Coronavirus Disease 2019-Associated Pulmonary Aspergillosis: Reframing the Debate.

Background: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has been reported in ~5%-10% of critically ill COVID-19 patients. However, incidence varies widely (0%-33%) across hospitals, most cases are unproven, and CAPA definitions and clinical relevance are debated. Methods: We reframed the debate by asking, what is the likelihood that patients with CAPA have invasive aspergillosis? We use diagnostic test performance in other clinical settings to estimate positive predictive values (PPVs) and negative predictive values (NPVs) of CAPA criteria for invasive aspergillosis in populations with varying CAPA incidence. Results: In a population with CAPA incidence of 10%, anticipated PPV/NPV of diagnostic criteria are ~30%-60%/≥97%; ~3%-5% of tested cohort would be anticipated to have true invasive aspergillosis. If CAPA incidence is 2%-3%, anticipated PPV and NPV are ~8%-30%/>99%. Conclusions: Depending on local epidemiology and clinical details of a given case, PPVs and NPVs may be useful in guiding antifungal therapy. We incorporate this model into a stepwise strategy for diagnosing and managing CAPA.

Coronavirus disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA): Re-framing the debate

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has been reported in ~5%-10% of critically-ill COVID-19 patients. However, incidence varies widely (0%-33%) across hospitals, most cases are unproven, and CAPA definitions and clinical relevance are debated. We re-frame the debate by asking, what is the likelihood that patients with CAPA have invasive aspergillosis? We use diagnostic test performance in other clinical settings to estimate positive and negative predictive values (PPV, NPV) of CAPA criteria for invasive aspergillosis in populations with varying CAPA incidence. In a population with CAPA incidence of 10%, anticipated PPV/NPV of diagnostic criteria are ~30%-60%/≥97%;~3%-5% of tested cohort would be anticipated to have true invasive aspergillosis. If CAPA incidence is 2%-3%, anticipated PPV/NPV are ~8%-30%/>99%. Depending on local epidemiology and clinical details of a given case, PPVs/NPVs may be useful in guiding antifungal therapy. We incorporate this model into a stepwise strategy for diagnosing and managing CAPA.

Invasive Pulmonary Aspergillosis Complicating Noninfluenza Respiratory Viral Infections in Solid Organ Transplant Recipients.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a complication of severe influenza and coronavirus disease 2019. The extent to which other respiratory viral infections (RVIs) predispose to IPA is unclear. METHODS: We performed a retrospective review of IPA occurring within 90 days of respiratory syncytial virus (RSV), parainfluenza, or adenovirus infections (noninfluenza respiratory viral infections [NI-RVIs]) in patients who underwent solid organ transplant between 1/15/2011 and 12/19/2017. RESULTS: At a median post-transplant follow-up of 43.4 months, 221 of 2986 patients (7.4%) developed 255 RSV, parainfluenza, or adenovirus infections. IPA complicating these NI-RVIs was exclusively observed in lung and small bowel transplant recipients, in whom incidence was 5% and 33%, respectively. Cumulative prednisone doses >140mg within 7 days and pneumonia at the time of NI-RVI were independent risk factors for IPA (odds ratio [OR], 22.6; 95% CI, 4.5-112; and OR, 7.2; 95% CI, 1.6-31.7; respectively). Mortality at 180 days following NI-RVI was 27% and 7% among patients with and without IPA, respectively (P = .04). CONCLUSIONS: In conclusion, IPA can complicate RSV, parainfluenza, and adenovirus infection in lung and small bowel transplant recipients. Future research is needed on the epidemiology of IPA complicating various RVIs. In the interim, physicians should be aware of this complication.

Single Dose of an mRNA Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) Vaccine Is Associated With Lower Nasopharyngeal Viral Load Among Nursing Home Residents With Asymptomatic Coronavirus Disease 2019 (COVID-19).

In nursing home residents with asymptomatic COVID-19 diagnosed through twice-weekly surveillance testing, single-dose BNT162b2 vaccination (Pfizer-BioNTech) was associated with -2.4 mean log10 lower nasopharyngeal viral load than detected in absence of vaccination (P = .004). Since viral load is linked to transmission, single-dose mRNA SARS-CoV-2 vaccination may help control outbreaks.

Introduction of the BNT162b2 vaccine during a COVID-19 nursing home outbreak.

BACKGROUND: Coronavirus disease 2019 (COVID-19) outbreaks often occur in nursing homes and prompt frequent surveillance testing for SARS-CoV-2. A single dose of the BNT162b2 vaccine reduces viral load and transmission. In this study, we describe the real-world efficacy of BNT162b2 single-dose vaccination during a COVID-19 outbreak at a Veterans Affairs Community Living Center (CLC). METHODS: From 12/2/20 to 5/14/21, twice weekly antigen testing was used to detect COVID-19 among 146 residents at the CLC. Residents without a prior history of COVID-19 who agreed to immunization were vaccinated with the BNT162b2 vaccine on 12/16/20 and 1/6/21. Single-dose vaccine efficacy was determined for days 1-21 and days 14-21 after the first vaccine dose. RESULTS: The outbreak occurred from 12/2/20 to 1/7/21 with an attack rate of 30.8% (45/146); 46.7% (21/45) of the cases were due to asymptomatic COVID-19. One unit accounted for 77.8% (35/45) of the cases. In the vaccine analysis, 116 residents were a median age of 74.5 years and 93.1% (108/116) had ≥ 1 comorbid condition. Between the first and second dose, 15.5% (15/97) of vaccinated residents, and 21.2% (4/19) of unvaccinated residents developed COVID-19 (P = .81). One week after the second dose, no cases of COVID-19 occurred. CONCLUSIONS: Albeit limited by the small numbers, a single dose of the BNT162b2 vaccine was not efficacious at preventing COVID-19 during this nursing home outbreak.

Invasive mould disease in fatal COVID-19: a systematic review of autopsies.

Invasive mould disease (IMD) might affect up to a third of critically ill patients with COVID-19. COVID-19-associated pulmonary aspergillosis (CAPA) is typically diagnosed on the basis of a combination of non-specific clinical, radiographical, and mycological findings, but whether most cases represent invasive disease is unresolved. We systematically reviewed autopsy series of three or more decedents with COVID-19 for evidence of IMD. We searched PubMed, Web of Science, OVID (Embase), and medRxiv for studies in English or French published from Jan 1, 2019, to Sept 26, 2020. We identified 1070 references, of which 50 studies met the criteria. These studies described autopsies from 677 decedents, with individual-level data for 443 decedents. The median age was 70·0 years (IQR 57·0-79·0). Of decedents with individual-level data, 133 (30%) had diabetes, 97 (22%) had pre-existing lung disease, and 27 (6%) had immunocompromising conditions. Of 548 decedents with such data, 320 (58%) received invasive mechanical ventilation; among 140 decedents for whom this was known, ventilation was for a median of 9·0 days (IQR 5·0-20·0). Treatment included immunomodulation in 60 decedents and antifungals in 50 decedents. Autopsy-proven IMD occurred in 11 (2%) of 677 decedents, including eight CAPA, two unspecified IMD, and one disseminated mucormycosis. Among 320 decedents who received mechanical ventilation, six (2%) had IMD. We conclude that IMD, including CAPA, is an uncommon autopsy finding in COVID-19.

Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis.

PURPOSE: Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance. METHODS: A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology. RESULTS: The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients' clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients. CONCLUSION: CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study.

Key considerations on the potential impacts of the COVID-19 pandemic on antimicrobial resistance research and surveillance.

Antibiotic use in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients during the COVID-19 pandemic has exceeded the incidence of bacterial coinfections and secondary infections, suggesting inappropriate and excessive prescribing. Even in settings with established antimicrobial stewardship (AMS) programmes, there were weaknesses exposed regarding appropriate antibiotic use in the context of the pandemic. Moreover, antimicrobial resistance (AMR) surveillance and AMS have been deprioritised with diversion of health system resources to the pandemic response. This experience highlights deficiencies in AMR containment and mitigation strategies that require urgent attention from clinical and scientific communities. These include the need to implement diagnostic stewardship to assess the global incidence of coinfections and secondary infections in COVID-19 patients, including those by multidrug-resistant pathogens, to identify patients most likely to benefit from antibiotic treatment and identify when antibiotics can be safely withheld, de-escalated or discontinued. Long-term global surveillance of clinical and societal antibiotic use and resistance trends is required to prepare for subsequent changes in AMR epidemiology, while ensuring uninterrupted supply chains and preventing drug shortages and stock outs. These interventions present implementation challenges in resource-constrained settings, making a case for implementation research on AMR. Knowledge and support for these practices will come from internationally coordinated, targeted research on AMR, supporting the preparation for future challenges from emerging AMR in the context of the current COVID-19 pandemic or future pandemics.

Antimicrobial resistance research in a post-pandemic world: Insights on antimicrobial resistance research in the COVID-19 pandemic.

Antimicrobial resistance must be recognised as a global societal priority - even in the face of the worldwide challenge of the COVID-19 pandemic. COVID-19 has illustrated the vulnerability of our healthcare systems in co-managing multiple infectious disease threats as resources for monitoring and detecting, and conducting research on antimicrobial resistance have been compromised during the pandemic. The increased awareness of the importance of infectious diseases, clinical microbiology and infection control and lessons learnt during the COVID-19 pandemic should be exploited to ensure that emergence of future infectious disease threats, including those related to AMR, are minimised. Harnessing the public understanding of the relevance of infectious diseases towards the long-term pandemic of AMR could have major implications for promoting good practices about the control of AMR transmission.

SARS-CoV-2 is associated with high viral loads in asymptomatic and recently symptomatic healthcare workers.

BACKGROUND: Healthcare workers (HCW) are at increased risk of SARS-CoV-2 infection from both patients and other HCW with coronavirus disease 2019 (COVID-19). RT-PCR cycle threshold (Ct) values of SARS-CoV-2 ≤ 34 and the first 7-9 days of symptoms are associated with enhanced infectivity. We determined Ct values and duration of symptoms of HCW with a positive SARS-CoV-2 test. As HCW often assume their greatest risk of acquiring SARS-CoV-2 is working on a COVID-19 unit, we also determined Ct values and symptom duration of inpatients with a positive SARS-CoV-2 test. METHODS: From 6/24/2020-8/23/2020, Ct values and duration of symptoms from 13 HCW, 12 outpatients, and 28 inpatients who had a positive nasopharyngeal swab for SARS-CoV-2 were analyzed. RESULTS: Among HCW with a positive SARS-CoV-2 test, 46.2% (6/13) were asymptomatic and requested testing due to an exposure to someone with COVID-19; 83.3% (5/6) of those exposures occurred in the community rather than in the hospital. The median Ct value of HCW was 23.2, and 84.6% (11/13) had a Ct value ≤ 34. The median Ct value of 29.0 among outpatients with COVID-19 did not significantly differ from HCW. In contrast, inpatients with a positive SARS-CoV-2 test had a median Ct value of 34.0 (p = 0.003), which translated into a median ~1,000-fold lower viral load than observed in HCW. Among those with symptoms related to COVID-19, no (0/6) HCW compared to 50% (6/12) of inpatients had symptoms for at least one week (p = 0.04). CONCLUSIONS: At our institution, asymptomatic COVID-19 accounted for nearly half of the cases among HCW. Symptomatic HCW had high viral loads and short duration of symptoms, both of which are associated with peak infectivity. Infection prevention programs should educate HCW on these findings in an effort to increase adherence to the requirement to maintain six feet separation in workspaces and breakrooms, in addition to consistently wearing personal protection equipment.

Bacterial Superinfections Among Persons With Coronavirus Disease 2019: A Comprehensive Review of Data From Postmortem Studies.

BACKGROUND: Limited clinical data suggest a ~16% prevalence of bacterial superinfections among critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: We reviewed postmortem studies of patients with COVID-19 published in English through September 26, 2020, for histopathologic findings consistent with bacterial lung infections. RESULTS: Worldwide, 621 patients from 75 studies were included. The quality of data was uneven, likely because identifying superinfections was not a major objective in 96% (72/75) of studies. Histopathology consistent with a potential lung superinfection was reported in 32% (200/621) of patients (22-96 years old; 66% men). Types of infections were pneumonia (95%), abscesses or empyema (3.5%), and septic emboli (1.5%). Seventy-three percent of pneumonias were focal rather than diffuse. The predominant histopathologic findings were intra-alveolar neutrophilic infiltrations that were distinct from those typical of COVID-19-associated diffuse alveolar damage. In studies with available data, 79% of patients received antimicrobial treatment; the most common agents were beta-lactam/beta-lactamase inhibitors (48%), macrolides (16%), cephalosoprins (12%), and carbapenems (6%). Superinfections were proven by direct visualization or recovery of bacteria in 25.5% (51/200) of potential cases and 8% of all patients in postmortem studies. In rank order, pathogens included Acinetobacter baumannii, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Lung superinfections were the cause of death in 16% of potential cases and 3% of all patients with COVID-19. CONCLUSIONS: Potential bacterial lung superinfections were evident at postmortem examination in 32% of persons who died with COVID-19 (proven, 8%; possible, 24%), but they were uncommonly the cause of death.

Coronavirus Disease 2019, Superinfections, and Antimicrobial Development: What Can We Expect?

Coronavirus disease 2019 (COVID-19) arose at a time of great concern about antimicrobial resistance (AMR). No studies have specifically assessed COVID-19-associated superinfections or AMR. Based on limited data from case series, it is reasonable to anticipate that an appreciable minority of patients with severe COVID-19 will develop superinfections, most commonly pneumonia due to nosocomial bacteria and Aspergillus. Microbiology and AMR patterns are likely to reflect institutional ecology. Broad-spectrum antimicrobial use is likely to be widespread among hospitalized patients, both as directed and empiric therapy. Stewardship will have a crucial role in limiting unnecessary antimicrobial use and AMR. Congressional COVID-19 relief bills are considering antimicrobial reimbursement reforms and antimicrobial subscription models, but it is unclear if these will be included in final legislation. Prospective studies on COVID-19 superinfections are needed, data from which can inform rational antimicrobial treatment and stewardship strategies, and models for market reform and sustainable drug development.

Impact of the Coronavirus Disease 2019 Pandemic on Outpatient Antibiotic Prescriptions in the United States.

In April 2020, there were significant reductions in prescription fills of each of the 10 most prescribed outpatient antibiotics in the United States. Monthly azithromycin, amoxicillin-clavulanate, and levofloxacin fills did not rebound significantly from April through July 2020. Coronavirus disease 2019 had an immediate and sustained impact on US outpatient antibiotic prescribing.

PRO: The COVID-19 pandemic will result in increased antimicrobial resistance rates.

We argue that the COVID-19 pandemic will result in increased antimicrobial resistance (AMR). Broad-spectrum antibiotic use is common among hospitalized COVID-19 patients and in excess of reported secondary infection rates, suggesting unnecessary prescribing. Selection pressure is likely to be particularly intense in COVID-19 epicentres and within non-epicentre hospital units dedicated to COVID-19 care. Risk factors that increase the likelihood of hospitalization or poor outcomes among COVID-19 patients, such as advanced age, nursing home residence, debilitation, diabetes and cardiopulmonary or other underlying systemic diseases, also predispose to AMR infections. Worry for AMR emergence is heightened since first-wave COVID-19 epicentres were also AMR epicentres. Disruptive direct and indirect effects of COVID-19 globally on economic systems, governance and public health expenditure and infrastructure may fuel AMR spread. We anticipate that the impact of COVID-19 on AMR will vary between epicentres and non-epicentres, by geographic region, hospital to hospital within regions and within specific hospital units.

Antibiotic Consumption and Stewardship at a Hospital outside of an Early Coronavirus Disease 2019 Epicenter.

There are scant data on the impact of coronavirus disease 2019 (COVID-19) on hospital antibiotic consumption, and no data from outside epicenters. At our nonepicenter hospital, antibiotic days of therapy (DOT) and bed days of care (BDOC) were reduced by 151.5/month and 285/month, respectively, for March to June 2020 compared to 2018-2019 (P = 0.001 and P < 0.001). DOT per 1,000 BDOC was increased (8.1/month; P = 0.001). COVID-19 will impact antibiotic consumption, stewardship, and resistance in ways that will likely differ temporally and by region.

Invasive Aspergillosis as an Under-recognized Superinfection in COVID-19.

Pulmonary aspergillosis has been increasingly reported following severe respiratory viral infections. Millions have been infected by SARS-CoV-2, placing large numbers of patients at-risk for COVID-19 associated pulmonary aspergillosis (CAPA). Prompt recognition of this syndrome and is paramount to improve outcomes.

Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion.

PURPOSE: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies. METHODS: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus. RESULTS: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung. CONCLUSION: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA.