The place for remdesivir in COVID-19 treatment Young, Barnaby; Tan, Thuan Tong; Leo, Yee Sin
Lancet. Infectious diseases/The Lancet. Infectious diseases,
01/2021, Volume:
21, Issue:
1
Journal Article
Peer reviewed
Open access
Final results from the ACTT-1 study4 sponsored by the National Institute of Allergy and Infectious Diseases are broadly similar: this randomised, placebo-controlled trial of patients with COVID-19 ...reported a 29-day mortality of 11·4% in 541 individuals assigned remdesivir and 15·2% in 521 assigned placebo (hazard ratio HR 0·73, 95% CI 0·52–1·03).4 The characteristic immunopathology of COVID-19 might explain these disappointing results. An initial phase of intense viral replication progresses to respiratory failure at day 8–9 in severe infections due to the host inflammatory response.5 Although severe acute respiratory syndrome coronavirus 2 is still detectable during the hyperinflammatory phase, viral concentrations are substantially lower in this phase than in the first week of illness.6 Suppressing hyperinflammation with corticosteroids was shown to be efficacious at reducing mortality in the RECOVERY trial, with the greatest benefit among those requiring mechanical ventilation (mortality 29·3% in the dexamethasone group vs 41·4% in the usual care group; RR 0·64, 95% CI 0·51–0·81).7 This natural history suggests a window of opportunity for antivirals before fulminant inflammation sets in. In the SOLIDARITY trial,3 there was a trend towards reduced mortality with remdesivir among patients requiring low-flow or high-flow oxygen at baseline, but not among those requiring mechanical ventilation at baseline, albeit without reaching statistical significance (12·2% in the remdesivir group vs 13·8% in the control group; RR 0·85, 95% CI 0·66–1·09).
Moraxella catarrhalis causes respiratory tract infections in children and in adults with chronic obstructive pulmonary disease. It is often isolated as a copathogen with Haemophilus influenzae. The ...underlying mechanism for this cohabitation is unclear. Here, in clinical specimens from a patient with M. catarrhalis infection, we document that outer membrane vesicles (OMVs) carrying ubiquitous surface protein (Usp) A1 and UspA2 (hereafter, UspA1/A2) were secreted. Further analyses revealed that OMVs isolated in vitro also contained UspA1/A2, which mediate interactions with, among other proteins, the third component of the complement system (C3). OMVs from M. catarrhalis wild-type clinical strains bound to C3 and counteracted the complement cascade to a larger extent than did OMVs without UspA1/A2. In contrast, UspA1/A2-deficient OMVs were significantly weaker inhibitors of complement-dependent killing of H. influenzae. Thus, our results suggest that a novel strategy exists in which pathogens collaborate to conquer innate immunity and that the M. catarrhalis vaccine candidates UspA1/A2 play a major role in this interaction.
•Common viruses caused two-fifths of respiratory-illness-related hospitalizations, amidst a COVID-19 outbreak.•The co-infection rate between SARS-CoV-2 and other respiratory viruses was low, at ...1.4%.•No increased morbidity or mortality with COVID-19 co-infections.•In-hospital mortality and intubation lower for COVID-19 compared with other respiratory viruses.
During the ongoing COVID-19 outbreak, co-circulation of other common respiratory viruses can potentially result in co-infections; however, reported rates of co-infections for SARS-CoV-2 vary.
We sought to evaluate the prevalence and etiology of all community acquired viral respiratory infections requiring hospitalization during an ongoing COVID-19 outbreak, with a focus on co-infection rates and clinical outcomes.
Over a 10-week period, all admissions to our institution, the largest tertiary hospital in Singapore, were screened for respiratory symptoms, and COVID-19 as well as a panel of common respiratory viral pathogens were systematically tested for. Information was collated on clinical outcomes, including requirement for mechanical ventilation and in hospital mortality.
One-fifth (19.3%, 736/3807) of hospitalized inpatients with respiratory symptoms had a PCR-proven viral respiratory infection; of which 58.5% (431/736) tested positive for SARS-CoV-2 and 42.2% (311/736) tested positive for other common respiratory viruses. The rate of co-infection with SARS-CoV-2 was 1.4% (6/431); all patients with co-infection had mild disease and stayed in communal settings. The in-hospital mortality rate and proportion of COVID-19 patients requiring invasive ventilation was low, at around 1% of patients; these rates were lower than patients with other community-acquired respiratory viruses admitted over the same period (p < 0.01).
Even amidst an ongoing COVID-19 outbreak, common respiratory viruses still accounted for a substantial proportion of hospitalizations. Coinfections with SARS-CoV-2 were rare, with no observed increase in morbidity or mortality.
Patients with COVID-19 may present with respiratory syndromes indistinguishable from those caused by common viruses. Early isolation and containment is challenging. Although screening all patients ...with respiratory symptoms for COVID-19 has been recommended, the practicality of such an effort has yet to be assessed.
Over a 6-week period during a SARS-CoV-2 outbreak, our institution introduced a "respiratory surveillance ward" (RSW) to segregate all patients with respiratory symptoms in designated areas, where appropriate personal protective equipment (PPE) could be utilized until SARS-CoV-2 testing was done. Patients could be transferred when SARS-CoV-2 tests were negative on 2 consecutive occasions, 24 hours apart.
Over the study period, 1,178 patients were admitted to the RSWs. The mean length-of-stay (LOS) was 1.89 days (SD, 1.23). Among confirmed cases of pneumonia admitted to the RSW, 5 of 310 patients (1.61%) tested positive for SARS-CoV-2. This finding was comparable to the pickup rate from our isolation ward. In total, 126 HCWs were potentially exposed to these cases; however, only 3 (2.38%) required quarantine because most used appropriate PPE. In addition, 13 inpatients overlapped with the index cases during their stay in the RSW; of these 13 exposed inpatients, 1 patient subsequently developed COVID-19 after exposure. No patient-HCW transmission was detected despite intensive surveillance.
Our institution successfully utilized the strategy of an RSW over a 6-week period to contain a cluster of COVID-19 cases and to prevent patient-HCW transmission. However, this method was resource-intensive in terms of testing and bed capacity.
Staff surveillance is crucial during the containment phase of a pandemic to help reduce potential healthcare-associated transmission and sustain good staff morale. During an outbreak of SARS-COV-2 ...with community transmission, our institution used an integrated strategy for early detection and containment of COVID-19 cases among healthcare workers (HCWs).
Our strategy comprised 3 key components: (1) enforcing reporting of HCWs with acute respiratory illness (ARI) to our institution's staff clinic for monitoring; (2) conducting ongoing syndromic surveillance to obtain early warning of potential clusters of COVID-19; and (3) outbreak investigation and management.
Over a 16-week surveillance period, we detected 14 cases of COVID-19 among HCWs with ARI symptoms. Two of the cases were linked epidemiologically and thus constituted a COVID-19 cluster with intrahospital HCW-HCW transmission; we also detected 1 family cluster and 2 clusters among HCWs who shared accommodation. No transmission to HCWs or patients was detected after containment measures were instituted. Early detection minimized the number of HCWs requiring quarantine, hence preserving continuity of service during an ongoing pandemic.
An integrated surveillance strategy, outbreak management, and encouraging individual responsibility were successful in early detection of clusters of COVID-19 among HCWs. With ongoing local transmission, vigilance must be maintained for intrahospital spread in nonclinical areas where social mingling of HCWs occurs. Because most individuals with COVID-19 have mild symptoms, addressing presenteeism is crucial to minimize potential staff and patient exposure.
Angiosarcomas are rare, clinically aggressive tumors with limited treatment options and a dismal prognosis. We analyzed angiosarcomas from 68 patients, integrating information from multiomic ...sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence for tumor-infiltrating immune cells. Through whole-genome sequencing (n = 18), 50% of the cutaneous head and neck angiosarcomas exhibited higher tumor mutation burden (TMB) and UV mutational signatures; others were mutationally quiet and non-UV driven. NanoString profiling revealed 3 distinct patient clusters represented by lack (clusters 1 and 2) or enrichment (cluster 3) of immune-related signaling and immune cells. Neutrophils (CD15+), macrophages (CD68+), cytotoxic T cells (CD8+), Tregs (FOXP3+), and PD-L1+ cells were enriched in cluster 3 relative to clusters 2 and 1. Likewise, tumor inflammation signature (TIS) scores were highest in cluster 3 (7.54 vs. 6.71 vs. 5.75, respectively; P < 0.0001). Head and neck angiosarcomas were predominant in clusters 1 and 3, providing the rationale for checkpoint immunotherapy, especially in the latter subgroup with both high TMB and TIS scores. Cluster 2 was enriched for secondary angiosarcomas and exhibited higher expression of DNMT1, BRD3/4, MYC, HRAS, and PDGFRB, in keeping with the upregulation of epigenetic and oncogenic signaling pathways amenable to targeted therapies. Molecular and immunological dissection of angiosarcomas may provide insights into opportunities for precision medicine.
Burkholderia pseudomallei is a gram negative bacteria that causes a spectrum of human diseases in the tropics. Although melioidosis is endemic in Southeast Asia, large clinical case series were ...rarely reported from metropolitan Singapore.
This is a retrospective study of 219 consecutive patients with culture proven infections due to Burkholderia pseudomallei between the years 2001 to 2016 managed in Singapore General Hospital (SGH). We aimed to review local patients' characteristics and identify clinical factors associated with mortality and recurrent melioidosis.
Culture proven melioidosis occurred in 219 patients, 83.1% were male with a mean age of 55.7 ± 14.3 years and 63.0% had diabetes mellitus. Most patients (71.7%) present within 4 weeks of symptom onset and the most common symptom was fever. The majority of patients had bacteremia (67.6%) and had infection involving the respiratory system (71.2%), presenting most frequently with multi-lobar pneumonia. Thirty-four (15.5%) deaths occurred during the initial hospitalisation with a median time from presentation to death of 6.0 days (interquartile range: 2.8-16.3). Twelve patients demised before the diagnosis of melioidosis was made. Univariate analysis identified patients with symptom duration of longer than 4 weeks, bacteremia, and disease requiring mechanical ventilation, inotropic support or temporary dialysis as factors that were significantly associated with mortality. Having bacteremia and disease requiring mechanical ventilation remained statistically significant factors in the multivariable analysis. Twenty-one (11.4%) patients developed at least 1 episode of culture proven recurrent infection, with 15 recurring within the first 12 months of their initial infection. Eight patients developed more than 1 episode of culture proven recurrent infection. Patients with multifocal infection were more likely to develop recurrent infection.
In metropolitan Singapore, melioidosis was associated with mortality in excess of 15%, where more than a third occurred before diagnosis. This study reminds local physicians that melioidosis is still a serious infection affecting local male diabetic patients and an important differential diagnosis in a patient presenting with severe multi-lobar pneumonia and septic shock. Recurrent infections occurred in 11.4% and the weight-based dosing of oral eradication antibiotics may improve the management of this disease locally.
•In hematology, Pneumocystis jirovecii pneumonia prophylaxis is recommended for selected patients.•Intravenous pentamidine is a potential alternative agent.•A total of 202 unique patients received ...239 courses of intravenous pentamidine 4 mg/kg (maximum 300 mg).•There was no breakthrough P. jirovecii pneumonia infection or adverse effects.
In hematology, prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for patients undergoing hematopoietic stem cell transplantation and in selected categories of intensive chemotherapy for hematologic malignancies. Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended first-line agent; however, its use is not straightforward. Inhaled pentamidine is the recommended second-line agent; however, aerosolized medications were discouraged during respiratory virus outbreaks, especially during the COVID-19 pandemic, in view of potential contamination risks. Intravenous (IV) pentamidine is a potential alternative agent. We evaluated the effectiveness and tolerability of IV pentamidine use for PCP prophylaxis in adult allogeneic hematopoietic stem cell transplantation recipients and patients with hematologic malignancies during COVID-19.
A total of 202 unique patients who received 239 courses of IV pentamidine, with a median of three doses received (1-29). The largest group of the patients (49.5%) who received IV pentamidine were undergoing or had received a hematopoietic stem cell transplant. The most common reason for not using TMP-SMX prophylaxis was cytopenia (34.7%). We have no patients who had breakthrough PCP infection while on IV pentamidine. None of the patients developed an infusion reaction or experienced adverse effects from IV pentamidine.
Pentamidine administered IV monthly is safe and effective.
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