Mark James Ponsford

Autosomal recessive mutations in TAP1, TAP2, TAPBP, or B2M , are associated with major histocompatibility complex (MHC) class I deficiency. Individuals may present with granulomatous skin ulceration, but the underlying antigenic triggers remain largely unknown. We identified TAP1 deficiency in a 32-year-old female referred with a 7-year history of localized skin ulceration. Histologic immunofluorescence revealed that rubella virus (RuV) infection was a likely driver of the associated inflammation, and modest clinical improvement was observed following topical calcineurin inhibition. To better define the natural history, clinical, and immunological manifestations of this condition, we also performed a scoping literature review. We identified 45 unique individuals from 36 reports with a combined follow-up duration of 1,184 patient years. Chronic necrotizing granulomatous skin lesions and childhood-onset bronchiectasis were common. Five deaths were reported (median age 36 years), typically linked to respiratory complications. Phenotypic heterogeneity was evident, with at least four individuals reaching adulthood without clinical symptoms. Diagnostic delay frequently exceeded a decade amongst symptomatic individuals, with misdiagnosis of granulomatous disease prompting systemic immunosuppression and infection-related morbidity. The presence of an abnormal CD8 ⁺ T-cell count or a history of consanguinity offered low sensitivity for MHC I deficiency (~ 50%), indicating a low threshold for further investigation is required for correct diagnosis. Graphical review of case reports identified morphologically similar lesions in other MHC I-deficient individuals. These findings suggest that the phenomenon of MHC I deficiency is underreported and that diagnosis should prompt testing for RuV.

Background: Limited evidence suggests a link between occult parasites and chronic-spontaneous-urticaria (CSU). This study aimed to evaluate the diagnostic yield of indirect-hem-agglutination (IHA) tests and its clinical impact. Methods: CSU patients were screened for all parasites, including IHA tests for Echinococcus granulosus ( EG ) and Fasciola hepatica ( FH ). Subjects with positive IHA results (group A) were allocated according to the presence of EG (group A1) or FH (group A2). Eighteen controls (group B) from the remaining CSU subjects were randomly selected. Group A received anti-parasitic treatment additionally whereas group B, only CSU treatment. Basal urticaria-control-test (UCT), 7-day-Urticaria-Activity-Score (UAS7), Medication-Score (MS), Chronic-Urticaria-Quality-of-Life-Questionnaire (CU-Q2oL) and laboratory parameters were compared between groups and to follow-up values. Results: Seventeen (group A) out of 1154 patients were infected with EG (n:9, group A1) or FH (n:8 group A2) by IHA. Rural residency, CSU-remission, follow-up UCT and abdominal symptoms (p:0.049, pConclusion: IHA testing for occult parasites may be considered particularly in CSU patients with abdominal symptoms, rural residency, eosinophilia, or elevated total IgE levels and anti-parasitic treatment can improve clinical outcomes.

We first conducted a national service evaluation to determine the outcomes of 2,508 adults with molecularly confirmed SARS-CoV-2 admitted across 18 major hospitals in Wales, representing over 60% of those hospitalised between 1 March and 1 July 2020.

Background: Clozapine is the only licensed pharmacotherapy for patients with treatment-resistant schizophrenia (TRS), but its use is limited due to adverse effects. Clozapine treatment has been recently associated with reductions in immunoglobulin (Ig) levels cross-sectionally, however prospective studies are required to establish longitudinal effects. This study aimed to determine whether reductions in immunoglobulin levels occur over 6 months after initiating clozapine treatment. An exploratory aim was to investigate relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment. Methods: In 56 participants with TRS, Ig A, M and G levels were measured in serum using a sandwich immunoassay. Samples for analysis were acquired prior to starting clozapine and at 6, 12 and 24 weeks after initiating clozapine treatment. Clinical symptoms were measured using the positive and negative syndrome scale for schizophrenia (PANSS). Results: All three classes of Ig decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: B – 32.7, 95% CI = -61.19, -4.2, p = 0.04; IgG: B – 55.94, 95% CI = -111.03, -0.844, p = 0.05). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: B = -21.73, 95% CI = -37.10, -6.35, p = 0.006; 24 weeks: B = -32.54, 95% CI = -48.89, 16.18, p = 0.0001). Changes in both IgA and IgG were correlated with the percentage change in PANSS total scores over 12 weeks, such that greater reductions in IgA and IgG during clozapine treatment were associated with greater reductions in symptom severity (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.50, p = 0.02) Conclusions: The observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. The associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine.

Background: SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome needing intensive care admission and may lead to death. As a virus that transmits by respiratory droplets and aerosols, determining the duration of viable virus shedding from the respiratory tract is critical for patient prognosis, and informs infection control measures both within healthcare settings and the public domain. Methods: We examined upper and lower airway respiratory secretions for both viral RNA and infectious virions in mechanically ventilated patients admitted to the intensive care unit of the University Hospital of Wales. Samples were taken from the oral cavity (saliva), oropharynx (sub-glottic aspirate), or lower respiratory tract (non-directed bronchoalveolar lavage (NBL) or bronchoalveolar lavage (BAL)) and analyzed by both qPCR and plaque assay. Results: 117 samples were obtained from 25 patients. qPCR showed extremely high rates of positivity across all sample types, however live virus was far more common in saliva (68%) than in BAL/NBAL (32%). Average titres of live virus were higher in subglottic aspirates (4.5×10 ⁷ ) than in saliva (2.2×10 ⁶ ) or BAL/NBAL (8.5×10 ⁶ ), and reached >10 ⁸ PFU/ml in some samples. The longest duration of shedding was 98 days, while the majority of patients (14/25) shed live virus for 20 days or longer. Conclusions: Intensive care unit patients infected with SARS-CoV-2 can shed high titres of virus both in the upper and lower respiratory tract, and tend to be prolonged shedders. This information is important for decision making around cohorting patients, de-escalation of PPE, and undertaking potential aerosol generating procedures. Summary: Patients on intensive therapy infected with SARS-CoV-2 tend to be prolonged shedders, excreting virus for far beyond the time periods specified in current guidelines, and live virus titres can be extremely high in both the upper and lower respiratory tracts.

Background: Little is known about the mortality of hospital-acquired (nosocomial) COVID-19 infection globally. We investigated the risk of mortality and critical care admission in hospitalised adults with nosocomial COVID-19, relative to adults requiring hospitalisation due to community-acquired infection.Methods: We systematically reviewed the peer-reviewed and pre-print literature from 1/1/2020 to 9/2/2021 without language restriction for studies reporting outcomes of nosocomial and community-acquired COVID-19. We performed a random effects meta-analysis (MA) to estimate the 1) relative risk of death and 2) critical care admission, stratifying studies by patient cohort characteristics and nosocomial case definition.Results: 21 studies were included in the primary MA, describing 8,251 admissions across 8 countries during the first wave, comprising 1513 probable or definite nosocomial COVID-19, and 6738 community-acquired cases. Across all studies, the risk of mortality was 1.3 times greater in patients with nosocomial infection, compared to community-acquired (95% CI: 1.005 to 1.683). Rates of critical care admission were similar between groups (Relative Risk, RR=0.74, 95% CI: 0.50 to 1.08). Immunosuppressed patients diagnosed with nosocomial COVID-19 were twice as likely to die in hospital as those admitted with community-acquired infection (RR=2.14, 95% CI: 1.76 to 2.61).Conclusions: Adults who acquire SARS-CoV-2 whilst already hospitalised are at greater risk of mortality compared to patients admitted following community-acquired infection; this finding is largely driven by a substantially increased risk of death in individuals with malignancy or who had undergone transplantation. These findings inform public health and infection control policy and argue for individualised clinical interventions to combat the threat of nosocomial COVID-19, particularly for immunosuppressed groups.Systematic Review Registration: PROSPERO CRD42021249023

The burden of nosocomial SARS-CoV-2 infection remains poorly defined. We report on the outcomes of 2508 adults with molecularly-confirmed SARS-CoV-2 admitted across 18 major hospitals, representing over 60% of those hospitalised across Wales between 1 March and 1 July 2020. Inpatient mortality for nosocomial infection ranged from 38% to 42%, consistently higher than participants with community-acquired infection (31%–35%) across a range of case definitions. Those with hospital-acquired infection were older and frailer than those infected within the community. Nosocomial diagnosis occurred a median of 30 days following admission (IQR 21–63), suggesting a window for prophylactic or postexposure interventions, alongside enhanced infection control measures.

Background Little is known about the mortality of hospital-acquired (nosocomial) COVID-19 infection globally. We investigated the risk of mortality and critical care admission in hospitalised adults with nosocomial COVID-19, relative to adults requiring hospitalisation due to community-acquired infection. Methods We systematically reviewed the peer-reviewed and pre-print literature from 1/1/2020 to 9/2/2021 without language restriction for studies reporting outcomes of nosocomial and community-acquired COVID-19. We performed a random effects meta-analysis (MA) to estimate the 1) relative risk of death and 2) critical care admission, stratifying studies by patient cohort characteristics and nosocomial case definition. Results 21 studies were included in the primary MA, describing 8,246 admissions across 8 countries during the first wave, comprising 1517 probable or definite nosocomial COVID-19, and 6729 community-acquired cases. Across all studies, the risk of mortality was 1.31 times greater in patients with nosocomial infection, compared to community-acquired (95% CI: 1.01 to 1.70). Rates of critical care admission were similar between groups (Relative Risk, RR=0.74, 95% CI: 0.50 to 1.08). Immunosuppressed patients diagnosed with nosocomial COVID-19 were twice as likely to die in hospital as those admitted with community-acquired infection (RR=2.14, 95% CI: 1.76 to 2.61). Conclusions Adults who acquire SARS-CoV-2 whilst already hospitalised are at greater risk of mortality compared to patients admitted following community-acquired infection; this finding is largely driven by a substantially increased risk of death in individuals with malignancy or who had undergone transplantation. These findings inform public health and infection control policy, and argue for individualised clinical interventions to combat the threat of nosocomial COVID-19, particularly for immunosuppressed groups. Systematic review registration: PROSPERO CRD42021249023