including radiology, endoscopy, microbiology, histology, biochemistry and serology. Patients were classified as either confirmed ATB [if mycobacteria tuberculosis (MTB) was cultured from abdominal site] or presumed ATB (if suggestive findings or high clinical suspicion). Subtypes of ATB were classified as tuberculosis (TB) peritonitis, luminal TB, solid organ TB or from a combination of sites. RESULTS: There were a total of 65 cases identified in this time period, with a mean of 6.5 cases per year (range 4-9). Mean age 42 years, 49.2% females. Fifty-two point three percent were South Asian, 38.5% African. Forty-nine point two percent had gastrointestinal endoscopy, 30.8% paracentesis and 24.6% surgery in order to obtain samples. Forty-seven point seven percent were defined as confirmed ATB with positive culture of MTB from abdominal sites, the rest were treated as presumed ATB. Twenty-four point six percent had co-existing sputum culture positive for MTB, and 30.8% had an abnormal chest X-ray. Subtypes of ATB: 35.4% had TB peritonitis; 27.7% luminal TB; 3.1% solid organ TB; and 33.8% TB at a combination of abdominal sites. Thirteen point nine percent were human immunodeficiency virus positive, all with CD4 count less than 300 cells/µL. Seventy point five percent had severe vitamin D deficiency, and 25% were vitamin D deficient. CONCLUSION: ATB mainly affects young South Asian and African patients, with difficulties in confirming diagnosis despite a range of non-invasive and invasive diagnostic tests.