Folate deficiency presenting as pyrexia: a case report

Folate deficiency is an uncommon cause of pyrexia. We describe the case of a 29-year-old male who presented with a pyrexial illness subsequently attributed to megaloblastic anaemia secondary to severe folate deficiency, after exclusion of other infective or inflammatory causes. A temperature chart documenting the course of the patient's pyrexia is presented and potential pathophysiological mechanisms are proposed. Folate deficiency is a reversible cause of pyrexia that should be considered in any patient who presents with a pyrexial illness of unknown cause

Cardiovascular events after clarithromycin use in lower respiratory tract infections:analysis of two prospective cohort studies

Objective: To study the association of clarithromycin with cardiovascular events in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia.Design: Analysis of two prospectively collected datasets.Setting: Chronic obstructive pulmonary disease dataset including patients admitted to one of 12 hospitals around the United Kingdom between 2009 and 2011; Edinburgh pneumonia study cohort including patients admitted to NHS Lothian Hospitals between 2005 and 2009.Population: 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease and 1631 patients admitted with community acquired pneumonia.Main outcome measures: Hazard ratios for cardiovascular events at one year (defined as hospital admissions with acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina). Secondary outcomes were all cause and cardiovascular mortality at one year.Results: 268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and 171 in the community acquired pneumonia cohort over one year. After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease was associated with an increased risk of cardiovascular events and acute coronary syndrome—hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68). After multivariable adjustment, clarithromycin use in community acquired pneumonia was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38) but not acute coronary syndrome (1.65, 0.97 to 2.80). The association between clarithromycin use and cardiovascular events persisted after matching for the propensity to receive clarithromycin. A significant association was found between clarithromycin use and cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26) but not all cause mortality (1.16, 0.90 to 1.51) in acute exacerbations of chronic obstructive pulmonary disease. No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality. Longer durations of clarithromycin use were associated with more cardiovascular events. Use of β lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin.Conclusions: The use of clarithromycin in the setting of acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia may be associated with increased cardiovascular events. These findings require confirmation in other datasets

The stability of influenza haemagglutinin and its significance for pathogenicity, transmission and control

Influenza A viruses are highly diverse and predominantly exist in animal reservoirs. In the rare but significant event that an influenza virus acquires the capability to jump from animal to human host, a pandemic can result. The most recent example of this occurred in 2009 when the pandemic H1N1 (pH1N1) virus emerged from swine causing the first influenza pandemic of the 21st century. Over the subsequent decade, it has circulated as a human seasonal virus, causing further morbidity and mortality worldwide. The ability of an influenza virus to infect and transmit between humans is multifactorial. In recent years, pH stability of the haemagglutinin (HA) surface protein has been realised as an important property associated with human adaptation and transmission. Understanding how pH stability impacts on virus/host interactions that support replication and transmission in humans is important for improving risk assessment of emerging viruses with pandemic potential. In this study, recombinant influenza viruses with point mutations that alter the pH stability of pH1N1 HA were used to investigate the consequences of pH stability for pathogenicity and transmissibility. The data show that a stable HA is beneficial for virus infectivity in the mammalian upper respiratory tract, enabling virus to withstand the acidic environment. Conversely, entry into host cells via endosomal uncoating is facilitated by a HA that is less pH stable. A novel technique for isolating influenza virus directly from air exhaled by infected ferrets revealed that HA stability enhances virus survival in airborne droplets. However, using the same apparatus airborne virus was not isolated from human volunteers infected with pH1N1 virus. Our findings indicate that different influenza viruses may show variation in how well they are controlled by antiviral strategies targeting pH-dependent steps in the virus replication cycle and how effective they are as part of nasally-administered live attenuated vaccines.Open Acces

SARS-CoV-2 antigen lateral flow tests for detecting infectious people: linked data analysis.

OBJECTIVES To investigate the proportion of lateral flow tests (LFTs) that produce negative results in those with a high risk of infectiousness from SARS-CoV-2, to investigate the impact of the stage and severity of disease, and to compare predictions made by influential mathematical models with findings of empirical studies. DESIGN Linked data analysis combining empirical evidence of the accuracy of the Innova LFT, the probability of positive viral culture or transmission to secondary cases, and the distribution of viral loads of SARS-CoV-2 in individuals in different settings. SETTING Testing of individuals with symptoms attending NHS Test-and-Trace centres across the UK, residents without symptoms attending municipal mass testing centres in Liverpool, and students without symptoms screened at the University of Birmingham. PARTICIPANTS Evidence for the sensitivity of the Innova LFT, based on 70 individuals with SARS-CoV-2 and LFT results. Infectiousness was based on viral culture rates on 246 samples (176 people with SARS-CoV-2) and secondary cases among 2 474 066 contacts; distributions of cycle threshold (Ct) values from 231 497 index individuals attending NHS Test-and-Trace centres; 70 people with SARS-CoV-2 detected in Liverpool and 62 people with SARS-CoV-2 in Birmingham (54 imputed). MAIN OUTCOME MEASURES The predicted proportions who were missed by LFT and viral culture positive and missed by LFT and sources of secondary cases, in each of the three settings. Predictions were compared with those made by mathematical models. RESULTS The analysis predicted that of those with a viral culture positive result, Innova would miss 20% attending an NHS Test-and-Trace centre, 29% without symptoms attending municipal mass testing, and 81% attending university screen testing without symptoms, along with 38%, 47%, and 90% of sources of secondary cases. In comparison, two mathematical models underestimated the numbers of missed infectious individuals (8%, 10%, and 32% in the three settings for one model, whereas the assumptions from the second model made it impossible to miss an infectious individual). Owing to the paucity of usable data, the inputs to the analyses are from limited sources. CONCLUSIONS The proportion of infectious people with SARS-CoV-2 missed by LFTs is substantial enough to be of clinical importance. The proportion missed varied between settings because of different viral load distributions and is likely to be highest in those without symptoms. Key models have substantially overestimated the sensitivity of LFTs compared with empirical data. An urgent need exists for additional robust well designed and reported empirical studies from intended use settings to inform evidence based policy

Asymptomatic immunodeficiency-associated vaccine-derived poliovirus infections in two UK children

Abstract Increasing detections of vaccine-derived poliovirus (VDPV) globally, including in countries previously declared polio free, is a public health emergency of international concern. Individuals with primary immunodeficiency (PID) can excrete polioviruses for prolonged periods, which could act as a source of cryptic transmission of viruses with potential to cause neurological disease. Here, we report on the detection of immunodeficiency-associated VDPVs (iVDPV) from two asymptomatic male PID children in the UK in 2019. The first child cleared poliovirus with increased doses of intravenous immunoglobulin, the second child following haematopoetic stem cell transplantation. We perform genetic and phenotypic characterisation of the infecting strains, demonstrating intra-host evolution and a neurovirulent phenotype in transgenic mice. Our findings highlight a pressing need to strengthen polio surveillance. Systematic collection of stool from asymptomatic PID patients who are at high risk for poliovirus excretion could improve the ability to detect and contain iVDPVs

Viral emissions into the air and environment after SARS-CoV-2 human challenge: a phase 1, open label, first-in-human study

BackgroundEffectively implementing strategies to curb SARS-CoV-2 transmission requires understanding who is contagious and when. Although viral load on upper respiratory swabs has commonly been used to infer contagiousness, measuring viral emissions might be more accurate to indicate the chance of onward transmission and identify likely routes. We aimed to correlate viral emissions, viral load in the upper respiratory tract, and symptoms, longitudinally, in participants who were experimentally infected with SARS-CoV-2.MethodsIn this phase 1, open label, first-in-human SARS-CoV-2 experimental infection study at quarantine unit at the Royal Free London NHS Foundation Trust, London, UK, healthy adults aged 18-30 years who were unvaccinated for SARS-CoV-2, not previously known to have been infected with SARS-CoV-2, and seronegative at screening were recruited. Participants were inoculated with 10 50% tissue culture infectious dose of pre-alpha wild-type SARS-CoV-2 (Asp614Gly) by intranasal drops and remained in individual negative pressure rooms for a minimum of 14 days. Nose and throat swabs were collected daily. Emissions were collected daily from the air (using a Coriolis μ air sampler and directly into facemasks) and the surrounding environment (via surface and hand swabs). All samples were collected by researchers, and tested by using PCR, plaque assay, or lateral flow antigen test. Symptom scores were collected using self-reported symptom diaries three times daily. The study is registered with ClinicalTrials.gov, NCT04865237.FindingsBetween March 6 and July 8, 2021, 36 participants (ten female and 26 male) were recruited and 18 (53%) of 34 participants became infected, resulting in protracted high viral loads in the nose and throat following a short incubation period, with mild-to-moderate symptoms. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Viral RNA was detected in 63 (25%) of 252 Coriolis air samples from 16 participants, 109 (43%) of 252 mask samples from 17 participants, 67 (27%) of 252 hand swabs from 16 participants, and 371 (29%) of 1260 surface swabs from 18 participants. Viable SARS-CoV-2 was collected from breath captured in 16 masks and from 13 surfaces, including four small frequently touched surfaces and nine larger surfaces where airborne virus could deposit. Viral emissions correlated more strongly with viral load in nasal swabs than throat swabs. Two individuals emitted 86% of airborne virus, and the majority of airborne virus collected was released on 3 days. Individuals who reported the highest total symptom scores were not those who emitted most virus. Very few emissions occurred before the first reported symptom (7%) and hardly any before the first positive lateral flow antigen test (2%).InterpretationAfter controlled experimental inoculation, the timing, extent, and routes of viral emissions was heterogeneous. We observed that a minority of participants were high airborne virus emitters, giving support to the notion of superspreading individuals or events. Our data implicates the nose as the most important source of emissions. Frequent self-testing coupled with isolation upon awareness of first symptoms could reduce onward transmissions.FundingUK Vaccine Taskforce of the Department for Business, Energy and Industrial Strategy of Her Majesty's Government