Role of HBsAg levels in guiding hepatitis B virus prophylaxis in pregnancy: Insights from a multi-ethnic cohort.

Pregnant mothers with chronic hepatitis B infection (CHB) need peri-partum antiviral prophylaxis (PAP) to reduce the risk of mother-to-child-transmission. Currently, PAP is recommended in those with high viral load (VL) that is, HBV DNA >200,000 IU/mL. Quantitative hepatitis B surface antigen (qHBsAg) >10,000 IU/mL, a cut-off derived primarily from hepatitis B e-antigen (HBeAg) positive antenatal cohorts in Chinese populations, is advocated as a surrogate marker of VL for guiding PAP. We investigated the utility of qHBsAg to predict high-VL in a multi-ethnic urban cohort with CHB. A consecutive cohort of women with CHB was identified from Barts Health NHS Trust databases in the United Kingdom. We included women with paired HBV DNA and qHBsAg during pregnancy. Women already on antiviral at conception were excluded. A total of 769 pregnancies in 678 CHB pregnant mothers (median age 31 years-old, 8.6% HBeAg+) were included. At median gestational age of 15.3 weeks, HBV DNA was 336 (IQR 44-2998) IU/mL, with 65 (8.5%) being high-VL. Serum qHBsAg was most useful in Black/Black-British/Caribbean/African (AUROC 0.946) with 100% sensitivity and 80.6% specificity to predict high-VL; but it performed less well for other ethnicities: Asian (AUROC 0.877), White (AUROC 0.797) and mixed ethnicities (AUROC 0.742). In conclusion, for settings where healthcare resources are not limited, HBV DNA remains the optimal marker to identify highly viraemic pregnancies for guiding PAP. For resource-limited settings where the prevailing cost is treatment, serum qHBsAg can be used in Black/Black British/Caribbean/African sub-cohorts, but not for other ethnicities.

Generation of Novel Severe Acute Respiratory Syndrome Coronavirus 2 Variants on the B.1.1.7 Lineage in 3 Patients With Advanced Human Immunodeficiency Virus-1 Disease.

The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is of public health concern in case of vaccine escape. Described are 3 patients with advanced human immunodeficiency virus (HIV)-1 and chronic SARS-CoV-2 infection in whom there is evidence of selection and persistence of novel mutations that are associated with increased transmissibility and immune escape.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Placental Infection Is Associated With Massive Perivillous Fibrin Deposition at the Maternal-Fetal Interface: A Preliminary Study.

We observed an increased frequency of massive perivillous fibrin deposition (MPFD) during the second coronavirus disease 2019 (COVID-19) pandemic wave dominated by the Alpha variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MPFD associated with 100% reverse transcription polymerase chain reaction (RT-PCR) positivity for SARS-CoV-2 and detection by immunohistochemistry. The Alpha variant was identified in all placentas with MPFD that could be sequenced.

Evaluating UK National Guidance for Screening of Children for Tuberculosis. A Prospective Multicenter Study.

RATIONALE: To identify infected contacts of tuberculosis (TB) cases, the UK National Institute for Health and Care Excellence (NICE) recommended the addition of IFN-γ release assays (IGRA) to the tuberculin skin test (TST) in its 2006 TB guidelines. Treatment for TB infection was no longer recommended for children who screened TST-positive but IGRA-negative. OBJECTIVES: We performed a cohort study to evaluate the risk of TB disease in this group. METHODS: Children exposed to an infectious case of TB in their household were recruited from 11 pediatric TB clinics. TST and IGRA were performed at baseline, with IGRA repeated at 8 weeks and TST repeated if initially negative. Children were treated according to 2006 NICE guidelines and followed for 24 months. MEASUREMENTS AND MAIN RESULTS: Of 431 recruited children, 392 completed the study. We diagnosed 48 (12.2%) cases of prevalent TB disease, 105 (26.8%) with TB infection, and 239 (60.9%) without TB infection or disease. Eighteen children aged 2 years and above had a positive TST but persistently negative IGRA. None received TB infection treatment and none developed TB disease. Ninety (26.1%) children qualified for TB infection treatment according to 2006 NICE guidelines. In contrast, 147 (42.7%) children would have qualified under revised NICE guidance, issued in 2016. CONCLUSIONS: In this low-prevalence setting we saw no incident cases of TB disease in children who were TST-positive but IGRA-negative and did not receive treatment for TB infection. Following the latest NICE guidance, significantly more children will require medication.

The impact of BCG vaccination on tuberculin skin test responses in children is age dependent: evidence to be considered when screening children for tuberculosis infection.

BACKGROUND: Following exposure to TB, contacts are screened to target preventive treatment at those at high risk of developing TB. The UK has recently revised its recommendations for screening and now advises a 5 mm tuberculin skin test (TST) cut-off irrespective of age or BCG status. We sought to evaluate the impact of BCG on TST responses in UK children exposed to TB and the performance of different TST cut-offs to predict interferon γ release assay (IGRA) positivity. METHODS: Children <15 years old were recruited from 11 sites in the UK between January 2011 and December 2014 if exposed in their home to a source case with sputum smear or culture positive TB. Demographic details were collected and TST and IGRA undertaken. The impact of BCG vaccination on TST positivity was evaluated in IGRA-negative children, as was the performance of different TST cut-offs to predict IGRA positivity. RESULTS: Of 422 children recruited (median age 69 months; IQR: 32-113 months), 300 (71%) had been vaccinated with BCG. BCG vaccination affected the TST response in IGRA-negative children less than 5 years old but not in older children. A 5 mm TST cut-off demonstrated good sensitivity and specificity in BCG-unvaccinated children, and an excellent negative predictive value but was associated with low specificity (62.7%; 95% CI 56.1% to 69.0%) in BCG-vaccinated children. For BCG-vaccinated children, a 10 mm cut-off provided a high negative predictive value (97.7%; 95% CI 94.2% to 99.4%) with the positive predictive value increasing with increasing age of the child. DISCUSSION: BCG vaccination had little impact on TST size in children over 5 years of age. The revised TST cut-off recommended in the recent revision to the UK TB guidelines demonstrates good sensitivity but is associated with impaired specificity in BCG-vaccinated children.

The origins of new SARS-COV-2 variants in immunocompromised individuals.

PURPOSE OF REVIEW: To explore the origins of new severe acute respiratory coronavirus 2 (SARS-CoV-2) variants in immunocompromised individuals and whether the emergence of novel mutations in these individuals is responsible for the development of variants of concern (VOC). RECENT FINDINGS: Next generation sequencing of samples from chronically infected immunocompromised patients has enabled identification of VOC- defining mutations in individuals prior to the emergence of these variants worldwide. Whether these individuals are the source of variant generation is uncertain. Vaccine effectiveness in immunocompromised individuals and with respect to VOCs is also discussed. SUMMARY: Current evidence on chronic SARS-CoV-2 infection in immunocompromised populations is reviewed including the relevance of this to the generation of novel variants. Continued viral replication in the absence of an effective immune response at an individual level or high levels of viral infection at the population level are likely to have contributed to the appearance of the main VOC.

Review article: emerging insights into the immunopathology, clinical and therapeutic aspects of hepatitis delta virus.

BACKGROUND: Hepatitis delta virus (HDV), which causes the most severe form of viral hepatitis, is an obligated hepatitis B (HBV) satellite virus that can either infect naïve subjects simultaneously with HBV (co-infection), or chronically infect HBV carriers (super-infection). An estimated 12 million people are infected by HDV worldwide. AIMS: To summarise the most relevant aspects of the molecular biology of HDV, and to discuss the latest understanding of the induced pathology, interactions with the immune system, as well as both approved and investigational treatment options. METHODS: References for this review were identified through searches of PubMed with the terms "HDV" "viral hepatitis" "co-infection" and "super-infection," published between 1980 and October 2021 RESULTS: The limited access to the HDV-infected liver has hampered the investigation of the intrahepatic compartment and our understanding of the mechanisms of HDV pathogenesis. In the absence of standardised and sensitive diagnostic tools, HDV is often underdiagnosed and owing to its strong dependence on host cellular factors, the development of direct antiviral agents has been challenging. New therapeutic agents targeting different steps of the viral cycle have recently been investigated, among which bulevirtide (which was conditionally approved by EMA in July 2020) and lonafarnib; both drugs having received orphan drug designation from both the EMA and FDA. CONCLUSIONS: The HBV cure programme potentially offers a unique opportunity to enhance HDV treatment strategies. In addition, a more comprehensive analysis of the intrahepatic compartment is mandated to better understand any liver-confined interaction of HDV with the host immune system.

The impact of out-of-hospital models of care on paediatric emergency department presentations.

OBJECTIVE: To estimate the potential impact of enhanced primary care and new out-of-hospital models (OOHMs) on emergency department (ED) presentations by children and young people (CYP). DESIGN: Observational study. PATIENTS & SETTING: Data collected prospectively on 3020 CYP 0-17.9 years from 6 London EDs during 14 days by 25 supernumerary clinicians. CYP with transient acute illness, exacerbation of long-term condition (LTC), complex LTC/disability and injury/trauma were considered manageable within OOHM. OOHMs assessed included nurse-led services, multispecialty community provider (MCP), primary and acute care system (PACS) plus current and enhanced primary care. MEASURES: Diagnosis, severity; record of investigations, management and outcome that occurred; objective assessment of clinical need and potential alternative management options/destinations. RESULTS: Of the patients 95.6% had diagnoses appropriate for OOHM. Most presentations required assessment by a clinician with skills in assessing illness (39.6%) or injuries (30.9%). One thousand two hundred and ninety-one (42.75%) required no investigations and 1007 (33.3%) were provided only with reassurance. Of the presentations 42.2% were judged to have been totally avoidable if the family had had better health education.Of the patients 26.1% were judged appropriate for current primary care (community pharmacy or general practice) with 31.5% appropriate for the combination of enhanced general practice and community pharmacy. Proportions suitable for new models were 14.1% for the nurse-led acute illness team, MCP 25.7%, GP federation CYP service 44.6%, comprehensive walk-in centre for CYP 64.3% and 75.5% for a PACS. CONCLUSIONS: High proportions of ED presentations by CYP could potentially be managed in new OOHMs or by enhancement of existing primary care.

Imported dengue fever in East London: a 6-year retrospective observational study.

Background: Dengue fever (DF) is a frequently imported arthropod-borne infection in the United Kingdom but its broad range of clinical presentations makes it potentially unrecognized by clinicians. Methods: We conducted a 6-year retrospective case note review of laboratory confirmed DF patients in East London in the period from 1 January 2010 through 31 December 2015. Epidemiological, clinical and laboratory features of imported DF were described. Risk factors associated with viraemic DF presentations were assessed. Results: Forty-four patients (4 from primary care clinics and 40 from three acute hospitals) were confirmed to have DF through RNA and/or IgM detection. In total, 86.4% (38/44) had primary infection compared to 13.6% (6/44) with secondary infection. Viraemic DF presentations accounted for 59.1% (26/44) of cases. The median age was 34 years (IQR 25-43). Most patients were males (68.2%, 30/44) and of non-white ethnicity (81.8%, 36/44). South Asia was the most frequent travel destination (52.3%, 23/44) followed by Southeast Asia (20.5%, 9/44). July-September was the peak season of presentation (43.2%, 19/44). The median interval between arrival in the UK and laboratory testing was 7 days (IQR 4-13). Arriving from abroad ≤ 7 days before molecular testing (age-adjusted odds ratios [OR] 16.98, 95% CI 2.43-118.75, P = 0.004) and travel to South or Southeast Asia regions (age-adjusted OR 4.41, 95% CI 1.07-18.21, P = 0.040) were associated with detectable viraemia at presentation. Only one DF patient met the WHO severity criteria. HIV serostatus was determined in 61.4% (27/44) of cases. Conclusion: Clinicians need to improve DF recognition as well as rates of HIV testing in tropical travellers. Region of travel and time since arrival from DF endemic settings may help clinicians optimize requests for molecular testing. Further research on the clinical and public health aspects of imported DF is needed.

Immunogenicity and safety of a combination pneumococcal-meningococcal vaccine in infants: a randomized controlled trial.

CONTEXT: The success of conjugate vaccines in decreasing invasive disease due to Streptococcus pneumoniae and group C Neisseria meningitidis has placed pressure on crowded infant immunization schedules, making development of combination vaccines a priority. OBJECTIVE: To determine the safety and immunogenicity of a combination 9-valent pneumococcal-group C meningococcal conjugate candidate vaccine (Pnc9-MenC) administered as part of the routine UK infant immunization schedule at ages 2, 3, and 4 months. DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized controlled trial conducted from August 2000 to January 2002 and enrolling 240 healthy infants aged 7 to 11 weeks from 2 UK centers, with home follow-up visits at ages 2, 3, 4, and 5 months. INTERVENTION: Pnc9-MenC (n = 120) or monovalent group C meningococcal conjugate vaccine (MenC) (n = 120) administered in addition to routine immunizations (diphtheria and tetanus toxoids and whole-cell pertussis [DTwP], Haemophilus influenzae type b [Hib] polyribosylribitol phosphate-tetanus toxoid protein conjugate, oral polio vaccine). MAIN OUTCOME MEASURES: Group C meningococcal immunogenicity measured by serum bactericidal titer (SBT) 1 month following the third dose; rates of postimmunization reactions. RESULTS: MenC component immunogenicity was reduced in the Pnc9-MenC vs the MenC group (geometric mean SBT, 179 [95% confidence interval {CI}, 133-243] vs 808 [95% CI, 630-1037], respectively; P<.001). The proportion with group C meningococcal SBT greater than 1:8 was lower in the Pnc9-MenC vs the MenC group (95% vs 100%, P = .05). The geometric mean concentration of antibodies to concomitantly administered Hib vaccine was reduced in the Pnc9-MenC vs the MenC group (2.11 [95% CI, 1.57-2.84] microg/mL vs 3.36 [95% CI, 2.57-4.39] microg/mL; P = .02), as were antibodies against diphtheria (0.74 [95% CI, 0.63-0.87] microg/mL vs 1.47 [95% CI, 1.28-1.69] microg/mL; P<.001). Pnc9-MenC was immunogenic for each of 9 contained pneumococcal serotypes, with responses greater than 0.35 microg/mL observed in more than 88% of infants. Increased irritability and decreased activity were observed after the third dose in the Pnc9-MenC group. CONCLUSIONS: Pnc9-MenC combination vaccine administered to infants at ages 2, 3, and 4 months demonstrated reduced group C meningococcal immunogenicity compared with MenC vaccine. The immunogenicity of concomitantly administered Hib and DTwP vaccines was also diminished. The Pnc9-MenC vaccine was safe and immunogenic for all contained pneumococcal serotypes. The reduced MenC immunogenicity may limit the development of the Pnc9-MenC vaccine.

Management and outcome of Bacille Calmette-Guérin vaccine adverse reactions.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine is one of the most widely used vaccines globally. Management of local BCG complications (injection site reactions and suppurative or non-suppurative lymphadenitis) varies between clinicians, and the optimal approach remains uncertain. AIM: To determine the clinical features, management and outcome of BCG complications at two large acute hospitals in London, United Kingdom. METHODS: All children presenting with complications of BCG vaccination between January 2008 and December 2013 were included in this observational study. Medical and electronic laboratory records were reviewed to determine clinical features, treatment and outcome. RESULTS: Sixty children presented with adverse reactions. Two-thirds (65%) presented with BCG lymphadenitis, one-third (30%) presented with injection site complications and two children (3%) presented with both injection site reaction and lymphadenitis; only one child (2%) had disseminated BCG disease. The majority (88%) of children with injection site reactions were managed conservatively; overall, 95% showed complete resolution within 6 months. Among children with lymphadenitis, 46% were managed conservatively, whilst 54% had anti-tuberculous therapy and/or a procedure (aspiration mostly, or surgery); complete resolution was seen in 59% of cases. CONCLUSIONS: Injection site reactions and non-suppurative lymphadenitis were generally managed conservatively, with good outcomes. There was more variation in management and outcome of suppurative lymphadenitis and the optimal approach remains uncertain.

Tropical disease vaccines.

Infectious diseases remain a key cause of morbidity and mortality in the Tropics. Many of these diseases are already preventable by effective vaccines. The Extended Program of Immunization provides protection against six serious infections. However, this program is still not optimally implemented in all developing countries. The Extended Program of Immunization could benefit from the addition of several vaccines, but unfortunately the cost is prohibitive in many areas of the Tropics. For some of the most important infections, such as malaria and HIV, vaccines are not yet available. Novel strategies for vaccine development and policy implementation offer the best hope to combat the infections targeted by the World Health Organization as causing the highest annual death toll worldwide.

Back pain, leg swelling and a cardiac arrest: an interesting case of endocarditis.

A 66-year-old woman with a history of tissue aortic valve replacement and chronic back pain presented to the emergency department with a suspected right leg deep vein thrombosis. A recent outpatient MRI had revealed discitis. A ventricular fibrillation cardiac arrest occurred in the emergency department. Cardiac output was restored on the fifth defibrillation. A transthoracic echocardiogram showed large aortic valve vegetations. Clinical impression was of infective endocarditis with cardiac arrest secondary to coronary artery embolisation. Peripheral blood cultures grew Cardiobacterium hominis, and appropriate intravenous antibiotic therapy was administered. The infected prosthetic valve was excised. The patient experienced postoperative complete heart block and a right hemisphere cerebrovascular accident, however she is now recovering well. This case describes an unusual case of infective endocarditis secondary to C. hominis, with disc, leg, coronary artery and brain septic embolisation. Infective endocarditis is an important differential diagnosis in multisystem presentations.

Gag-specific CD4+ T-cell responses are associated with virological control of paediatric HIV-1 infection.

HIV-specific Elispot responses were investigated in 57 antiretroviral therapy-naive children, of median age 9.9 years. CD8(+) T-cell responses were detected in 96% children; Nef was the immunodominant protein. Responses broadened over time, but there was no association between magnitude, breadth or specificity of response and viraemia. Gag-specific CD4(+) T-cell responses, detectable in 26% children, correlated inversely with viraemia (R = -0.43, P < 0.001), suggesting that preservation of this cell population may be an important goal of therapeutic/vaccine strategies.

Comparison of interferon-gamma release assays and tuberculin skin test in predicting active tuberculosis (TB) in children in the UK: a paediatric TB network study.

BACKGROUND: The value of interferon-gamma release assays (IGRA) to diagnose active tuberculosis (TB) in children is not established, but these assays are being widely used for this purpose. The authors examined the sensitivity of commercially available IGRA to diagnose active TB in children in the UK compared with the tuberculin skin test (TST). METHODS: The authors established a paediatric tuberculosis network and conducted a retrospective analysis of data from children investigated for active TB at six large UK paediatric centres. All centres had used TST and at least one of the commercially available IGRA (T-Spot.TB or Quantiferon-Gold in Tube) in the diagnostic work-up for active TB. Data were available from 333 children aged 2 months to 16 years. The authors measured the sensitivity of TST and IGRA in definite (culture confirmed) and probable TB in children, agreement between TST and either IGRA, and their combined sensitivity. RESULTS: Of 333 children, 49 fulfilled the criteria of definite TB, and 146 had probable TB. Within the definite cohort, TST had a sensitivity of 82%, Quantiferon-Gold in tube (QFT-IT) had a sensitivity of 78% and T-Spot.TB of 66%. Neither IGRA performed significantly better than a TST with a cut-off of 15 mm. Combining the results of TST and IGRA increased the sensitivity to 96% for TST plus T-Spot.TB and 91% for TST plus QFG-IT in the definite TB cohort. CONCLUSIONS: A negative IGRA does not exclude active TB disease, but a combination of TST and IGRA increases the sensitivity for identifying children with active TB.