False-negative RT-PCR for COVID-19 and a diagnostic risk score: a retrospective cohort study among patients admitted to hospital.

OBJECTIVE: To describe the characteristics and outcomes of patients with a clinical diagnosis of COVID-19 and false-negative SARS-CoV-2 reverse transcription-PCR (RT-PCR), and develop and internally validate a diagnostic risk score to predict risk of COVID-19 (including RT-PCR-negative COVID-19) among medical admissions. DESIGN: Retrospective cohort study. SETTING: Two hospitals within an acute NHS Trust in London, UK. PARTICIPANTS: All patients admitted to medical wards between 2 March and 3 May 2020. OUTCOMES: Main outcomes were diagnosis of COVID-19, SARS-CoV-2 RT-PCR results, sensitivity of SARS-CoV-2 RT-PCR and mortality during hospital admission. For the diagnostic risk score, we report discrimination, calibration and diagnostic accuracy of the model and simplified risk score and internal validation. RESULTS: 4008 patients were admitted between 2 March and 3 May 2020. 1792 patients (44.8%) were diagnosed with COVID-19, of whom 1391 were SARS-CoV-2 RT-PCR positive and 283 had only negative RT-PCRs. Compared with a clinical reference standard, sensitivity of RT-PCR in hospital patients was 83.1% (95% CI 81.2%-84.8%). Broadly, patients with false-negative RT-PCR COVID-19 and those confirmed by positive PCR had similar demographic and clinical characteristics but lower risk of intensive care unit admission and lower in-hospital mortality (adjusted OR 0.41, 95% CI 0.27-0.61). A simple diagnostic risk score comprising of age, sex, ethnicity, cough, fever or shortness of breath, National Early Warning Score 2, C reactive protein and chest radiograph appearance had moderate discrimination (area under the receiver-operator curve 0.83, 95% CI 0.82 to 0.85), good calibration and was internally validated. CONCLUSION: RT-PCR-negative COVID-19 is common and is associated with lower mortality despite similar presentation. Diagnostic risk scores could potentially help triage patients requiring admission but need external validation.

Experience of a novel community testing programme for COVID-19 in London: Lessons learnt.

We describe the London community testing programme developed for COVID-19, audit its effectiveness and report patient acceptability and patient adherence to isolation guidance, based upon a survey conducted with participants.Any patients meeting the Public Health England (PHE) case definition for COVID-19 who did not require hospital admission were eligible for community testing. 2,053 patients with suspected COVID-19 were tested in the community between January and March 2020. Of those tested, 75 (3.6%) were positive. 88% of patients that completed a patient survey felt safe and 82% agreed that community testing was preferable to hospital admission. 97% were able to remain within their own home during the isolation period but just 41% were able to reliably isolate from other members of their household.The London community testing programme allowed widespread testing for COVID-19 while minimising patient transport, hospital admissions and staff exposures. Community testing was acceptable to patients and preferable to admission to hospital. Patients were able to reliably isolate in their home but not from household contacts. The authors believe in the importance, feasibility and acceptability of community testing for COVID-19 as a part of a package of interventions to mitigate a second wave of infection.

Resolution of group B streptococcal panspinal epidural abscess in a patient with diabetes after treatment with ceftriaxone and linezolid.

Panspinal epidural abscesses are an extremely rare yet potentially fatal condition. Whether cases are best managed surgically or medically is currently controversial. A 63-year-old patient with diabetes presented initially with abdominal pain, back pain, urinary retention and constipation. He subsequently developed fevers, radicular pain and new-onset weakness in the right leg. MRI confirmed a panspinal epidural abscess extending from C7 to L5, with group B Streptococcus (GBS) cultured on sampling. Due to the significant risks of surgery he was managed conservatively, initially with ceftriaxone, and subsequently in combination with linezolid. Repeat MRI 3 months after presentation revealed complete resolution of the abscess. This case illustrates how conservative management is a valid option for patients with this condition, and supports the use of synergistic linezolid in this scenario. It also highlights how some cases may not initially present with the classically described triad of fever, back pain and loss of neurological function.

Gender-dependent differences in plasma matrix metalloproteinase-8 elevated in pulmonary tuberculosis.

Tuberculosis (TB) remains a global health pandemic and greater understanding of underlying pathogenesis is required to develop novel therapeutic and diagnostic approaches. Matrix metalloproteinases (MMPs) are emerging as key effectors of tissue destruction in TB but have not been comprehensively studied in plasma, nor have gender differences been investigated. We measured the plasma concentrations of MMPs in a carefully characterised, prospectively recruited clinical cohort of 380 individuals. The collagenases, MMP-1 and MMP-8, were elevated in plasma of patients with pulmonary TB relative to healthy controls, and MMP-7 (matrilysin) and MMP-9 (gelatinase B) were also increased. MMP-8 was TB-specific (p<0.001), not being elevated in symptomatic controls (symptoms suspicious of TB but active disease excluded). Plasma MMP-8 concentrations inversely correlated with body mass index. Plasma MMP-8 concentration was 1.51-fold higher in males than females with TB (p<0.05) and this difference was not due to greater disease severity in men. Gender-specific analysis of MMPs demonstrated consistent increase in MMP-1 and -8 in TB, but MMP-8 was a better discriminator for TB in men. Plasma collagenases are elevated in pulmonary TB and differ between men and women. Gender must be considered in investigation of TB immunopathology and development of novel diagnostic markers.

The seasonality of tuberculosis, sunlight, vitamin D, and household crowding.

BACKGROUND: Unlike other respiratory infections, tuberculosis diagnoses increase in summer. We performed an ecological analysis of this paradoxical seasonality in a Peruvian shantytown over 4 years. METHODS: Tuberculosis symptom-onset and diagnosis dates were recorded for 852 patients. Their tuberculosis-exposed cohabitants were tested for tuberculosis infection with the tuberculin skin test (n = 1389) and QuantiFERON assay (n = 576) and vitamin D concentrations (n = 195) quantified from randomly selected cohabitants. Crowding was calculated for all tuberculosis-affected households and daily sunlight records obtained. RESULTS: Fifty-seven percent of vitamin D measurements revealed deficiency (<50 nmol/L). Risk of deficiency was increased 2.0-fold by female sex (P < .001) and 1.4-fold by winter (P < .05). During the weeks following peak crowding and trough sunlight, there was a midwinter peak in vitamin D deficiency (P < .02). Peak vitamin D deficiency was followed 6 weeks later by a late-winter peak in tuberculin skin test positivity and 12 weeks after that by an early-summer peak in QuantiFERON positivity (both P < .04). Twelve weeks after peak QuantiFERON positivity, there was a midsummer peak in tuberculosis symptom onset (P < .05) followed after 3 weeks by a late-summer peak in tuberculosis diagnoses (P < .001). CONCLUSIONS: The intervals from midwinter peak crowding and trough sunlight to sequential peaks in vitamin D deficiency, tuberculosis infection, symptom onset, and diagnosis may explain the enigmatic late-summer peak in tuberculosis.

Spontaneous intraperitoneal rupture of a hepatic hydatid cyst with subsequent anaphylaxis: a case report.

Hydatid cyst rupture into the abdomen is a serious complication of cystic hydatid disease of the liver (Cystic Echinococcosis) with an incidence of up to 16% in some series and can result in anaphylaxis or anaphylactoid reactions in up to 12.5% of cases. At presentation, 36-40% of hydatid cysts have ruptured or become secondarily infected. Rupture can be microscopic or macroscopic and can be fatal without surgery. Hydatid disease of the liver is primarily caused by the tapeworm Echinococcus granulosus and occurs worldwide, with incidence of up to 200 per 100,000 in endemic areas. Our case describes a 24-year-old Bulgarian woman presenting with epigastric pain and evidence of anaphylaxis. Abdominal CT demonstrated a ruptured hydatid cyst in the left lobe of the liver. A partial left lobe hepatectomy, cholecystectomy, and peritoneal washout was performed with good effect. She was treated for anaphylaxis and received antihelminthic treatment with Albendazole and Praziquantel. She made a good recovery following surgery and medical treatment and was well on follow-up. Intraperitoneal rupture with anaphylaxis is a rare occurrence, and there do not seem to be any reported cases from UK centres prior to this.

Discriminating active from latent tuberculosis in patients presenting to community clinics.

BACKGROUND: Because of the high global prevalence of latent TB infection (LTBI), a key challenge in endemic settings is distinguishing patients with active TB from patients with overlapping clinical symptoms without active TB but with co-existing LTBI. Current methods are insufficiently accurate. Plasma proteomic fingerprinting can resolve this difficulty by providing a molecular snapshot defining disease state that can be used to develop point-of-care diagnostics. METHODS: Plasma and clinical data were obtained prospectively from patients attending community TB clinics in Peru and from household contacts. Plasma was subjected to high-throughput proteomic profiling by mass spectrometry. Statistical pattern recognition methods were used to define mass spectral patterns that distinguished patients with active TB from symptomatic controls with or without LTBI. RESULTS: 156 patients with active TB and 110 symptomatic controls (patients with respiratory symptoms without active TB) were investigated. Active TB patients were distinguishable from undifferentiated symptomatic controls with accuracy of 87% (sensitivity 84%, specificity 90%), from symptomatic controls with LTBI (accuracy of 87%, sensitivity 89%, specificity 82%) and from symptomatic controls without LTBI (accuracy 90%, sensitivity 90%, specificity 92%). CONCLUSIONS: We show that active TB can be distinguished accurately from LTBI in symptomatic clinic attenders using a plasma proteomic fingerprint. Translation of biomarkers derived from this study into a robust and affordable point-of-care format will have significant implications for recognition and control of active TB in high prevalence settings.

Impact on and use of an inner-city London Infectious Diseases Department by international migrants: a questionnaire survey.

BACKGROUND: The UK has witnessed a considerable increase in immigration in the past decade. Migrant may face barriers to accessing appropriate health care on arrival and the current focus on screening certain migrants for tuberculosis on arrival is considered inadequate. We assessed the implications for an inner-city London Infectious Diseases Department in a high migrant area. METHODS: We administered an anonymous 20-point questionnaire survey to all admitted patients during a 6 week period. Questions related to sociodemographic characteristics and clinical presentation. Analysis was by migration status (UK born vs overseas born). RESULTS: 111 of 133 patients completed the survey (response rate 83.4%). 58 (52.2%) were born in the UK; 53 (47.7%) of the cohort were overseas born. Overseas-born were over-represented in comparison to Census data for this survey site (47.7% vs 33.6%; proportional difference 0.142 [95% CI 0.049-0.235]; p = 0.002): overseas born reported 33 different countries of birth, most (73.6%) of whom arrived in the UK pre-1975 and self-reported their nationality as British. A smaller number (26.4%) were new migrants to the UK (< or =10 years), mostly refugees/asylum seekers. Overseas-born patients presented with a broad range and more severe spectrum of infections, differing from the UK-born population, resulting in two deaths in this group only. Presentation with a primary infection was associated with refugee/asylum status (n = 8; OR 6.35 [95% CI 1.28-31.50]; p = 0.023), being a new migrant (12; 10.62 [2.24-50.23]; p = 0.003), and being overseas born (31; 3.69 [1.67-8.18]; p = 0.001). Not having registered with a primary-care physician was associated with being overseas born, being a refugee/asylum seeker, being a new migrant, not having English as a first language, and being in the UK for < or =5 years. No significant differences were found between groups in terms of duration of illness prior to presentation or duration of hospitalisation (mean 11.74 days [SD 12.69]). CONCLUSION: Migrants presented with a range of more severe infections, which suggests they face barriers to accessing appropriate health care and screening both on arrival and once settled through primary care services. A more organised and holistic approach to migrant health care is required.