Early detection of variants of concern via funnel plots of regional reproduction numbers (preprint)

Tools to early detect the emergence of a new variant of concern are essential to develop strategies that contain epidemic outbreaks and their health-economic-social consequences. For example, knowing in which region a variant of concern appears or starts spreading enables prompt actions to circumscribe the diffusion area. This paper presents ‘funnel plots’ as a statistical process control method that can quickly identify regions of a country where the reproduction number is anomalous with respect to the national one, while keeping false alarms under control. Unlike tools whose purpose is to identify rises of Rt, the proposed method detects when a regional Rt behaves differently from the national average and thus represents an abnormal situation that needs to be investigated through cross-cutting research. 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.

Ventilator-associated Pneumonia Due to MRSA vs MSSA: What Should Guide Empiric Therapy? (preprint)

The guidelines on ventilator-associated pneumonia (VAP) recommend an empiric therapy against methicillin-resistant Staphylococcus aureus (MRSA) according to its the prevalence rate. Considering the MRSA and MSSA VAP prevalence over the last 9 years in our tertiary care Hospital, we firstly compared patients with MRSA VAP to those with MSSA VAP in terms of length of stay (LOS) in intensive care unit (ICU) and mortality and secondly, 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 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.

Dynamic NLR and PLR in predicting Covid-19 severity: a retrospective cohort study (preprint)

Background: the hyperinflammation phase of severe SARS-CoV-2 is characterized 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 study NLR and PLR trends at different timepoints and compute optimal cutoffs to predict four outcomes: use of Continuous Positive Airways Pressure (CPAP), ICU admission, invasive ventilation and death. Methods: we retrospectively included all adult patients with SARS-CoV-2 pneumonia admitted from 23rd January 2020 to 18th May 2021. Data were extracted using ICD9 codes and our Covid-19 registry. Analyses included descriptive statistics and non parametric tests to study the ability of NLR and PLR to distinguish the patients’ outcomes at each timepoint. ROC curves were built for NLR and PLR at each timepoint (minus discharge) in order to identify cutoffs to distinguish severe and non severe disease and their statistical significance was assessed with the Chi-square test. NLR and PLR were compared with DeLong’s test. Results: we included 2169 patients. NLR and PLR were higher in severe Covid-19 at all the timepoints, with a difference that gets bigger and a trend that is steeper in more severe disease. Both ratios were able to distinguish the outcomes at each timepoint. For NLR, the areas under the curve (AUROC) ranged between 0.59 and 0.81, for PLR, between 0.53 and 0.67. From each ROC curve we computed an optimal cutoff value (e.g. NLR 7 for CPAP for males at admission). NLR performed better than PLR. Conclusion: our results are in line with other studies that computed NLR and PLR trends and values in disease, especially with those that distinguished between different grades of severity. Our study is retrospective and single centre, and is limited by selection bias, but includes more than 2000 patients, thus limiting the confounding factors and outliers. Our cutoffs do not only deal with severity and mortality but allow for a more tailored approach. Future prospect include validating our cutoffs in a prospective cohort and comparing their performance against other Covid19 scores. 

Immunity to SARS-CoV-2 up to 15 months after infection (preprint)

Background: Information concerning the longevity of immunity to severe acute respiratory syndrome coronavirus 2 (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 convalescent coronavirus disease-2019 (COVID-19) patients up to 15 months after symptoms onset. Methods: The levels of anti-spike and anti-receptor binding domain antibodies and neutralizing activities were tested in a total of 188 samples from 136 convalescent patients who experience mild to critical COVID-19. Specific memory B and T cell responses were measured in 76 peripheral blood mononuclear cell samples collected from 54 patients. Twenty-three vaccinated individuals were included for comparison. Findings: Following a peak at day 15-28 post-infection, the IgG antibody response and plasma neutralizing titers gradually decreased over time but stabilized after 6 months. Plasma neutralizing activity against G614 was still detected in 87% of the patients at 6-15 months. Compared to G614, the median neutralizing titers against Beta, Gamma and Delta variants in plasma collected at early (15-103 days) and late (9-15 month) convalescence were 16- and 8-fold lower, respectively. SARS-CoV-2-specific memory B and T cells reached a peak at 3-6 months and persisted in the majority of patients up to 15 months although a significant decrease in specific T cells was observed between 6 and 15 months. Conclusion: The data suggest that antiviral specific immunity especially memory B cells in COVID-19 convalescent patients is long-lasting, but some variants of concern, including the fast-spreading Delta variant, may at least partially escape the neutralizing activity of plasma antibodies. Funding: EU-ATAC consortium, the Italian Ministry of Health, the Swedish Research Council, SciLifeLab, and KAW.

Preemptive periodic epidemic control reduces life and healthcare system costs without aggravation of social and economic losses (preprint)

Many countries are managing COVID-19 epidemic by switching between lighter and heavier restrictions. While an open-close and a close-open cycle have comparable socio-economic costs, the former leads to a much heavier burden in terms of deaths and pressure on the healthcare system. An empirical demonstration of the toll ensuing from procrastination was recently observed in Israel, where both cycles were enforced from late August to mid-December 2020, yielding some 1,600 deaths with open-close compared to 440 with close-open.

Vaccination and SARS-CoV-2 variants: how much containment is still needed? A quantitative assessment (preprint)

Despite the progress in medical care, combined population-wide interventions (such as physical distancing, testing and contact tracing) are still crucial to manage the SARS-CoV-2 pandemic, aggravated by the emergence of new highly transmissible variants. We combine the compartmental SIDARTHE model, predicting the course of COVID-19 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 impact on the epidemic evolution than vaccination, which advocates for the need to keep containment measures in place throughout the vaccination campaign. We also show that, if intermittent open-close strategies are adopted, deaths and healthcare system costs can be drastically reduced, without any aggravation of socioeconomic losses, as long as one has the foresight to start with a closing phase rather than an opening one.

Vaccination and SARS-CoV-2 variants: how much containment is still needed? A quantitative assessment. (preprint)

Despite the progress in medical care, combined population-wide interventions (such as physical distancing, testing and contact tracing) are still crucial to manage the SARS-CoV-2 pandemic, aggravated by the emergence of new highly transmissible variants. We combine the compartmental SIDARTHE model, predicting the course of COVID-19 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 impact on the epidemic evolution than vaccination, which advocates for the need to keep containment measures in place throughout the vaccination campaign. We also show that, if intermittent open-close strategies are adopted, deaths and healthcare system costs can be drastically reduced, without any aggravation of socioeconomic losses, as long as one has the foresight to start with a closing phase rather than an opening one.

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

Background: The longevity of the immune response against SARS-CoV-2 is currently debated. We thus profiled the serum anti-SARS-CoV-2 antibody levels and virus specific memory B- and T-cell responses over time in convalescent COVID-19 patients. Methods: A cohort of COVID-19 patients from the Lombardy region in Italy who experienced mild to critical disease and Swedish volunteers with mild symptoms, were tested for the presence of elevated anti-spike and anti-receptor binding domain antibody levels over a period of eight months. In addition, specific memory B- and T-cell responses were tested in selected patient samples. Results: Anti-SARS-CoV-2 antibodies were present in 85% samples collected within 4 weeks after onset of symptoms in COVID-19 patients. Levels of specific IgM or IgA antibodies declined after 1 month while levels of specific IgG antibodies remained stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG antibodies were still present, though at a significantly lower level, in 80% samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B- and T-cell responses were developed in vast majority of the patients tested, regardless of disease severity, and remained detectable up to 6-8 months after infection. Conclusions: Although the serum levels of anti-SARS-CoV-2 IgG antibodies started to decline, virus-specific T and/or memory B cell responses increased with time and maintained during the study period (6-8 months after infection).

Honors and Costs of Being Heroes: Risk Factors and Epidemiology of COVID-19 Infection among Health Care Workers of a Severely Hit COVID-19-Referral Hospital in Italy (preprint)

Purpose: During the COVID-19 pandemic, the health care workers (HCWs) at the frontline have been largely exposed to infected patients, running an high risk of being infected by the SARS-CoV-2 virus. This study investigates the epidemiological, clinical and lifestyles characteristics that might play roles in the susceptibility of HCWs to COVID-19 in a hit Italian hospital. Methods:Demographic, lifestyle, work-related and comorbidities data of 1447 HCWs which underwent a nasopharyngeal swab for SARS-CoV-2 were retrospectively collected. For the 164 HCWs positive for SARS-CoV-2, data about safety in the workplace, symptoms and clinical course of COVID-19 were also collected. Cumulative incidence of SARS-CoV-2 infection was estimated. Risk factors for SARS-CoV-2 infection were assessed using a multivariable Poisson regression. Results: The cumulative incidence of SARS-CoV-2 infection among the screened HCWs was 11.33 (9.72-13.21). Working in a COVID-19 ward, being a former smoker (vs being a person who never smoked) and BMI were positively associated with SARS-CoV-2 infection, whereas being a current smoker was negatively associated with this variable. Conclusions: Assuming an equal accessibility and proper use of PPE of all the HCWs of our Hospital, the great and more prolonged contact with COVID-19 patients remains the crucial risk factor for SARS-CoV-2. Therefore, increased and particular care needs to be focused specifically on the most exposed HCWs groups, which should be safeguarded. Furthermore, in order to limit the risk of asymptomatic spread of SARS-CoV-2 infection, the HCWs mild symptoms of COVID-19 should be considered when evaluating the potential benefits of universal staff testing

In-hospital mortality from Coronavirus Disease 2019 in a northern Italian centre:results of a competing risk analysis from SMAtteo COvid19 REgistry (SMACORE) (preprint)

Objectives An accurate prediction of the clinical outcomes of European patients requiring hospitalisation for Coronavirus Disease 2019 (COVID-19) is lacking. The aim of the study is to identify predictors of in-hospital mortality and discharge in a cohort of Lombardy patients with COVID-19. MethodsAll consecutive hospitalised patients from February 21stto March 30th, 2020, with confirmed COVID-19 from the IRCCS Policlinico San Matteo, Pavia, Lombardy, Italy, were included. In-hospital mortality and discharge were evaluated by competing risk analysis. The Fine and Gray model was fitted in order to estimate the effect of covariates on the cumulative incidence functions (CIFs) for in-hospital mortality and discharge.Results 426 adult patients (median age 68 (IQR, 56 to 77 years) were admitted with confirmed COVID-19 over a 5-week period; 292 (69%) were male. By 21 April 2020, 141 (33%) of these patients had died, 239 (56%) patients had been discharged and 46 (11%) were still hospitalised. Regression on the CIFs for in-hospital mortality showed that older age, male sex, number of comorbidities and hospital admission after March 4thwere independent risk factors associated with in-hospital mortality.Conclusions Olderage, male sex and number of comorbidities definitively predicted in-hospital mortality in hospitalised patients with COVID-19 

A SIDARTHE Model of COVID-19 Epidemic in Italy (preprint)

In late December 2019, a novel strand of Coronavirus (SARS-CoV-2) causing a severe, potentially fatal respiratory syndrome (COVID-19) was identified in Wuhan, Hubei Province, China and is causing outbreaks in multiple world countries, soon becoming a pandemic. Italy has now become the most hit country outside of Asia: on March 16, 2020, the Italian Civil Protection documented a total of 27980 confirmed cases and 2158 deaths of people tested positive for SARS-CoV-2. In the context of an emerging infectious disease outbreak, it is of paramount importance to predict the trend of the epidemic in order to plan an effective control strategy and to determine its impact. This paper proposes a new epidemic model that discriminates between infected individuals depending on whether they have been diagnosed and on the severity of their symptoms. The distinction between diagnosed and non-diagnosed is important because non-diagnosed individuals are more likely to spread the infection than diagnosed ones, since the latter are typically isolated, and can explain misperceptions of the case fatality rate and of the seriousness of the epidemic phenomenon. Being able to predict the amount of patients that will develop life-threatening symptoms is important since the disease frequently requires hospitalisation (and even Intensive Care Unit admission) and challenges the healthcare system capacity. We show how the basic reproduction number can be redefined in the new framework, thus capturing the potential for epidemic containment. Simulation results are compared with real data on the COVID-19 epidemic in Italy, to show the validity of the model and compare different possible predicted scenarios depending on the adopted countermeasures.