COVID-19: A Possible Contribution of the MAPK Pathway.

BACKGROUND: COVID-19 is characterized by an uncontrolled inflammatory response with high pro-inflammatory cytokine production through the activation of intracellular pathways, such as mitogen-activated protein kinase (MAPK). Viruses are able to exploit the MAPK pathway to their advantage; this pathway relevance to severe COVID-19 is poorly described. The aim of this study was to quantify biomarkers involved in the MAPK pathway and to clarify its possible role in affecting some COVID-19-related clinical features. METHODS: H-RAS, C-RAF, MAPK1, MAPK2, and ERK were quantified through ELISA, and genetic polymorphisms were evaluated through real-time PCR. RESULTS: We prospectively recruited 201 individuals (158 positive and 43 negative for SARS-CoV-2): 35 were male, and their median age was 65 years. MAPK-related biomarker levels were increased in SARS-CoV-2-positive participants (n = 89) compared to negative ones (n = 29). Dyspnea was reported by 48%; this symptom was associated with PBMC C-RAF levels in positive participants (p = 0.022) and type of ventilation (p = 0.031). The highest degree of ventilation was used by 8% for invasive ventilation and 41% for continuous positive airway pressure (CPAP). CONCLUSIONS: This is the first study that showed a possible contribution of MAPK-related biomarkers in affecting COVID-19 clinical features, and this may be relevant for identifying COVID-19 positive participants at risk of serious complications.

Risk of hospitalization and sequelae in patients with COVID-19 treated with 3-day early remdesivir vs. controls in the vaccine and Omicron era: A real-life cohort study.

Recently, a benefit from administration of a 3-day course of early remdesivir (ER) in the outpatients' setting was reported. However, real-life data on its use is scarce. Therefore, we explored the ER clinical outcome in our outpatients' s cohort, compared to untreated controls. We included all patients who were prescribed ER from February to May 2022 and followed them up for 3 months and compared patients who received treatment with untreated controls. In the two groups the following outcomes were investigated: hospitalization and mortality rate, time of negativization and symptom's resolution, and postacute coronavirus disease 19 (COVID-19) syndrome prevalence. Overall, 681 patients were analyzed, mostly females (53.6%), and with a median age of 66 years (interquartile range: 54-77), 316 (46.4%) patients received ER, and 365 (53.6%) did not receive antiviral treatment (control group). Overall, 8.5% patients eventually required oxygen support, 8.7% were hospitalized for COVID-19, and 1.5% died. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization and ER (adjusted odds ratio [aOR]: 0.049 [0.015; 0.16], p < 0.001) independently reduced hospitalization risk. ER was significantly associated with a shorter duration of SARS-CoV-2 positivity at nasopharyngeal swabs (aß -8.15 [-9.21; -7.09], p < 0.001) and of symptoms (aß -5.11 [-5.82; -4.39], p < 0.001), and with lower rate of COVID-19 sequelae compared to control group (aOR: 0.18 [0.10; 0.31], p < 0.001). Even in the SARS-CoV-2 vaccination and Omicron era, in patients at high risk of developing severe disease, ER demonstrated to have a good safety profile and to significantly reduce the risk of disease progression and COVID-19 sequelae compared to untreated controls.

Real-life Evidence of Lower Lung Virulence in COVID-19 Inpatients Infected with SARS-CoV-2 Omicron Variant Compared to Wild-Type and Delta SARS-CoV-2 Pneumonia.

In vitro and animal models described lower replication capacity and virulence of SARS-CoV-2 Omicron lineage in lower respiratory airways compared to wild type and other variants of concern (oVOCs). Among adult subjects admitted to our hospital (Turin, Italy) due to wild type, oVOCs, and Omicron SARS-CoV-2-related pneumonia (n = 100 for each lineage), the cases of Omicron pneumonia showed lower degree of lung parenchyma involvement (aß -1.471, p = 0.037), less tendency to parenchyma consolidation (aOR 0.500, p = 0.011), and better respiratory functions (assessed by ambient air arterial blood gas analysis). After adjusting for demographic, previous immunity, and comorbidities, Omicron pneumonia still associated with lower risk of respiratory failure (for severe respiratory failure, Wild-type versus Omicron aOR 15.6, p = 0.005 and oVOCs versus Omicron aOR 31.7, p < 0.001). These observations are in line with preliminary findings from in vitro and animal models and could explain why Omicron infection has been associated with lower mortality and hospitalization in human.

Determinants of SARS-CoV-2 Contagiousness in Household Contacts of Symptomatic Adult Index Cases.

Background: Identifying determinants of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) transmission in settings of contagion is fundamental to inform containment strategies. We assessed SARS-CoV-2 cycle threshold value (Ct) from the first diagnostic nasal-pharyngeal swab of symptomatic index cases and which demographic or clinical characteristics among cases and contacts are associated with transmission risk within households. Methods: This is a retrospective prevalence study on secondary SARS-CoV-2 cases (SC) among the household contacts of symptomatic adult index cases randomly sampled from all the SARS-CoV-2-positive diagnostic nasopharyngeal swabs analyzed at our regional referral hospital (Amedeo di Savoia Hospital, Turin, Italy) in March, 2020. Index cases underwent a telephone survey to collect their demographic and clinical data and all their household contacts. The Ct value of RdRp gene from the first diagnostic swab of index cases was recorded and index cases were grouped according to Ct tertiles (A < first tertile, first ≤ B ≤ second tertile, C ≥ second tertile). Post hoc analysis was performed in SC as well as contacts that did not undergo SARS-CoV-2 testing but developed compatible signs and symptoms. Non-parametric tests and generalized linear models were run. Results: Index (n = 72) and contact (n = 164) median age was 54 (48-63) and 32 (20-56) years, respectively. A total of 60, 50, and 54 subjects were contacts of group A, B, and C index cases, respectively; 35.9% of contacts were SC. Twenty-four further subjects (14.6%) met the criteria for symptom-based likely positive SC. The secondary attack rate was 36.0% (28.6-43.4), assuming a mean incubation period of 5 days and a maximum infectious period of 20 days. SC prevalence differed between Ct groups (53.3% A, 32.0% B, 20.4% C; p < 0.001). No difference in SC was found according to sex, presence of signs/symptoms, and COVID-19 severity of index cases, or according to contacts' sex and number per household. The age of both index cases [aOR 4.52 (1.2-17.0) for 60 vs. ≤45 years old] and contacts [aOR 3.66 (1.3-10.6) for 60 vs. ≤45years old] and the Ct of the index [aOR 0.17 (0.07-0.4) for Ct ≥ 31.8 vs. Ct < 24.4] independently associated with SC risk. Sensitivity analysis including symptoms-based likely positive SC supported all the previous results. Conclusion: In confined transmission settings such as households, PCR Ct values may inform on the contagiousness of infected subjects and age may modulate transmission/contagion risk.

Factors Associated with Severe COVID-19 and Post-Acute COVID-19 Syndrome in a Cohort of People Living with HIV on Antiretroviral Treatment and with Undetectable HIV RNA.

SARS-CoV-2 can produce both severe clinical conditions and long-term sequelae, but data describing post-acute COVID-19 syndrome (PACS) are lacking for people living with HIV (PLWH). We aimed at assessing the prevalence and factors associated with severe COVID-19 and PACS in our cohort. We included all unvaccinated adult PLWH on antiretroviral treatment and plasma HIV-RNA < 40 cp/mL since at least six months before SARS-CoV-2 infection at the Infectious and Tropical Diseases Unit of Padua (Italy), from 20 February 2020 to 31 March 2021. COVID-19 severity was defined by WHO criteria; PACS was defined as the persistence of symptoms or development of sequelae beyond four weeks from SARS-CoV-2 infection. Demographic and clinical variables were collected, and data were analyzed by non-parametric tests. 123 subjects meeting the inclusion criteria among 1800 (6.8%) PLWH in care at the Infectious and Tropical diseases Unit in Padua were diagnosed with SARS-CoV-2 infection/COVID-19 during the study period. The median age was 51 years (40-58), 79.7% were males, and 77.2% of Caucasian ethnicity. The median CD4+ T-cell count and length of HIV infection were 560 cells/mmc (444-780) and 11 years, respectively. Of the patients, 35.0% had asymptomatic SARS-CoV-2 infection, 48% developed mild COVID-19, 17.1% presented moderate or severe COVID-19 requiring hospitalization and 4.1% died. Polypharmacy was the single independent factor associated with severe COVID-19. As for PACS, among 75 patients who survived SARS-CoV-2 symptomatic infection, 20 (26.7%) reported PACS at a median follow-up of six months: asthenia (80.0%), shortness of breath (50.0%) and recurrent headache (25.0%) were the three most common complaints. Only the severity of the COVID-19 episode predicted PACS after adjusting for relevant demographic and clinical variables. In our study, PLWH with sustained viral suppression and good immunological response showed that the risk of hospital admission for COVID-19 was low, even though the severity of the disease was associated with high mortality. In addition, the likelihood of developing severe COVID-19 and PACS was mainly driven by similar risk factors to those faced by the general population, such as polypharmacy and the severity of SARS-CoV-2 infection.

Clinical Phenotype and Contagiousness of Early Breakthrough SARS-CoV-2 Infections after BNT162b2 COVID-19 mRNA Vaccine: A Parallel Cohort Study in Healthcare Workers.

We evaluated the clinical protection of BNT162b2 mRNA vaccine in healthcare workers (HCWs) and how COVID-19 manifestations and contagiousness change as the time since first dose increases. A matched (1:2 ratio) parallel cohort study was performed. During the first three months of vaccination campaign, HCWs of the entire health district ASL Città di Torino (Turin, Italy) were classified according to SARS-CoV-2-positivity in respect of the vaccination schedule: post-first-dose (fHCWs, <12 days), partially (PHCWs, ≥12 from first dose to ≤7 days after the second), and totally vaccinated (THCWs, ≥8 days after the second dose). Age-/sex-matched unvaccinated controls were randomly selected from all the SARS-CoV-2-positivity detected in the same district and period. Previous infections were excluded. Clinical and virologic data (ORF1ab gene cycle threshold values, Ct) were recorded. In total, 6800 HCWs received at least one dose, and 55 tested positive subsequently: 20 fHCWs, 25 PHCWs, 10 THCWs. Furthermore, 21.8% of breakthrough infections were in male, with a median age of 49 years (32-56), and 51.4% occurred while SARS-CoV-2 B.1.1.7 variant was predominant. The incident relative risk was 0.13 (0.12-0.15) for PHCWs and 0.06 (0.05-0.07) for THCWs. Compared to controls (n = 110), no difference was observed in fHCWs, while PHCWs and THCWs showed higher prevalence of asymptomatic infections, fewer signs/symptoms with a milder systemic involvement, and significantly higher Ct values (PHCWs 30.3 (24.1-35.5) vs. 22.3 (19.6-30.6), p = 0.023; THCWs 35.0 (31.3-35.9) vs. 22.5 (18.2-30.6), p = 0.024). Duration of symptoms was also shorter in THCWs (5 days (3-6) vs. 9 (7-14), p = 0.028). A linear increase of 3.81 points in Ct values was observed across the groups by vaccination status (p = 0.001) after adjusting for age, sex, comorbidities, and time between COVID-19 onset and swab collection. BNT162b2 decreased the risk of PCR-confirmed infections and severe disease, and was associated with a virologic picture of lesser epidemiologic concern as soon as 12 days after the first vaccine dose.

The Manifesto of Pharmacoenosis: Merging HIV Pharmacology into Pathocoenosis and Syndemics in Developing Countries.

Pathocoenosis and syndemics theories have emerged in the last decades meeting the frequent need of better understanding interconnections and reciprocal influences that coexistent communicable and non-communicable diseases play in a specific population. Nevertheless, the attention to pharmacokinetic and pharmacodynamics interactions of co-administered drugs for co-present diseases is to date limitedly paid to alert against detrimental pharmacological combos. Low and middle-income countries are plagued by the highest burden of HIV, tuberculosis, malaria, and helminthiasis, and they are experiencing an alarming rise in non-communicable disorders. In these settings, co-infections and comorbidities are common, but no tailored prescribing nor clinical trials are used to assess and exploit existing opportunities for the simultaneous and potentially synergistic treatment of intertwined diseases. Pharmacoenosis is the set of interactions that take place within a host as well as within a population due to the compresence of two or more diseases and their respective treatments. This framework should pilot integrated health programmes and routine clinical practice to face drug-drug interaction issues, avoiding negative co-administrations but also exploiting potential favourable ones to make the best out of the worst situations; still, to date, guiding data on the latter possibility is limited. Therefore, in this narrative review, we have briefly described both detrimental and favourable physiopathological interactions between HIV and other common co-occurring pathologies (malaria, tuberculosis, helminths, and cardiovascular disorders), and we have presented examples of advantageous potential pharmacological interactions among the drugs prescribed for these diseases from a pharmacokinetics, pharmacodynamics, and pharmacogenetics standpoint.

Seroprevalence of SARS-CoV-2 Among Workers in Northern Italy.

BACKGROUND: The spread of severe acute respiratory coronavirus 2 (SARS-CoV-2) among active workers is poor known. The aim of our study was to evaluate the seroprevalence of immunoglobulin G (IgG) among a convenience sample of workers and to identify high-risk job sectors during the first pandemic way. METHODS: We conducted a cross-sectional study among workers tested for SARS-CoV-2 between 28 March and 7 August 2020, recorded by a private healthcare center located in North-West Italy. Association among seroprevalence and demographic and occupational variables was evaluated using chi square test and the seroprevalence and 95% confidence intervals (CI) were calculated. RESULTS: We collected the results for 23568 serological tests from a sample of 22708 workers from about 1000 companies. Median age was 45 years and about 60% of subjects were male. The overall seroprevalence was 4.97% [95%CI 4.69-5.25]. No statistical difference was found among gender while seroprevalence was associated with subjects' age, geographical location, and occupational sector. Significantly higher values of positivity were observed for the logistics sector (31.3%), weaving factory (12.6%), nursing homes (9.8%), and chemical industry (6.9%) workers. However, we observed some clusters of cases in single companies independently from the sector.Then, a detailed focus on 940 food workers shown a seroprevalence of 5.21% [95%CI 3.79-6.63] and subjects who self-reported COVID-19 symptoms and who worked during lockdown had a higher probability of being infected (p < 0.001). CONCLUSIONS: Data obtained might be useful for future public health decision; more than occupation sector, it seems that failure on prevention system in single companies increase the SARS-CoV-2 transmission.

The role of antirheumatics in patients with COVID-19.

The COVID-19 pandemic has resulted in more than 2 million deaths globally. Two interconnected stages of disease are generally recognised; an initial viral stage and a subsequent immune response phase with the clinical characteristics of hyperinflammation associated with acute respiratory distress syndrome. Therefore, many immune modulators and immunosuppressive drugs, which are widely used in rheumatological practice, have been proposed as treatments for patients with moderate or severe COVID-19. In this Review, we provide an overview of what is currently known about the efficacy and safety of antirheumatic therapies for the treatment of patients with COVID-19. Dexamethasone has been shown to reduce COVID-19 related mortality, interleukin-6 inhibitors to reduce risk of cardiovascular or respiratory organ support, and baricitinib to reduce time to recovery in hospitalised patients requiring oxygen support. Further studies are needed to identify whether there is any role for glucocorticoids in patients with less severe COVID-19. Although evidence on the use of other antirheumatic drugs has suggested some benefits, results from adequately powered clinical trials are urgently needed. The heterogeneity in dosing and the absence of uniform inclusion criteria and defined stage of disease studied in many clinical trials have affected the conclusions and comparability of trial results. However, after the success of dexamethasone in proving the anti-inflammatory hypothesis, the next 12 months will undoubtedly bring further clarity about the clinical utility and optimal dose and timing of other anti-rheumatic drugs in the management of COVID-19.

Early low-molecular-weight heparin administration is associated with shorter time to SARS-CoV-2 swab negativity.

BACKGROUND: Antiviral and immune-modulating properties of low-molecular-weight heparin (LMWH) against Coronaviridae have been reported by in vitro studies, but no in vivo evidence is yet available. We sought to know whether the timing of prophylactic doses of LMWH during the course of COVID-19 may affect the time to SARS-CoV-2 nasal-oropharyngeal swab negativization. METHODS: Retrospective monocentric cross-sectional study on patients requiring sub-intensive ward admission due to first SARS-CoV-2 infection and undergoing early (EH; within 7 days from COVID-19 signs and symptoms onset) versus delayed prophylactic LMWH (DH; after 7 days). SARS-CoV-2 RNA was measured by reverse transcription real-time PCR according to scheduled time points: first swab after 2 weeks from COVID-19 onset, then at 1-week intervals until negativity. RESULTS: Time to SARS-CoV-2 swab negativity was shorter in EH (38 patients) compared with DH (55 patients): 22 versus 37 days (P=0.004). The number of confirmative negative swabs in EH was significantly higher compared with DH at week 2 (21.1% versus 3.6%; P=0.017) and 4 (60.0% versus 19.6%; P<0.001). At univariate, EH differed from DH for several disease severity and clinical management parameters. Nevertheless, after accounting for the differences, Cox regression showed early LMWH administration (hazard ratio [HR] 2.91 [1.51, 5.63]; P=0.002) and higher lymphocytes nadir (HR 1.04 [1.01, 1.08]; P=0.020) as predictors of shorter time to swab negativity. CONCLUSIONS: This potential antiviral and/or immune-modulating activity of LMWH needs further in vivo confirmations by randomized controlled trials.

On the SARS-CoV-2 "Variolation Hypothesis": No Association Between Viral Load of Index Cases and COVID-19 Severity of Secondary Cases.

Background: Emerging evidence supports the "variolation hypothesis" in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), but the derivative idea that the viral load of index cases may predict disease severity in secondary cases could be unsubstantiated. We assessed whether the prevalence of symptomatic infections, hospitalization, and deaths in household contacts of 2019 novel coronavirus disease (COVID-19) cases differed according to the SARS-CoV-2 PCR cycle threshold (Ct) from nasal-pharyngeal swab at diagnosis of linked index cases. Methods: Cross-sectional study on household contacts of COVID-19 cases randomly sampled from all the infections diagnosed in March at our Microbiology Laboratory (Amedeo di Savoia, Turin). Data were retrospectively collected by phone interviews and from the Piedmont regional platform for COVID-19 emergency. Index cases were classified as high (HVl) and low viral load (LVl) according to two exploratory cut-offs of RdRp gene Ct value. Secondary cases were defined as swab confirmed or symptom based likely when not tested but presenting compatible clinical picture. Results: One hundred thirty-two index cases of whom 87.9% symptomatic and 289 household contacts were included. The latter were male and Caucasian in 44.3 and 95.8% of cases, with a median age of 34 years (19-57). Seventy-four were swab confirmed and other 28 were symptom based likely secondary cases. Considering both, the contacts of HVl and LVl did not differ in the prevalence of symptomatic infections nor COVID-19-related hospitalization and death. No difference in median Ct of index cases between symptomatic and asymptomatic, hospitalized and not hospitalized, or deceased and survived secondary cases was found. Negative findings were confirmed after adjusting for differences in time between COVID-19 onset and swab collection of index cases (median 5 days) and after removing pediatric secondary cases. Conclusions: The amount of SARS-CoV-2 of the source at diagnosis does not predict clinical outcomes of linked secondary cases. Considering the impelling release of assays for SARS-CoV-2 RNA exact quantification, these negative findings should inform clinical and public health strategies on how to interpret and use the data.

Diagnostic SARS-CoV-2 Cycle Threshold Value Predicts Disease Severity, Survival, and Six-Month Sequelae in COVID-19 Symptomatic Patients.

To date, there is no severe acute respiratory syndrome coronavirus 2-(SARS-CoV-2)-specific prognostic biomarker available. We assessed whether SARS-CoV-2 cycle threshold (Ct) value at diagnosis could predict novel CoronaVirus Disease 2019 (COVID-19) severity, clinical manifestations, and six-month sequelae. Hospitalized and outpatient cases were randomly sampled from the diagnoses of March 2020 and data collected at 6 months by interview and from the regional database for COVID-19 emergency. Patients were stratified according to their RNA-dependent-RNA-polymerase Ct in the nasopharyngeal swab at diagnosis as follows: Group A ≤ 20.0, 20.0 < group B ≤ 28.0, and Group C > 28.0. Disease severity was classified according to a composite scale evaluating hospital admission, worst oxygen support required, and survival. Two hundred patients were included, 27.5% in Groups A and B both, 45.0% in Group C; 90% of patients were symptomatic and 63.7% were hospitalized. The median time from COVID-19 onset to swab collection was five days. Lethality, disease severity, type, and number of signs and symptoms, as well as six-month sequelae distributed inversely among the groups with respect to SARS-CoV-2 Ct. After controlling for confounding, SARS-CoV-2 Ct at diagnosis was still associated with COVID-19-related death (p = 0.023), disease severity (p = 0.023), number of signs and symptoms (p < 0.01), and presence of six-month sequelae (p < 0.01). Early quantification of SARS-CoV-2 may be a useful predictive marker to inform differential strategies of clinical management and resource allocation.

Risk for SARS-CoV-2 Infection in Healthcare Workers, Turin, Italy.

We measured severe acute respiratory syndrome coronavirus 2 spike protein subunits S1/S2 antibodies by using capillary electrophoresis and a chemiluminescence immunoassay for 5,444 active healthcare workers in Italy. Seroprevalence was 6.9% and higher among participants having contact with patients. Seroconversion was not observed in 37/213 previously infected participants.