High pretreatment disease burden as a risk factor for infectious complications following CD19 chimeric antigen receptor T-cell therapy for large B-cell lymphoma.

Infection has emerged as the chief cause of non-relapse mortality (NRM) post CD19-targeting chimeric antigen receptor T-cell therapy (CAR-T) therapy. Even though up to 50% of patients may remain infection-free, many suffer multiple severe, life-threatening, or fatal infectious events. The primary aim of this study was to explore severe and life-threatening infections post licensed CAR-T therapy in large B-cell lymphoma, with a focus on the role of disease burden and disease sites in assessing individual risk. We sought to understand the cohort of patients who experience ≥2 infections and those at the highest risk of infectious NRM. Our analysis identifies a higher disease burden after bridging therapy as associated with infection events. Those developing ≥2 infections emerged as a uniquely high-risk cohort, particularly if the second (or beyond) infection occurred during an episode of immune effector cell-associated neurotoxicity syndrome (ICANS) or while on steroids and/or anakinra for ICANS. Herein, we also describe the first reported cases of "CAR-T cold sepsis," a phenomenon characterized by the lack of an appreciable systemic inflammatory response at the time of detection of infection. We propose a risk-based strategy to encourage heightened clinician awareness of cold sepsis, with a view to reducing NRM.

Community-acquired Staphylococcus aureus bacteraemia among people who inject drugs: a national cohort study in England, 2017-2020.

BACKGROUND: People who inject drugs (PWID) are at increased risk of community-acquired Staphylococcus aureus bacteraemia (CA-SAB), but little is known about clinical outcomes of CA-SAB in PWID compared with the wider population of patients with CA-SAB. METHODS: Three national datasets were linked to provide clinical and mortality data on patients hospitalised with CA-SAB in England between 1 January 2017 and 31 December 2020. PWID were identified using the ICD-10 code for "mental health and behavioural disorder due to opioid use" (F11). Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) for associations of PWID with 30-day all-cause mortality and 90-day hospital readmission. RESULTS: In 10,045 cases of CA-SAB, 1,612 (16.0%) were PWID. Overall, 796 (7.9%) patients died within 30 days of CA-SAB admission and 1,189 (11.8%) patients were readmitted to hospital within 90 days of CA-SAB. In those without infective endocarditis there was strong evidence of lower odds of mortality among PWID compared with non-PWID (aOR: 0.47, 95% confidence interval, CI: 0.33-0.68, p < 0.001) whereas there was no association in CA-SAB case fatality with endocarditis (aOR 1.40, CI 0.87-2.25, p = 0.163). PWID were less likely to be re-admitted within 90 days of CA-SAB (aOR 0.79, CI 0.65-0.95, p = 0.011). CONCLUSIONS: In this large cohort study of patients with CA-SAB in England, PWID had lower odds of death in the absence of endocarditis and lower odds of re-admission within 90 days compared to non-PWID patients. This study highlights the over-representation of PWID among patients with CA-SAB nationally.

Correction: The increasing incidence of visceral leishmaniasis relapse in South Sudan: A retrospective analysis of field patient data from 2001-2018.

[This corrects the article DOI: 10.1371/journal.pntd.0010696.].

Steps towards eliminating Hansen's disease stigma.

Persons affected by Hansen's disease (PAHD) can develop long-term physical disabilities and psychological problems if the disease is not managed promptly and correctly. The complex and multi-faceted nature of stigma related to Hansen's Disease, and the discrimination arising from it, demands multiple parallel steps to improve the health, well-being and lived experience of People Affected by Hansen's Disease, including: 1) adoption and pursuance of a human rights based approach; 2) revocation of discriminatory laws; 3) education and training for healthcare workers; 4) new techniques and therapies to diagnose and treat HD without side-effects and to reduce risk of disabilities; 5) elimination of stigmatising terminology.

Attribution of nosocomial seeding to long-term care facility COVID-19 outbreaks.

Residents of long-term care facilities (LTCFs) were disproportionately affected by the COVID-19 pandemic. We assessed the extent to which hospital-associated infections contributed to COVID-19 LTCF outbreaks in England. We matched addresses of cases between March 2020 and June 2021 to reference databases to identify LTCF residents. Linkage to health service records identified hospital-associated infections, with the number of days spent in hospital before positive specimen date used to classify these as definite or probable. Of 149,129 cases in LTCF residents during the study period, 3,748 (2.5%) were definite or probable hospital-associated and discharged to an LTCF. Overall, 431 (0.3%) were identified as index cases of potentially nosocomial-seeded outbreaks (2.7% (431/15,797) of all identified LTCF outbreaks). These outbreaks involved 4,521 resident cases and 1,335 deaths, representing 3.0% and 3.6% of all cases and deaths in LTCF residents, respectively. The proportion of outbreaks that were potentially nosocomial-seeded peaked in late June 2020, early December 2020, mid-January 2021, and mid-April 2021. Nosocomial seeding contributed to COVID-19 LTCF outbreaks but is unlikely to have accounted for a substantial proportion. The continued identification of such outbreaks after the implementation of preventative policies highlights the challenges of preventing their occurrence.

Chest CT features and functional correlates of COVID-19 at 3 months and 12 months follow-up.

Long-term pulmonary sequelae of Coronavirus 2019 (COVID-19) remain unclear. Thus, we aimed to establish post-COVID-19 temporal changes in chest computed tomography (CT) features of pulmonary fibrosis and to investigate associations with respiratory symptoms and physiological parameters at 3 and 12 months' follow-up. Adult patients who attended our initial COVID-19 follow-up service and developed chest CT features of interstitial lung disease, in addition to cases identified using British Society of Thoracic Imaging codes, were evaluated retrospectively. Clinical data were gathered on respiratory symptoms and physiological parameters at baseline, 3 months, and 12 months. Corresponding chest CT scans were reviewed by two thoracic radiologists. Associations between CT features and functional correlates were estimated using random effects logistic or linear regression adjusted for age, sex and body mass index. In total, 58 patients were assessed. No changes in reticular pattern, honeycombing, traction bronchiectasis/bronchiolectasis index or pulmonary distortion were observed. Subpleural curvilinear lines were associated with lower odds of breathlessness over time. Parenchymal bands were not associated with breathlessness or impaired lung function overall. Based on our results, we conclude that post-COVID-19 chest CT features of irreversible pulmonary fibrosis remain static over time; other features either resolve or remain unchanged. Subpleural curvilinear lines do not correlate with breathlessness. Parenchymal bands are not functionally significant. An awareness of the different potential functional implications of post-COVID-19 chest CT changes is important in the assessment of patients who present with multi-systemic sequelae of COVID-19 infection.

Incidence of infant Gram-negative invasive bacterial infections in England, 2011-2019: an observational study using population-wide surveillance data.

OBJECTIVE: Invasive bacterial infections account for an estimated 15% of infant deaths worldwide. We aimed to estimate the incidence and trends in invasive bacterial infections in infants caused by Gram-negative pathogens in England during 2011-2019. METHODS: Laboratory-confirmed invasive bacterial infections in infants (<1 year old) were identified in the UK Health Security Agency national laboratory surveillance data from April 2011 to March 2019. Polymicrobial infections were defined as two or more bacterial species from the same normally sterile sample site. Early-onset infections were defined as <7 days from birth and late-onset as ≥7 days (neonates 7-28 days; infants ≥29 days). Trend analyses were carried out using Poisson (for episodes/incidence) and beta (for proportions) regression. RESULTS: The annual incidence of invasive bacterial infections increased by 35.9%, from 189.8 to 258.0 cases per 100 000 live births (p<0.001). Late-onset infections in both neonates and infants increased substantially over the study period (p<0.001), whereas early-onset infections increased slightly (p=0.002). Escherichia coli was the most common Gram-negative pathogen isolated and accounted for 27.2% of the overall rise in Gram-negative infant disease incidence. Polymicrobial infections almost doubled, increasing from 29.2 to 57.7 per 100 000 live births (p<0.001), and mostly involved two species (81.3%, 1604/1974 episodes). CONCLUSIONS: The incidence of Gram-negative invasive bacterial infections in infants increased between 2011/2012 and 2018/2019 in England, driven mainly by an increase in late-onset infections. Further work is required to elucidate the risk factors and drivers of this increased incidence so that opportunities for prevention can be identified.

Systematic Review of Hansen Disease Attributed to Mycobacterium lepromatosis.

In 2008, bacilli from 2 Hansen disease (leprosy) cases were identified as a new species, Mycobacterium lepromatosis. We conducted a systematic review of studies investigating M. lepromatosis as a cause of HD. Twenty-one case reports described 27 patients with PCR-confirmed M. lepromatosis infection (6 dual M. leprae/M. lepromatosis): 10 case-patients in the United States (7 originally from Mexico), 6 in Mexico, 3 in the Dominican Republic, 2 each in Singapore and Myanmar, and 1 each in Indonesia, Paraguay, Cuba, and Canada. Twelve specimen surveys reported 1,098 PCR-positive findings from 1,428 specimens, including M. lepromatosis in 44.9% (133/296) from Mexico, 3.8% (5/133) in Colombia, 12.5% (10/80) in Brazil, and 0.9% (2/224) from the Asia-Pacific region. Biases toward investigating M. lepromatosis as an agent in cases of diffuse lepromatous leprosy or from Mesoamerica precluded conclusions about clinicopathologic manifestations and geographic distribution. Current multidrug treatments seem effective for this infection.

Time to negative throat culture following initiation of antibiotics for pharyngeal group A Streptococcus: a systematic review and meta-analysis up to October 2021 to inform public health control measures.

BackgroundPublic health guidance recommending isolation of individuals with group A streptococcal (GAS) infection or carriage for 12-24 h from antibiotic initiation to prevent onward transmission requires a strong evidence base.AimTo estimate the pooled proportion of individuals who remain GAS culture-positive at set intervals after initiation of antibiotics through a systematic literature review (PROSPERO CRD42021290364) and meta-analysis.MethodsWe searched Ovid MEDLINE (1946-), EMBASE (1974-) and Cochrane library. We included interventional or observational studies with ≥ 10 participants reporting rates of GAS throat culture positivity during antibiotic treatment for culture-confirmed GAS pharyngitis, scarlet fever and asymptomatic pharyngeal GAS carriage. We did not apply age, language or geographical restrictions.ResultsOf 5,058 unique records, 43 were included (37 randomised controlled studies, three non-randomised controlled trials and three before-and-after studies). The proportion of individuals remaining culture-positive on day 1, day 2 and days 3-9 were 6.9% (95% CI: 2.7-16.8%), 5.4% (95% CI: 2.1-13.3%) and 2.6% (95% CI: 1.6-4.2%). For penicillins and cephalosporins, day 1 positivity was 6.5% (95% CI: 2.5-16.1%) and 1.6% (95% CI: 0.04-42.9%), respectively. Overall, for 9.1% (95% CI: 7.3-11.3), throat swabs collected after completion of therapy were GAS culture-positive. Only six studies had low risk of bias.ConclusionsOur review provides evidence that antibiotics for pharyngeal GAS achieve a high rate of culture conversion within 24 h but highlights the need for further research given methodological limitations of published studies and imprecision of pooled estimates. Further evidence is needed for non-beta-lactam antibiotics and asymptomatic individuals.

Is Panton-Valentine leucocidin (PVL) toxin associated with poor clinical outcomes in patients with community-acquired Staphylococcus aureus bacteraemia?

Introduction. Panton-Valentine leucocidin (PVL) toxin is a potential determinant of virulence associated with S. aureus infection.Gap Statement. The contribution of PVL to S. aureus pathogenicity remains unclear.Aim. To compare clinical outcomes in hospitalized patients with PVL-positive and PVL-negative community-acquired (CA) S. aureus bacteraemia.Methods. Three national datasets were combined to provide clinical and mortality data for patients with CA S. aureus blood culture isolates sent to the UK reference laboratory for PVL testing, August 2018 to August 2021. Multivariable logistic regression models were built for the effect of PVL positivity on 30 day all-cause mortality and 90 day readmission.Results. In 2191 cases of CA S. aureus bacteraemia, there was no association between PVL and mortality (adjusted odds ratio, aOR: 0·90, 95 % confidence interval, CI: 0·50-1·35, P=0·602) and no difference in median LOS (14 versus 15 days, P=0.169). PVL-positive cases had lower odds of readmission (aOR 0·74, CI 0·55-0.98, P=0·038). There was no evidence that MRSA status modified this effect (P=0·207).Conclusions. In patients with CA S. aureus bacteraemia PVL toxin detection was not associated with worse outcomes.

Developmental referrals of pre-school children in a diverse community in England: The importance of parental migration for referral rates.

BACKGROUND: Children born to migrant parents have higher rates of language difficulties, intellectual disability and autism. This study explores the relationship between migration, ethnicity and reasons for early years referrals to community paediatrics in a diverse multi-cultural population in a city in south west England. METHODS: Observational retrospective study from a community paediatric service serving a multi-cultural urban population from June 2012 to February 2016. We tested associations of ethnicity and parental birth origin with reason for referral (developmental or non-developmental) for children under 5 years old and estimated crude rate ratios for referrals using population census data. RESULTS: Data were available for 514 children (52% white or mixed race, 16% Asian, 21% African diaspora, and 11.5% Somali); 53% had two UK-born parents while 22% had two migrant (non-UK-born) parents. Referrals were for developmental reasons in 307 (60%) including 86 for possible autism. Parental birth origin and ethnicity were associated with reason for referral (p < 0.001). Children from African diaspora, Asian or Somali backgrounds had more than twice the rate (rate ratio [RR] 2.37, 95% CI 1.88-2.99, p < 0.001) of developmental referrals compared with white or mixed-race children. Children of Somali or African diaspora ethnicity were, respectively, six-times (RR 5.99, 95% CI 3.24-10.8, p < 0.001) and four times (RR 4.23, 95% CI 2.44-7.29, p < 0.001) more likely to be referred for possible autism spectrum than their white or mixed-race peers. Developmental referral as a proportion of all referrals was twice as high among children with one migrant parent (20.4%) and three times as high among children with two migrant parents (29.5%), compared with children whose parents were both UK-born (10.7%). CONCLUSIONS: This study supports the importance of ethnicity and parental migration as factors in young children experiencing developmental difficulties, especially concerns about social communication or autism.

Clinical and radiological evaluation of maxillofacial and otorhinolaryngological manifestations of Hansen's disease.

To characterize maxillofacial, otorhinolaryngological and oral manifestations of Hansen's disease (HD), we conducted a cross-sectional study in 21 current patients attending the Unidade Básica de Saúde de Jardim América, Espírito Santo, Brazil and 16 former patients resident at Pedro Fontes Hospital using data from computed tomography imaging, rhinoscopy, and oroscopy. Maxillofacial characteristics were compared with 37 controls. Differences in bone alterations across the three groups were determined mainly by severe resorption/atrophy being more frequent in former HD patients, with severe resorption/atrophy of the anterior alveolar process of maxilla in 50.0% (8/16) of former patients, 28.6% (6/21) of current patients and 10.8% (4/37) of controls and of nasal bones and aperture in 31.3% (5/16) of former patients compared with 0/21 current patients and two controls. There were no substantial differences in otorhinolaryngological and oroscopic findings between the two patient groups. HD patients had more tooth loss than the age-matched control group. Maxillofacial, otorhinolaryngological and oroscopic finding scores were strongly correlated only in current HD patients. Correlation between otorhinolaryngological and maxillofacial scores suggests that protocols for HD patient assessment and follow-up could include otorhinolaryngological evaluation, with radiological imaging where necessary, subject to replication of our findings in a larger study.

The increasing incidence of visceral leishmaniasis relapse in South Sudan: A retrospective analysis of field patient data from 2001-2018.

BACKGROUND: Visceral Leishmaniasis (VL) is endemic in South Sudan, manifesting periodically in major outbreaks. Provision of treatment during endemic periods and as an emergency response is impeded by instability and conflict. Médecins Sans Frontières (MSF) has provided health care in South Sudan since the late 1980's, including treatment for 67,000 VL patients. In recent years, MSF monitoring data have indicated increasing numbers of VL relapse cases. A retrospective analysis of these data was performed in order to provide insight into the possible causes of this increase. METHODOLOGY/PRINCIPAL FINDINGS: Programme monitoring data from the MSF hospital in Lankien, Jonglei State, South Sudan, for the period 2001-2018 were analysed to detect trends in VL relapse as a proportion of all VL cases presenting to MSF treatment centres. Routinely collected patient-level data from relapse and primary VL cases treated at all MSF sites in South Sudan over the same period were analysed to describe patient characteristics and treatments received. VL relapse as a proportion of all VL cases increased by 6.5% per annum (95% CI 0.3% to 13.0%, p = 0.04), from 5.2% during 2001-2003 to 14.4% during 2016-2018. Primary VL and VL relapse patients had similar age, sex and anthropometric characteristics, the latter indicating high indices of undernutrition which were relatively constant over time. Clinical factors (Hb, spleen size, and VL severity score) also did not vary substantially over time. SSG/PM was the main treatment regimen from 2001-2018, used in 68.7% of primary and 70.9% of relapse VL cases; AmBisome was introduced in 2013, received by 22.5% of primary VL and 32.6% of VL relapse cases from 2013-2018. CONCLUSION: Increasing incidence of VL relapse in South Sudan does not appear to be explained by changes in patient characteristics or other factors. Our data are concerning and may indicate an emergence of treatment-resistant parasite strains, decreasing the effectiveness of treatment regimens. This warrants further investigation as a causal factor. New chemical entities that will enable safe and highly effective short-course oral treatments for VL are urgently needed.

Hansen's disease and COVID-19 co-infection in Brazil.

BACKGROUND: The implications of COVID-19 co-infection in patients under treatment for Hansen's disease (HD, leprosy) remain uncertain. We aimed to describe clinical characteristics, treatments, and outcomes in patients with HD and COVID-19 in Brazil. METHODS: Cross-sectional study recruiting adult HD patients with PCR-confirmed COVID-19 from five HD treatment centers in Brazil between March 1, 2020, and March 31, 2021. At the time of this study, no patient had received COVID-19 vaccine. RESULTS: Of 1377 patients under treatment for HD, 70 (5.1%) were diagnosed with COVID-19. Of these, 41 (58.6%) had PCR-confirmed COVID-19, comprising 19 men and 22 women, aged 24-67 (median 45) years. HD was multibacillary in 39/41 patients. Eight patients ceased WHO Multi-Drug Therapy for HD, three for lack of drugs, two because of COVID-19, and three for other reasons. Of the 33 who continued treatment, 26 were on the standard regimen and seven an alternative regimen. Seventeen patients were receiving oral prednisone, including nine patients with type 1 reaction, four with type 2 reaction, three with neuritis, and one with rheumatologic disease. Twelve patients were hospitalized for COVID-19, and six patients died, of whom three had hypertension and one also had type 2 diabetes and obesity. CONCLUSIONS: COVID-19 and Hansen's disease co-infection did not appear to change the clinical picture of either disease in this cross-sectional study. The wider impact of the pandemic on persons affected by HD requires follow-up and monitoring.

Incidence and aetiology of infant Gram-negative bacteraemia and meningitis: systematic review and meta-analysis.

BACKGROUND: One in six infant deaths worldwide are caused by invasive bacterial infections, of which a substantial but unquantified proportion are caused by Gram-negative bacteria. METHODS: We conducted a systematic review of studies published from 31 May 2010 to 1 June 2020 indexed in MEDLINE, Embase and Global Health databases. We performed meta-analyses of the incidence of Gram-negative bacteraemia and of individual Gram-negative species as proportions of all infant bacteraemia, stratified by onset (early vs late) and country income (low/middle vs high). RESULTS: 152 studies from 54 countries were included, 60 in high-income countries (HIC) and 92 in low-income/middle-income countries (LMIC). Gram-negatives represented a higher proportion (53%, 95% CI 49% to 57%) of all infant bacteraemia in LMIC compared with HIC (28%, 95% CI 25% to 32%). Incidence of infant Gram-negative bacteraemia was 2.01 (95% CI 1.15 to 3.51) per 1000 live births; it was five times higher in LMIC (4.35, 95% CI 2.94 to 6.43) compared with HIC (0.73, 95% CI 0.39 to 7.5). In HIC, Escherichia coli was the leading Gram-negative pathogen, representing 19.2% (95% CI 15.6% to 23.4%) of early and 7.3% (95% CI 5.3% to 10.1%) of all late-onset bacteraemia; Klebsiella spp were the next most common cause (5.3%) of late-onset bacteraemia. In LMIC, Klebsiella spp caused 16.4% (95% CI 11.5% to 22.7%) of early and 15.0% (95% CI 10.1% to 21.8%) of late-onset bacteraemia, followed by E. coli (early-onset 7.50%, 95% CI 4.98% to 11.1%; late-onset 6.53%, 95% CI 4.50% to 9.39%) and Pseudomonas spp (early-onset 3.93%, 95% CI 2.04% to 7.44%; late-onset 2.81%, 95% CI 1.99% to 3.95%). CONCLUSION: E. coli, Klebsiella and Pseudomonas spp cause 20%-28% of early-onset infant bacteraemia and 14% cases of infant meningitis worldwide. Implementation of preventive measures could reduce the high incidence of Gram-negative bacteraemia in LMIC. PROSPERO REGISTRATION NUMBER: CRD42020191618.