Coronavirus and other airborne agents with pandemic potential.

The recent emergence of a novel coronavirus (severe acute respiratory syndrome coronavirus 2) has caused a pandemic, which is the most severe infectious disease outbreak in many decades. Other infective agents such as influenza as well as other neglected viruses such as Lassa virus, Nipah virus or poxviruses are also a cause for concern owing to their attack rate and potential for global spread. Drug-resistant bacteria, such as Mycobacterium tuberculosis, are already a significant public health issue in many countries, and it is expected that they will be expanding in the near future. Finally, airborne bioterrorism agents have high morbidity and mortality rates and should be looked with concern in the current international unrest.

Viral hepatitis in persons living with HIV in the post-COVID era.

Coinfection with hepatitis viruses A to E is frequent in persons living with HIV (PLWH) and causes significant morbidity and mortality. Oro-fecal transmissible hepatitis A and E mostly produce acute self-limited episodes in poor income regions and in non-vaccinated travelers. In high-income countries, outbreaks of hepatitis A occur in men having sex with men (MSM) and chronic hepatitis E is occasionally reported among PLWH with severe immunodeficiency. Chronic hepatitis B, C, and D are frequent in PLWH in highly endemic regions and globally in persons who inject drugs (PWID) and MSM. Progression to liver cirrhosis and development of hepatocellular carcinoma (HCC) is major clinical complications in coinfected patients. Current estimates for PLWH are of 38 million worldwide. Roughly 12% have chronic viral hepatitis (5 million). Coinfection figures are of 5-10% for HBV (2-4 million), 4% for HCV (1.5 million), and 15% of HBsAg+ for HDV (0.5 million). Oral direct-acting antivirals (DAA) cure almost all treated patients with hepatitis C. However, given that there is no protective HCV immunity, PLWH with high-risk behaviors may experience HCV reinfection episodes. Tenofovir is the drug of choice in PLWH with chronic hepatitis B, given its dual effect on HIV and HBV. Lifelong oral tenofovir suppresses HBV replication and ameliorate liver damage. However, the risk of HCC persists even in the absence of cirrhosis. Finally, HDV causes the worst of viral hepatitis with faster progression to cirrhosis and HCC. An entry inhibitor, bulevirtide, has recently been approved and another drug, lonafarnib, is completing Phase 3 trials. Combination antiviral therapy for hepatitis D could improve dramatically the poor prognosis of HIV-HDV coinfected patients. The resumption of good medical practices in PLWH after the big disruption caused by COVID-19 will reduce the burden of viral hepatitis coinfections. Renewed efforts on HAV and HBV vaccination of susceptible individuals and earlier and wider prescription of antiviral therapy for HBV, HCV, and/or HDV coinfection should be prioritized in PLWH. The benefits of innovative strategies for viral hepatitis, including pre-exposure prophylaxis or use of long-acting antivirals, warrant further consideration in PLWH.

Cross-Sectional Analysis of Risk Factors for Outbreak of COVID-19 in Nursing Homes for Older Adults in the Community of Madrid.

INTRODUCTION: Nursing homes for older adults have been hot spots for SARS-CoV-2 infections and mortality. Factors that facilitate COVID-19 outbreaks in these settings need to be assessed. METHODS: A retrospective cross-sectional study of a cohort of residents and workers in nursing homes taking occasion of a point seroprevalence survey was done in the Community of Madrid. Factors related to outbreaks in these facilities were analyzed. RESULTS: A total of 369 nursing homes for older adults, making a population of 23,756 residents and 20,795 staff members, were followed from July to December 2020. There were 54.2% SARS-CoV-2 IgG+ results in residents and in 32.2% of workers. Sixty-two nursing homes (16.8%) had an outbreak during the follow-up. Nursing homes with outbreaks had more residents than those without (median number of 81 [IQR, 74] vs. 50 [IQR, 56], p < 0.001). Seropositivity for SARS-CoV-2 was lower in facilities with versus without outbreaks, for residents (42.2% [IQR, 55.7] vs. 58.7% [IQR, 43.4], p = 0.002) and for workers (23.9% [IQR, 26.4] vs. 32.8% [IQR, 26.3], p = 0.01). For both residents and staff, the number of infections in outbreaks was larger in centers with lower, as compared with intermediate or high seroprevalence. The size of the facility did not correlate with the number of cases in the outbreak. Taking the incidence of cases in the community as a time-dependent variable (p = 0.03), a Cox analysis (HR [95% CI], p) showed that intermediate or high seroprevalence among residents in the facility was related to a reduction of 55% (0.45 [0.25-0.80], p = 0.007) and 78% (0.22 [0.10-0.48], p < 0.001) in the risk of outbreaks, respectively, as compared with low sero-prevalence. Also, as compared with smaller, medium (1.91 [1.00-3.65], p = 0.05) or large centers (4.57 [2.38-8.75], p < 0.001) had more respective risk of outbreaks. CONCLUSIONS: The size of the facility and the seroprevalence among residents in nursing homes, and the incidence of infections in the community, are associated with the risk of outbreaks of COVID-19. Facilities with greater proportion of seropositives had smaller number of cases. Monitoring of immunity in nursing homes may help detect those at a greater risk of future cases.

Temporal Series Analysis of Population Cycle Threshold Counts as a Predictor of Surge in Cases and Hospitalizations during the SARS-CoV-2 Pandemic.

Tools to predict surges in cases and hospitalizations during the COVID-19 pandemic may help guide public health decisions. Low cycle threshold (CT) counts may indicate greater SARS-CoV-2 concentrations in the respiratory tract, and thereby may be used as a surrogate marker of enhanced viral transmission. Several population studies have found an association between the oscillations in the mean CT over time and the evolution of the pandemic. For the first time, we applied temporal series analysis (Granger-type causality) to validate the CT counts as an epidemiological marker of forthcoming pandemic waves using samples and analyzing cases and hospital admissions during the third pandemic wave (October 2020 to May 2021) in Madrid. A total of 22,906 SARS-CoV-2 RT-PCR-positive nasopharyngeal swabs were evaluated; the mean CT value was 27.4 (SD: 2.1) (22.2% below 20 cycles). During this period, 422,110 cases and 36,727 hospital admissions were also recorded. A temporal association was found between the CT counts and the cases of COVID-19 with a lag of 9-10 days (p ≤ 0.01) and hospital admissions by COVID-19 (p < 0.04) with a lag of 2-6 days. According to a validated method to prove associations between variables that change over time, the short-term evolution of average CT counts in the population may forecast the evolution of the COVID-19 pandemic.

Pre-Exposure Prophylaxis for viral infections other than HIV

SUMMARY The battle against human viral infections has historically relied on two medical strategies, namely vaccines to protect from contagion and antivirals to treat infected patients. In the absence of vaccines, antivirals have occasionally been used as peri-exposure prophylaxis, given either before (pre-exposure prophylaxis) or right after (post-exposure prophylaxis). In an unprecedented way, the use of antiretrovirals as chemoprophylaxis has triumphed in the HIV field. Indeed, oral antiretrovirals given either daily or at demand to HIV-uninfected individuals engaged in high-risk behaviors protect from contagion. More recently, the advent of long-acting formulations has allowed HIV protection following intramuscular injections every three months. Can we envision a similar prophylactic strategy for other human viral infections? The advent of such ‘chemical vaccines’ would fill an unmet need when classical vaccines do not exist, cannot be recommended, immune responses are suboptimal, escape mutants emerge or immunity wanes. In this review, we discuss the opportunities for antiviral chemoprophylaxis for viral hepatitis B and C, retroviruses HTLV-1 and HIV-2, and respiratory viruses influenza and SARS-CoV-2, among others.

Humoral and Cellular Response after mRNA Vaccination in Nursing Homes: Influence of Age and of History of COVID-19.

BACKGROUND: Most residents and staff in nursing homes have received full vaccination. Factors related to the immune response to vaccination might be related to the risk of future severe COVID-19 and may guide the need for vaccine boosters. DESIGN: Nursing homes that were tested in a point survey in July-October 2020 were again analyzed after a vaccination campaign in June-July 2021. Immune responses according to IgG against nucleocapsid and spike antigens, and CD4 and CD8 interferon-gamma release assay against spike antigens, were evaluated. RESULTS: A total of 1973 subjects were tested (61.7% residents, 48.3% staff), with a mean (SD) follow-up of 46.4 (3.6) weeks between assessments. More than half of residents and more than a third of staff had evidence of COVID-19 before vaccination; 26.9% and 22.7% had seroreversion of IgG-N, and 8.9% and 4.6% had IgG-N seroconversion at second assessment, respectively. Up to 96.8% of residents and 98.1% of workers had positive IgG-S after a mean of 19.9 (2.1) weeks after vaccination. In residents with vs without a history of COVID-19, IgG-S titers were 4.11 (0.54) vs. 2.73 (0.74) logAU/mL (p < 0.001); in workers these titers were 3.89 (0.61) vs. 3.15 (0.64) logAU/mL (p < 0.001). Linear regression analysis showed that younger age (OR: -0.03 per 10 years-older [95% CI, -0.04 to -0.02], p < 0.001) and evidence of COVID-19 (OR: 1.14 [95% CI, 1.08 to 1.20], p < 0.001) are associated with greater IgG-S titers after vaccination. A direct association was found between IgG-S titers and the intensity of IFN-gamma response against spike antigens. CONCLUSIONS: Waning of humoral response and reinfection seems to be more frequent in older as compared to younger adults, although cellular responses shortly after vaccination are comparable between these groups. Younger age and prior COVID-19 are related to greater humoral response after vaccination against SARS-CoV-2.

Impact of scaling up SARS-CoV-2 vaccination on COVID-19 hospitalizations in Spain.

BACKGROUND: The advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has been associated with a significant decline in coronavirus disease 2019 (COVID-19) hospitalizations and deaths. However, little is known about the benefits experienced by different population groups and/or using distinct vaccines. METHODS: The Spanish public registry was analyzed to examine associations between weekly vaccination scale-up and the incidence of COVID-19 hospitalizations by age, sex, and vaccine modality. The study period extended from January 2020 to June 2021. RESULTS: A total of 363 960 COVID-19 hospitalizations were recorded in Spain during the study period, with three peaks in March 2020, November 2020, and January 2021. The incidence of COVID-19 hospitalizations per 100 000 population increased exponentially with age, on average 71.5% for each decade older. Overall, individuals older than 60 years of age accounted for 65% of all COVID-19 hospitalizations. The speedy vaccination rollout since the end of 2020, with prioritization of the elderly groups, resulted in a rapid fall in COVID-19 hospitalizations starting in February 2021. The benefit was already noticed 3-4 weeks after the first dose, regardless of the vaccine modality. CONCLUSIONS: COVID-19 hospitalizations increased exponentially with age in all three peaks of SARS-CoV-2 infection in Spain. Early mass vaccination of people over 60 years of age prevented a fourth wave of COVID-19 hospitalizations during the spring of 2021.

Oral antivirals for the prevention and treatment of SARS-CoV-2 infection.

Vaccines and antivirals are the classical weapons deployed to contain, prevent, and treat life-threatening viral illnesses. Specifically, for SARS-CoV-2 infection, vaccines protect against severe COVID-19 disease manifestations and complications. However, waning immunity and emergence of vaccine escape mutants remains a growing threat. This is highlighted by the current surge of the omicron COVID-19 variant. Thus, there is a race to find treatment alternatives. We contend that oral small molecule antivirals that halt SARSCoV- 2 infection are essential. Compared to currently available monoclonal antibodies and remdesivir, where parenteral administration is required, oral antivirals offer treatments in an outpatient setting with dissemination available on a larger scale. In response to this need at 2021's end, regulatory agencies provided emergency use authorization for both molnupiravir and nirmatrelvir. These medicines act on the viral polymerase and protease, respectively. Each is given for 5 days and can reduce disease progression by 30% and 89%, respectively. The advent of additional oral antivirals, the assessment of combination therapies, the formulation of extended-release medications, and their benefit for both early treatment and prophylaxis will likely transform the landscape of the COVID-19 pandemic.

A Pilot Study for the Evaluation of an Interferon Gamma Release Assay (IGRA) To Measure T-Cell Immune Responses after SARS-CoV-2 Infection or Vaccination in a Unique Cloistered Cohort.

Assessment of T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens may be of value to determine long-lasting protection to breakthrough infections or reinfections. Interferon gamma release assay is a validated method to test cellular immunity in mycobacterial infections and has been proposed for patients with SARS-CoV-2 infection or vaccination. Quantitative IgG to spike and qualitative IgG to nucleocapsid antigens were determined by chemiluminescence microparticle immunoassay using the Architect platform (Abbott), and interferon gamma release assays against two Qiagen proprietary mixes of SARS-CoV-2 spike protein (antigen 1 and antigen 2) were performed for a selected group of subjects. A total of 121 subjects in a cloistered institution after a COVID-19 outbreak was studied. IgG spike levels and interferon gamma concentrations were highest among subjects after two doses of vaccine, followed by patients with a longer history of past COVID-19 and no vaccination. The best cutoff for the interferon gamma assay was 25 IU/L for all subgroups of individuals and the two sets of SARS-CoV-2 antigens studied. Testing T-cell response may be of clinical utility to determine immunity after exposure to SARS-CoV-2 antigens, with the interferon gamma concentration of 25 IU/L as the best cutoff either after infection or vaccination.

Third wave of COVID-19 in Madrid, Spain.

A third wave of COVID-19 occurred after Christmas 2020 in Madrid, one of the European pandemic epicenters. We noticed 6 major differential features to previous waves. First, household contacts were a large proportion of cases. Second, access to rapid antigen tests allowed prompt diagnosis and isolation. Third, clinically severe cases and mortality rates were lower. Fourth, the more transmissible B.1.1.7 strain was increasingly found. Fifth, vaccination benefits were seen in healthcare workers and nursing homes. Lastly, reinfections were more common. By Easter 2021, approximately 25% of the population in Madrid had been infected with SARS-CoV-2. Therefore, massive and accelerated vaccination campaigns are warranted to prevent new COVID-19 waves.

The demography and characteristics of SARS-CoV-2 seropositive residents and staff of nursing homes for older adults in the Community of Madrid: the SeroSOS study.

BACKGROUND: Nursing homes for older adults have concentrated large numbers of severe cases and deaths for coronavirus disease 2019 (COVID-19). METHODS: Point seroprevalence study of nursing homes to describe the demography and characteristic of severe acute respiratory syndrome by coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG)-positive residents and staff. RESULTS: Clinical information and blood samples were available for 9,332 residents (mean age 86.7 ± 8.1 years, 76.4% women) and 10,614 staff (mean age 45.6 ± 11.5, 86.2% women). Up to 84.4% of residents had frailty, 84.9% co-morbidity and 69.3% cognitive impairment; 65.2% of workers were health-aides.COVID-19 seroprevalence was 55.4% (95% confidence interval (CI), 54.4-56.4) for older adults and 31.5% (30.6-32.4) for staff. In multivariable analysis, frailty of residents was related with seropositivity (odds ratio (OR): 1.19, P = 0.02). In the case of staff, age > 50 years (2.10, P < 0.001), obesity (1.19, P = 0.01), being a health-aide (1.94, P < 0.001), working in a center with high seroprevalence in residents (3.49, P < 0.001) and contact with external cases of COVID-19 (1.52, P < 0.001) were factors associated with seropositivity. Past symptoms of COVID-19 were good predictors of seropositivity for residents (5.41, P < 0.001) and staff (2.52, P < 0.001). CONCLUSIONS: Level of dependency influences risk of COVID-19 among residents. Individual and work factors, contacts outside the nursing home are associated with COVID-19 exposure in staff members. It is key to strengthen control measures to prevent the introduction of COVID-19 into care facilities from the community.

Social Restrictions versus Testing Campaigns in the COVID-19 Crisis: A Predictive Model Based on the Spanish Case.

The global COVID-19 spread has forced countries to implement non-pharmacological interventions (NPI) (i.e., mobility restrictions and testing campaigns) to preserve health systems. Spain is one of the most severely impacted countries, both clinically and economically. In an effort to support policy decision-making, we aimed to assess the impacts of different NPI on COVID-19 epidemiology, healthcare costs and Gross Domestic Product (GDP). A modified Susceptible-Exposed-Infectious-Removed epidemiological model was created to simulate the pandemic evolution. Its output was used to populate an economic model to quantify healthcare costs and GDP variation through a regression model which correlates NPI and GDP change from 42 countries. Thirteen scenarios combining different NPI were consecutively simulated in the epidemiological and economic models. Both increased testing and stringency could reduce cases, hospitalizations and deaths. While policies based on increased testing rates lead to higher healthcare costs, increased stringency is correlated with greater GDP declines, with differences of up to 4.4% points. Increased test sensitivity may lead to a reduction of cases, hospitalizations and deaths and to the implementation of pooling techniques that can increase throughput testing capacity. Alternative strategies to control COVID-19 spread entail differing economic outcomes. Decision-makers may utilize this tool to identify the most suitable strategy considering epidemiological and economic outcomes.

Virological Correlates of IgM-IgG Patterns of Response to SARS-CoV-2 Infection According to Targeted Antigens.

The virological meaning of the different patterns of serology in COVID-19 has been little examined in clinical settings. Asymptomatic subjects with IgM-spike (S) and IgG-nucleocapsid (N) determinations by chemiluminescence were studied for SARS-CoV-2 shedding in respiratory secretions by transcription-mediated amplification (TMA). In subjects showing IgM-S positive and IgG-N negative, IgG-S was determined by lateral flow assay. A total of 712 individuals were tested: 30.0% presented IgM-S(+)/IgG-N(-), 25.8% had IgM-S(+)/IgG-N(+) and 44.2% had IgM-S(-)/IgG-N(+); the proportion with TMA(+) were comparable in these three groups: 12.1, 8.7 and 10.5%, respectively. In individuals with IgM-S(+)/IgG-N(-), IgG-S(+) was detected in 66.5%. The frequency of IgM-S(+)/IgG-S(-) in the total population was 10.0%, of whom 24.1% had TMA(+); the chances for TMA(+) in subjects with an IgM-S(+) alone pattern were 2.4%. Targeting of the same SARS-CoV-2 antigen seems to be better for the characterization of IgM/IgG patterns of response. IgM-S(+) alone reactivity is rare, and a small proportion is associated with viral shedding.

Main differences between the first and second waves of COVID-19 in Madrid, Spain.

BACKGROUND: The emergence and rapid global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents a major challenge to health services, and has disrupted social and economic activities worldwide. In Spain, the first pandemic wave started in mid-March 2020 and lasted for 3 months, requiring home confinement and strict lockdown. Following relaxation of the measures during the summer, a second wave commenced in mid-September 2020 and extended until Christmas 2020. METHODS: The two pandemic waves were compared using information collected from rapid diagnostic tests and polymerase chain reaction assays at one university clinic in Madrid, the epicentre of the pandemic in Spain. RESULTS: In total, 1569 individuals (968 during the first wave and 601 during the second wave) were tested for SARS-CoV-2-specific antibodies using fingerprick capillary blood. In addition, during the second wave, 346 individuals were tested for SARS-CoV-2-specific antigen using either oral swabs or saliva. The overall seroprevalence of first-time-tested individuals was 12.6% during the first wave and 7.7% during the second wave (P < 0.01). Seroconversions and seroreversions within 6 months occurred at low rates, both below 5%. During the second wave, 3.5% of tested individuals were SARS-CoV-2 antigen positive, with two cases considered as re-infections. Severe clinical symptoms occurred in a greater proportion of cases during the first wave compared with the second wave (27.8% vs 10.6%, respectively; P = 0.03). CONCLUSION: The cumulative seroprevalence of SARS-CoV-2 antibodies in Madrid at the end of 2020 was approximately 20%. Seroreversions within 6 months occurred in 4% of cases. Seroconversions and re-infections were clinically less severe during the second wave than during the first wave. Hypothetically, a lower viral inoculum as a result of social distancing, increased use of face masks, promotion of outdoor activities and restrictions on gatherings may have contributed to this lower pathogenicity.

Unveiling Long COVID-19 Disease.

The clinical spectrum of "Severe Acute Respiratory Syndrome Coronavirus type 2" (SARS-CoV-2) infection is wider than initially thought. The coronavirus does not establish a chronic cellular infection, in contrast with HIV or the hepatitis B virus, that keeps their genomes, respectively, as proviruses integrated within the chromosomes or as episomes (Soriano et al. J Antimicrob Chemother 2014).