key: cord-293630-zc8huo1j
authors: Capone, Alessandro
title: Simultaneous circulation of COVID-19 and flu in Italy: potential combined effects on the risk of death?
date: 2020-08-05
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.07.077
sha: 
doc_id: 293630
cord_uid: zc8huo1j

Based on data updated to May 20, 2020, in Italy the total recorded number of patients who died due to COVID-19-related reasons is 31,851. Demographic and clinical characteristics of died patients (including the number of comorbidities) are extremely relevant, especially to define those with a higher risk of mortality. Health authority recommends flu vaccination in a number of categories at risk of serious medical complications: subjects over 65, patients with diabetes, cardiovascular diseases, COPD, renal failure, cancer, immunodeficiencies, chronic hepatopathies and chronic inflammatory bowel diseases. The peak of the seasonal flu certainly preceded the pandemic one; however, it would seem clear that for a while the two viruses have been circulating simultaneously in Italy. Hence, after its peak, Influenza-like Illness-related (ILI) deaths started to grow again. While some of the excess mortality reported in the ILI group may be attributable to COVID-19, a question arises: do we have to consider this observation as a result of a random sequence of events or a potential relationship between the two viruses play a role? A cooperation mechanism intended at establishing an absolute advantage over the host could also be assumed. This system often takes place to boost their reproductive probabilities. A characterization of patients died due to virus-related reasons can be done by cross-linking data stored in different warehouses of the same geographical area and developing electronic health records. It would be of great relevance to identify patients at a very high risk of mortality as a result of an overlapping or combination of risk factors reported separately in patients died from COVID-19 or influenza. The description of the subgroup of patients at higher risk of mortality will be crucial for the prioritization and implementation of future public health prevention and treatment programmes.

Social distancing and other forms of precautionary public health measures have led to an effective control of beta coronavirus circulation in China, in Italy, in other European countries, and in the USA as well. The blood toll paid in Italy has been early and particularly high. At present, a "ceasefire" has been successfully achieved, but the war against COVID-19 may not yet be over. Indeed, a resurgence of infections due to beta coronavirus could be observed at the time of possible simultaneous circulation of COVID-19 and influenza. Such an event could be expected between late autumn and early winter this year.

Based on data updated to May 20, 2020, in Italy the total recorded number of patients who came into contact with COVID-19 and died corresponds to 31,851 [1] . Preliminary case-fatality rate (CFR) among patients with COVID-19 was estimated by Onder et al [2] . The authors calculated the overall crude CFR corresponded to 7,2%, a remarkably higher value than the average reported in China (2,3%) [3] . Demographic and clinical characteristics of died patients (including the number of comorbidities) are extremely relevant, especially to define those with a higher risk of mortality. Age was recognised as one of the main risk factors for death associated with COVID-19. The median age of deceased patients corresponded to 82 years (interquartile range: 74-88). This value is actually 20 years higher compared with the median age of infected patients (died patients 82 years, and infected patients 62 years, respectively) [4] . Indeed, Italy is one of the countries with the highest mean age in J o u r n a l P r e -p r o o f the world, along with Japan and Germany. Pre-existing chronic diseases (diagnosed before the COVID-19 infection) is an additional and substantial risk factor. The most frequent comorbidities reported include high blood pressure (67,9%), type 2 diabetes (30,0%), ischemic heart disease (28,2%) and renal failure (20,4%) [4] . Unfortunately, the comorbidity assessment was derived from a carefully analysis of medical records of only 3,602 out of 33,532 died patients (about 10% of the overall supposed number) [4] . The average number of diseases observed in this population was 3,3 ± 1,9.

On the other hand, a study lately performed by the Italian National Institute of Health (ISS), has shown that the excess of mortality associated with Influenza-like Illness (ILI) was between 11,6 and 41,2 per 100,000, reaching a total of over 68,000 deaths in a 4-year time period [5] . In other words, patients with diabetes or other metabolic diseases (including those with a BMI >30), cardiovascular diseases, COPD, renal failure, cancer, immunodeficiencies, chronic hepatopathies and chronic inflammatory bowel diseases [6] .

The comparison between individuals at risk of mortality associated with both diseases (i.e. COVID-19 and influenza) is of the utmost importance. Indeed, a sub-stratification of patients at a very high risk of mortality might be predictable, in particular when the circulation of both viruses is supposed to occur in the same period.

Although attempts are being made to develop unique data collection platforms in Italy, the information needed for accurate mortality risk estimation are commonly located in different repositories. This is true for both flu and COVID-19. The national sentinel influenza surveillance system (known as InfluNet) is a network of general practitioners and pediatricians working as sensors and providing health care to at least 2% of the whole Italian population [5] . As a consequence, estimating the role of flu in the overall mortality calculation is quite complex, since the diagnosis is not always confirmed by laboratory tests and most death cases are due to complications. For these reasons, although the death case is flu-related, flu may not be officially reported in all death certificates or registries. An indirect measure of its impact on mortality is given by the attributable excess of mortality, which can be calculated as the differential between the number of deaths observed during the flu season and the expected baseline value (in the absence of flu). Several statistical regression models have been adopted to estimate the excess mortality attributable to influenza, considering the potential confounding effect of variables such as temperature, viral genotypes and age distribution patterns of the population [5, [7] [8] [9] .

As far as COVID-19 related deaths are concerned, the National Institute of Health (ISS) has set up a specific web platform (similar to InfluNet) for epidemiological and immunological data collection, including recommended procedures for molecular diagnostics. However, as not all COVID-19related death are assumed to have been hospitalized (i.e. some deaths occurred at home or often in health care homes), mortality data are supposed to be underestimated. Nonetheless, it is very important to point out that the cause of death may not be surely or purely virus-dependent. This circumstance might be more frequently detected in patients with multiple comorbidities (more than 80% of died patients were affected by ≥ 2 comorbidities) [1] . Moreover, data pertaining to drugs previously prescribed in patients with chronic clinical conditions (such as high blood pressure, diabetes, ischemic heart disease or COPD) may not be detailed enough to identify patients at higher risk of death or those having factors increasing the risk itself. When we look at the shape and trend of curves over time, something immediately jumps out: the two death curves show an absolutely overlapping profile, although the magnitude of numbers associated with COVID-19 is remarkably greater. That's not surprising. In any case, ILI-related deaths have also started growing again. The peak of the seasonal flu has certainly preceded the pandemic one, however, it would seem clear that for a while the two viruses have been circulating simultaneously in Italy.

While some of the excess mortality reported in the ILI group (in over 65) may be attributable to COVID-19 infection actually, a question arises: do we have to consider this observation as a result of a random sequence of events or a potential relationship between the two viruses play a role?

Although they show a different binding affinity for their own specific redundant receptors (i.e. sialic acids of glycoproteins or glycolipids and ACE2 for influenza and COVID-19, respectively) [12, 13] , a cellular access pattern with different effectiveness, and consequently a diverse pathophysiology, both have an elective tropism for the respiratory tract. Taking viral signaling into consideration, a J o u r n a l P r e -p r o o f cooperation mechanism intended at establishing an absolute advantage over the host could also be envisaged [14] . This system often takes place between different viral strains sharing the same interest in boosting their own reproductive probabilities. An example of effective viral cooperation was found in several oncogenic genotypes of high-risk and low-risk human Papillomavirus [15] . Moreover, the virulence also has usually turned out to be based on a cooperative effect between different genes which encoding for specific viral capabilities such as transmissibility and fatality [16] . Hence, it's become increasingly clear that many viruses actively work together, teaming up to co-infect hosts and neutralise antiviral immune procedures. Although at this stage it is merely a hypothesis that needs further investigation, the simultaneous or sequential infection of both viruses (COVID-19 and influenza) leading to strengthen the effectiveness of the single infection cannot be excluded.

At present, several data needed to estimate the real impact of influenza and coronavirus on overall mortality are still missing. In addition, assuming the potential simultaneous circulation of the two viruses (during the flu season), it is suggested that health authorities undertake a study (or perform a full assessment) specifically aimed at establishing the predominant risk factors of virus-related death.

In particular, it would be of great relevance to identify patients at a very high risk of mortality as a result of an overlapping or combination of risk factors reported separately in patients died from COVID-19 or influenza. Subjects aged 65-70 years and over, suffering from hypertension or diabetes and especially those with metabolic syndrome or with 2-3 comorbidities (mentioned above in the two groups separately) are likely to be the elective target of prevention programmes. This is the reason why a similar investigation is mandatory.

A detailed characterization of patients died due to virus-related reasons can be done by cross-linking data stored in different archives or warehouses of the same geographical area (classically a Region).

This guarantees a high intrinsic quality of the analysis and at the same time reduces the need to use J o u r n a l P r e -p r o o f alternative proxies or sources that could introduce a systematic bias. Administrative and demographic databases can be queried retrospectively using a unique code referring to a single individual in order to develop a longitudinal electronic health record with a predetermined time interval. The description of the subgroup of patients at higher risk of mortality will be crucial for the prioritization and implementation of future public health prevention and treatment programmes such as a mass flu vaccination campaign.

Italy was not as ready to manage a so-rapid and dramatic pandemic, as many other countries were, actually. The gathering of data and assessment of consequences associated with COVID-19 infections in Italy took some time and appropriate responses (i.e. quarantine and social distancing measures) could have been delayed a bit. This event may also have contributed to smoothing the viral transmission and worsening some patients' clinical conditions. Now, probably nothing will happen in the late fall, but an integrated pandemic plan for Italy we must be prepared as soon as possible.

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 

Characteristics of SARS-CoV-2 patients dying in Italy

Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy

Characteristics of and important lessons from the coronavirus disease

National Institute of Health (Istituto Superiore di Sanità)

Investigating the impact of influenza on excess mortality in all ages in Italy during recent seasons (2013/14-2016/17 seasons)

Prevenzione e controllo dell'influenza: raccomandazioni per la stagione

Multinational impact of the 1968 Hong Kong influenza pandemic: evidence for a smoldering pandemic

Mortality due to influenza in the United States -an annualized regression approach using multiple-cause mortality data

Trends for Influenza-related deaths during Pandemic and Epidemic Seasons

Impatto dell'epidemia COVID-19 sulla mortalità totale della popolazione residente. Primo quadrimestre 2020. Full text available for download from the ISTAT website

Avian influenza A viruses differ from human viruses by recognition of sialyloligosaccharides and ganglosides and by a higher conservation of the HA receptor-binding site

Coronavirus Infections -More Than Just the Common Cold

Communication between viruses guides lysislysogeny decisions

Koilocytosis: a cooperative interaction between the human papillomavirus E5 and E6 oncoproteins

Fenner and White's Medical Virology