Dynamic NLR and PLR in Predicting COVID-19 Severity: A Retrospective Cohort Study.

INTRODUCTION: The hyperinflammation phase of severe SARS-CoV-2 is characterised by complete blood count alterations. In this context, the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) can be used as prognostic factors. We studied NLR and PLR trends at different timepoints and computed optimal cutoffs to predict four outcomes: use of continuous positive airways pressure (CPAP), intensive care unit (ICU) admission, invasive ventilation and death. METHODS: We retrospectively included all adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia admitted from 23 January 2020 to 18 May 2021. Analyses included non-parametric tests to study the ability of NLR and PLR to distinguish the patients' outcomes at each timepoint. Receiver operating characteristic (ROC) curves were built for NLR and PLR at each timepoint (minus discharge) to identify cutoffs to distinguish severe and non-severe disease. Their statistical significance was assessed with the chi-square test. Collection of data under the SMACORE database was approved with protocol number 20200046877. RESULTS: We included 2169 patients. NLR and PLR were higher in severe coronavirus disease 2019 (COVID-19). Both ratios were able to distinguish the outcomes at each timepoint. For NLR, the areas under the receiver operating characteristic curve (AUROC) ranged between 0.59 and 0.81, and for PLR between 0.53 and 0.67. From each ROC curve we computed an optimal cutoff value. CONCLUSION: NLR and PLR cutoffs are able to distinguish severity grades and mortality at different timepoints during the course of disease, and, as such, they allow a tailored approach. Future prospects include validating our cutoffs in a prospective cohort and comparing their performance against other COVID-19 scores.

Real-life lack of evidence of viable SARS-CoV-2 transmission via inanimate surfaces: The SURFACE study.

INTRODUCTION: Although the potential role of inanimate surfaces in SARS-CoV-2 transmission has yet to be adequately assessed, it is still routine practice to apply deep and expensive environmental disinfection protocols. The aim of this study was to verify the presence of viable virus on different surfaces exposed to droplets released by coughing in SARS-CoV-2 RNA positive patients. METHODS: Patients admitted to hospital with a positive SARS-CoV-2 real-time (RT)-PCR swab were asked to cough on steel, cardboard, plastic and their hands. Surfaces were tested at baseline (T0) and at different timepoints thereafter using swabs dipped in medium, and quickly seeded on VERO E6 cells that were checked every other day for cytopathic effect (CPE). Laboratory-propagated SARS-CoV-2 strains were examined at the same time points and on identical materials. RESULTS: Ten RNA-positive patients were enrolled into the study. The median cycle threshold value was 20.7 (range 13-28.3). Nasopharyngeal swabs from 3 of the patients yielded viable virus 2-10 days post-inoculation. However, in none of the patients was it possible to isolate viable SARS-CoV-2 from sputum under identical experimental conditions. A CPE was instead already visible using laboratory-propagated SARS-CoV-2 strains at 20', 60', 180' while an effect at 24 h required a 6-day incubation. CONCLUSION: The evidence emerging from this real-life study suggests that droplets delivered by SARS-CoV-2 infected patients on common inanimate surfaces did not contain viable virus. In contrast, and in line with several laboratory-based experiments, in vitro adapted viruses could survive and grow on the same fomites.

Early detection of variants of concern via funnel plots of regional reproduction numbers.

Early detection of the emergence of a new variant of concern (VoC) is essential to develop strategies that contain epidemic outbreaks. For example, knowing in which region a VoC starts spreading enables prompt actions to circumscribe the geographical area where the new variant can spread, by containing it locally. This paper presents 'funnel plots' as a statistical process control method that, unlike tools whose purpose is to identify rises of the reproduction number ([Formula: see text]), detects when a regional [Formula: see text] departs from the national average and thus represents an anomaly. The name of the method refers to the funnel-like shape of the scatter plot that the data take on. Control limits with prescribed false alarm rate are derived from the observation that regional [Formula: see text]'s are normally distributed with variance inversely proportional to the number of infectious cases. The method is validated on public COVID-19 data demonstrating its efficacy in the early detection of SARS-CoV-2 variants in India, South Africa, England, and Italy, as well as of a malfunctioning episode of the diagnostic infrastructure in England, during which the Immensa lab in Wolverhampton gave 43,000 incorrect negative tests relative to South West and West Midlands territories.

Assessing the Efficacy of Early Therapies against SARS-CoV-2 in Hematological Patients: A Real-Life Study from a COVID-19 Referral Centre in Northern Italy.

Early therapies to prevent severe COVID-19 have an unclear impact on patients with hematological malignancies. The aim of this study was to assess their efficacy in this group of high-risk patients with COVID-19 in preventing hospitalizations and reducing the SARS-CoV-2 shedding. This was a single-center, retrospective, observational study conducted in the Fondazione IRCSS Policlinico San Matteo of Pavia, Northern Italy. We extracted the data of patients with hematologic malignancies and COVID-19 who received and did not receive early COVID-19 treatment between 23 December 2021, and May 2022. We used a Cox proportional hazard model to assess whether receiving any early treatment was associated with lower rates of hospitalization and reduced viral shedding. Data from 88 patients with hematologic malignancies were extracted. Among the patients, 55 (62%) received any early treatment, whereas 33 (38%) did not. Receiving any early therapy did not significantly reduce the hospitalization rate in patients with hematologic malignancies (HR 0.51; SE 0.63; p-value = 0.28), except in the vaccinated non-responders subgroup of patients with negative anti SARS-CoV-2 antibodies at the time of infection, who benefited from early therapies against SARS-CoV-2 (HR 0.07; SE 1.04; p-value = 0.001). Moreover, no difference on viral load decay was observed. In our cohort of patients with hematologic malignancies infected with SARS-CoV-2, early treatment were not effective in reducing the hospitalization rate due to COVID-19, neither in reducing its viral shedding.

Despite Vaccination: A Real-Life Experience of Severe and Life-Threatening COVID-19 in Vaccinated and Unvaccinated Patients.

Some vaccinated individuals still develop severe COVID-19, and the underlying causes are not entirely understood. We aimed at identifying demographic, clinical, and coinfection characteristics of vaccinated patients who were hospitalized. We also hypothesized that coinfections might play a role in disease severity and mortality. We retrospectively collected data from our COVID-19 registry for whom vaccination data were available. Patients were split into groups based on the number of administered doses (zero, one, two, or three). Data were assessed with Chi-square and Kruskal-Wallis tests and multiple logistic regression analysis. We collected data from 1686 patients and found that intra-hospital mortality was not associated to the vaccination status (e.g., p = 0.2 with three doses), while older age, sepsis, and non-viral pneumonia were (p < 0.001). Unvaccinated patients needed mechanical ventilation more often (8.5%) than vaccinated patients, in whom the probability of mechanical ventilation decreased with increasing doses (8.7%, 2.8%, 0%). We did not find more coinfections in vaccinated people. We concluded that there is a lack of real-life data to adequately characterize the pathophysiology and risk factors of patients who develop severe COVID-19, but coinfections do not appear to play a role in disease severity.

Serum and breastmilk SARS-CoV-2 specific antibodies following BNT162b2 vaccine: prolonged protection from SARS-CoV-2 in newborns and older children.

OBJECTIVES: Vaccination is the best strategy against COVID-19. We aimed to determine antibodies against SARS-CoV-2 in breastmilk and serum of mothers vaccinated with the mRNA vaccine. METHODS: This prospective study included 18 lactating women vaccinated with the BNT162b2 vaccine. Serum and breastmilk were collected before the first dose (T0), at the second dose (T1), 3 weeks after the second dose (T2), and 6 months after the first dose (T3). Serum anti-SARS-CoV-2 Spike (S) Immunoglobulin G (IgG) and Immunoglobulin A (IgA) were measured using a semi-quantitative enzyme-linked immunosorbent assay (ELISA) and secretory antibody (s) IgG and IgA in breastmilk using quantitative analysis. RESULTS: We detected serum anti-S IgG and IgA in all women after vaccination. Specific IgG and IgA were higher at T1, T2, and T3 compared with T0 (P <0.0001). Higher antibody levels were observed at T2 and lower values at T3 versus T2 (P = 0.007). After 6 months, all patients had serum IgG, but three of 18 (16%) had serum IgA. In breastmilk, sIgA was present at T1 and T2 and decreased after 6 months at T3 (P = 0.002). Breastmilk sIgG levels increased at T1 and T2 and peaked at T3 (P = 0.008). CONCLUSION: Secretory antibodies were transmitted through breastmilk until 6 months after anti-COVID-19 mRNA vaccination. Protection of the newborn through breastfeeding needs to be addressed.

Ventilator-Associated Pneumonia Due to MRSA vs. MSSA: What Should Guide Empiric Therapy?

The guidelines on ventilator-associated pneumonia (VAP) recommend an empiric therapy against methicillin-resistant Staphylococcus aureus (MRSA) according to its prevalence rate. Considering the MRSA and MSSA VAP prevalence over the last 9 years in our tertiary care hospital, we assessed the clinical value of the MRSA nasal-swab screening in either predicting or ruling out MRSA VAP. We extracted the data of 1461 patients with positive bronchoalveolar lavage (BAL). Regarding the MRSA nasal-swab screening, 170 patients were positive for MRSA or MSSA. Overall, MRSA had a high prevalence in our ICU. Despite the COVID-19 pandemic, there was a significant downward trend in MRSA prevalence, while MSSA remained steady over time. Having VAP due to MRSA did not have any impact on LOS and mortality. Finally, the MRSA nasal-swab testing demonstrated a very high negative predictive value for MRSA VAP. Our results suggested the potential value of a patient-centered approach to improve antibiotic stewardship.

Early remdesivir to prevent severe COVID-19 in recipients of solid organ transplant: a real-life study from Northern Italy.

OBJECTIVES: The effectiveness of a 3-day course of remdesivir to prevent severe disease in patients with COVID-19 who received solid organ transplant (SOT) is unknown. We wanted to study the efficacy of this therapeutic option in patients with COVID-19 who received SOT in preventing both hospitalizations for outpatients and clinical worsening due to COVID-19 for those already hospitalized for other reasons. METHODS: This is a single-center, retrospective, observational study conducted in the Fondazione IRCSS Policlinico San Matteo of Pavia, Northern Italy. We extracted all the data of patients with COVID-19 receiving SOT who received and did not receive pre-emptive remdesivir between December 23, 2021, and February 26, 2022. We used a Cox proportional hazard model to assess whether receiving pre-emptive remdesivir was associated with lower rates of hospitalization. RESULTS: A total of 24 patients who received SOT were identified. Among these, seven patients (29, 1%) received pre-emptive remdesivir, whereas 17 (70, 9%) patients did not. Receiving remdesivir significantly reduced the hospitalization rate in outpatients who received SOT and the clinical worsening of the condition of already hospitalized patients who received SOT (hazard ratio 0.05; confidence interval [0.00-0.65], P-value = 0.01). CONCLUSION: In our cohort of patients infected with SARS-CoV-2 who received SOT, pre-emptive remdesivir was effective in reducing the hospitalization rate due to COVID-19 and in preventing the clinical worsening of the condition of patients who received SOT who were hospitalized for reasons other than COVID-19.

Mortality due to COVID-19 during the pandemic: A comparison of first, secondo and third SMAtteo COvid19 REgistry (SMACORE).

COVID-19 tide had shattered on European countries with three distinct and tough waves, from March and April, 2020; October and November, 2020 and March and April, 2021 respectively. We observed a 50% reduction in the hazard of death during both wave II and III compared with wave I (HR 0.54, 95%CI 0.39-0.74 and HR 0.57, 95%CI 0.41-0.80, respectively). Sex and age were independent predictors of death. We compare in-hospital mortality of COVID-19 patients admitted at our Referral Hospital of Northern Italy during the different waves, discuss the reasons of the observed differences and suggest approaches to the challenges ahead.

COVID vaccination and asthma exacerbation: might there be a link?

INTRODUCTION: There is ongoing debate regarding the role of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in asthma exacerbation, and its long-term impact on the lung function of individuals with asthma. In contrast, the potential impact of coronavirus disease 2019 (COVID-19) vaccination on asthma is entirely unexplored. CASE STUDY: This study examined a challenging case of severe asthma exacerbation in a 28-year-old female following two doses of the mRNA-based vaccine BNT162b2 (Pfizer-BioNTech) at IRCCS Policlinico San Matteo in Pavia, Italy. The patient, a fourth-year resident at the hospital, was vaccinated in early 2021. She was an occasional smoker with a 10-year history of asthma and seasonal allergic rhinitis. She tested negative for SARS-CoV-2 on several molecular swabs and serology tests. RESULTS: After receiving the second dose of vaccine, the patient started to experience worsening of respiratory symptoms. Following several episodes and a severe asthma attack, the patient required treatment with mepolizumab, a biologic drug (interleukin-5) antagonist monoclonal antibody. CONCLUSION: This single case study is insufficient to draw conclusions about the association between asthma exacerbation and the COVID-19 vaccine. While the cause-effect link between vaccination against SARS-CoV-2 and worsening of asthmatic disease might only be suggested at present, this case is a valuable prompt for further investigation. This is particularly true from the perspective of mass vaccination of adolescents and children currently underway across the globe.

Immunity to SARS-CoV-2 up to 15 months after infection.

Information concerning the longevity of immunity to SARS-CoV-2 following natural infection may have considerable implications for durability of immunity induced by vaccines. Here, we monitored the SARS-CoV-2 specific immune response in COVID-19 patients followed up to 15 months after symptoms onset. Following a peak at day 15-28 postinfection, the IgG antibody response and plasma neutralizing titers gradually decreased over time but stabilized after 6 months. Compared to G614, plasma neutralizing titers were more than 8-fold lower against variants Beta, Gamma, and Delta. SARS-CoV-2-specific memory B and T cells persisted in the majority of patients up to 15 months although a significant decrease in specific T cells, but not B cells, was observed between 6 and 15 months. Antiviral specific immunity, especially memory B cells in COVID-19 convalescent patients, is long-lasting, but some variants of concern may at least partially escape the neutralizing activity of plasma antibodies.

Impact of Pneumococcal Urinary Antigen Testing in COVID-19 Patients: Outcomes from the San Matteo COVID-19 Registry (SMACORE).

Despite low rates of bacterial co-infections, most COVID-19 patients receive antibiotic therapy. We hypothesized that patients with positive pneumococcal urinary antigens (PUAs) would benefit from antibiotic therapy in terms of clinical outcomes (death, ICU admission, and length of stay). The San Matteo COVID-19 Registry (SMACORE) prospectively enrolls patients admitted for COVID-19 pneumonia at IRCCS Policlinico San Matteo, Pavia. We retrospectively extracted the data of patients tested for PUA from October to December 2020. Demographic, clinical, and laboratory data were recorded. Of 469 patients, 42 tested positive for PUA (8.95%), while 427 (91.05%) tested negative. A positive PUA result had no significant impact on death (HR 0.53 CI [0.22-1.28] p-value 0.16) or ICU admission (HR 0.8; CI [0.25-2.54] p-value 0.70) in the Cox regression model, nor on length of stay in linear regression (estimate 1.71; SE 2.37; p-value 0.47). After adjusting for age, we found no significant correlation between urinary antigen positivity and variations in the WHO ordinal scale and laboratory markers at admission and after 14 days. We found that a positive PUA result was not frequent and had no impact on clinical outcomes or clinical improvement. Our results did not support the routine use of PUA tests to select COVID-19 patients who will benefit from antibiotic therapy.

Modeling vaccination rollouts, SARS-CoV-2 variants and the requirement for non-pharmaceutical interventions in Italy.

Despite progress in clinical care for patients with coronavirus disease 2019 (COVID-19)1, population-wide interventions are still crucial to manage the pandemic, which has been aggravated by the emergence of new, highly transmissible variants. In this study, we combined the SIDARTHE model2, which predicts the spread of SARS-CoV-2 infections, with a new data-based model that projects new cases onto casualties and healthcare system costs. Based on the Italian case study, we outline several scenarios: mass vaccination campaigns with different paces, different transmission rates due to new variants and different enforced countermeasures, including the alternation of opening and closure phases. Our results demonstrate that non-pharmaceutical interventions (NPIs) have a higher effect on the epidemic evolution than vaccination alone, advocating for the need to keep NPIs in place during the first phase of the vaccination campaign. Our model predicts that, from April 2021 to January 2022, in a scenario with no vaccine rollout and weak NPIs ([Formula: see text] = 1.27), as many as 298,000 deaths associated with COVID-19 could occur. However, fast vaccination rollouts could reduce mortality to as few as 51,000 deaths. Implementation of restrictive NPIs ([Formula: see text] = 0.9) could reduce COVID-19 deaths to 30,000 without vaccinating the population and to 18,000 with a fast rollout of vaccines. We also show that, if intermittent open-close strategies are adopted, implementing a closing phase first could reduce deaths (from 47,000 to 27,000 with slow vaccine rollout) and healthcare system costs, without substantive aggravation of socioeconomic losses.

SARS-CoV-2 specific T-cell immunity in COVID-19 convalescent patients and unexposed controls measured by ex vivo ELISpot assay.

OBJECTIVES: SARS-CoV-2 T-cell response characterization represents a crucial issue for defining the role of immune protection against COVID-19. The aim of the study was to assess the SARS-CoV-2 T-cell response in a cohort of COVID-19 convalescent patients and in a group of unexposed subjects. METHODS: SARS-CoV-2 T-cell response was quantified from peripheral blood mononuclear cells (PBMCs) of 87 COVID-19 convalescent subjects (range 7-239 days after symptom onset) and 33 unexposed donors by ex vivo ELISpot assay. Follow-up of SARS-CoV-2 T-cell response was performed in ten subjects up to 12 months after symptom onset. The role of SARS-CoV-2 specific CD4 and CD8 T cells was characterized in a group of COVID-19 convalescent subjects. Moreover, neutralizing antibodies were determined in serum samples. RESULTS: In 14/33 (42.4%) unexposed donors and 85/87 (97.7%) COVID-19 convalescent subjects a positive result for at least one SARS-CoV-2 antigen was observed. A positive response was observed up to 12 months after COVID-19 infection (median 246 days after symptom onset; range 118-362 days). Of note, SARS-CoV-2 T-cell response seems to be mainly mediated by CD4 T cells. A weak positive correlation was observed between Spike-specific T-cell response and neutralizing antibody titre (p 0.0028; r2 = 0.2891) and positive SARS-CoV-2 T-cell response was observed in 8/9 (88.9%) COVID-19 convalescent subjects with undetectable SARS-CoV-2 neutralizing antibodies. DISCUSSION: Cross-reactive SARS-CoV-2 T-cell response in uninfected patients may be due to previous infections with other common coronaviruses. Our data suggest that long-term SARS-CoV-2 T-cell response might accompany a waning humoral response.

Persistence of SARS-CoV-2-specific B and T cell responses in convalescent COVID-19 patients 6-8 months after the infection.

BACKGROUND: Monitoring the adaptive immune responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection provides useful information for the development of vaccination strategies against this virus and its emerging variants. We thus profiled the serum anti-SARS-CoV-2 antibody (Ab) levels and specific memory B and T cell responses in convalescent coronavirus disease 2019 (COVID-19) patients. METHODS: A total of 119 samples from 88 convalescent donors who experienced mild to critical disease were tested for the presence of elevated anti-spike and anti-receptor binding domain Ab levels over a period of 8 months. In addition, the levels of SARS-CoV-2 neutralizing Abs and specific memory B and T cell responses were tested in a subset of samples. FINDINGS: Anti-SARS-CoV-2 Abs were present in 85% of the samples collected within 4 weeks after the onset of symptoms in COVID-19 patients. Levels of specific immunoglobulin M (IgM)/IgA Abs declined after 1 month, while levels of specific IgG Abs and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG Abs were still present, although at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B and T cell responses developed with time and were persistent in all of the patients followed up for 6-8 months. CONCLUSIONS: Our data suggest that protective adaptive immunity following natural infection of SARS-CoV-2 may persist for at least 6-8 months, regardless of disease severity. Development of medium- or long-term protective immunity through vaccination may thus be possible. FUNDING: This project was supported by the European Union's Horizon 2020 research and innovation programme (ATAC, no. 101003650), the Italian Ministry of Health (Ricerca Finalizzata grant no. GR-2013-02358399), the Center for Innovative Medicine, and the Swedish Research Council. J.A. was supported by the SciLifeLab/KAW national COVID-19 research program project grant 2020.