Editor's note: We are sincerely grateful to Daniela Ovadia and Fabio Turone for this extensive local account and hope all of our readers will learn a great deal about COVID-19, whether or not they are directly involved in the management of this global pandemic.
The first case of COVID-19, the disease caused by the newly identified SARS-CoV-2 virus, appeared in Italy on January 30: a couple of Chinese tourists coming from Wuhan via Beijing were admitted to Spallanzani Hospital in Rome, highly specialised in infectious diseases. The same day, the Minister of Health Roberto Speranza announced an air traffic embargo for flights coming to Italy from any Chinese city, including the autonomous regions of Hong Kong and Macau, in an attempt to block the spread of the infection. In the days following the hospitalisation of the Chinese couple in Rome, a few new cases were detected in a group of Italians who were repatriated from the Wuhan region. Experts started to sigh in relief as all cases came from abroad and no local contagion seemed to show up.
The alarm in the middle of the night
Then, quite abruptly, on February 20 at midnight, the Councillor for Welfare in Lombardy, Giulio Gallera, announced that Mattia, a 38-year-old Italian from the small city of Codogno, in Lombardy, was hospitalised for a severe case of atypical pneumonia and tested positive for the SARS-CoV-2 virus. He had not travelled to China nor had any contact with people coming from Asia. He was tested only because a young anesthesiologist, faced with the worsening condition of the patient, broke protocol and asked for permission to test a patient with no apparent risk factors. Codogno was the focus of a local outbreak of the disease: new cases were identified in the following days and the whole area was put under strict quarantine for two weeks. Alas, it was too late. As of March 12, Italy counts 15,113 official cases, 1,016 deaths and 1,258 recovered patients. The whole country is on lockdown. Cities like Milan and Bergamo, in Lombardy, are facing an exponential growth of hospitalised people with COVID-19. Schools, universities, and most shops are closed (all except the ones selling basic goods like food, drugs, electronics and warehouses) and the National Health System is trying to cope with the flood of patients needing ventilation support. Roberto Cosentini, head of the Emergency Department at Pope John XXIII Hospital in Bergamo, one of the most affected cities, has been living in the hospital for the last three weeks: “It's like a wave,” he says. “We have now around 60-80 new COVID-19 patients per day coming to the emergency. Most of them are in severe conditions and they arrive all together between 4 and 6 pm. We learnt that the respiratory distress worsens at the end of the afternoon and we now know that we will have to deal with most of the severe cases showing up one after another in a short time, every day.” But Italy learnt from the Chinese experience: Italian experts looked at Wuhan's management of the crisis and Foreign Minister Luigi Di Maio asked his Chinese counterpart Wang Yi for assistance with supplies. Other countries in Europe are looking at Italy in order to prepare for SARS-CoV-2.
Adjusting the testing strategy
“There is a huge debate about the way we test for the SARS-CoV-2 virus,” explains Giovanni Maga, director of the Institute of Molecular Genetics of the Italian National Research Council in Pavia, in Lombardy. “Many countries test only people with symptoms. At the beginning of the crisis, we decided to test everyone who was in contact with a person infected with the virus and this is what WHO also recommends. But in the long run it became impossible and now we test only symptomatic people with severe impairment.” However, this makes the analysis of the epidemic trends quite challenging: “If you test everybody, you will find more positive cases, with mild symptoms,” says Maga. The strategy for testing might heavily influence the visible part of the epidemic: “According to many epidemiologists, other countries could be in the same situation as Italy was few weeks ago,” continues Maga. “But since they do not check asymptomatic people, they just don’t know it.” The choice of testing strategies is a crucial one for preparedness. “There are pros and cons for any choice, but what is important is to try to be as consistent as possible on the criteria since the beginning of the outbreak,” he says.
Intensive care units under unprecedented strain
The COVID-19 outbreak is a stress test for the health services. Italy’s Health Service, which provides universal coverage for the whole population, is national, but the organisation is distributed to regional health authorities. When the crisis became evident, the Government regained control of crucial decisions, such as the coordination of intensive care unit availability. Antonio Pesenti, the coordinator of the ICU network in Lombardy and Head of the Crisis Unit explains how Italy is trying to cope with the situation. “Since the first days of the outbreak we established a protocol to transfer patients needing ICU for non-COVID-19 diseases to the regions in Central and Southern Italy using the Civil Protection CROSS system. We prefer not to transfer COVID-19 patients because they require special isolation.” Italy has around 6,000 beds for intensive care, which the government plans to increase to 9,000 in the coming weeks, partly by repurposing and refitting operating rooms used for elective surgeries. According to Pesenti, the projected demand of ICU beds is up to ten times the current availability: “The number of hospitalised patients expected by March 26, in two weeks, is 18,000 just in Lombardy. Between 2,700 and 3,200 will require intensive care.”
The Chinese experience with intermediate care
To face such a tsunami, Italy is learning from China. Intermediate care units will be opened both in the hospitals and in other areas, such as exhibition pavilions in the Bergamo and Milan Fair. They will be equipped with ventilators coming from China and with special helmets to facilitate non-invasive ventilatory support that seems to be very useful for patients who can stand without invasive ventilation. “We need such tools because 33 percent of the people in intensive care are between 50 and 64 years old: they are fit people who do not have pre-existent conditions. If we put them in invasive ventilation, they occupy an intensive care unit for two-three weeks,” says Pesenti. “Any alternative is useful to relieve ICUs.” Doctors also had to deal with ethical issues. The Italian College of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) published guidelines for triage in the case of ventilator shortages, in order to facilitate the decision making process in a critical situation. The authors chose “the most widely shared criteria regarding distributive justice and the appropriate allocation of limited health resources” to draw their recommendations. “Informed by the principle of maximising benefits for the largest number, the allocation criteria need to guarantee that those patients with the highest chance of therapeutic success will retain access to intensive care,” reads the document.
Epidemiology and data collection
Epidemiological curves are the new weather forecast for the citizen in quarantine. And policy makers rely on them to decide new policies for containment. “The available predictive models are based on data we got from China” explains Paolo Vineis, an Italian epidemiologist based at Imperial College in London, who is consulting for the scientific committee supporting the Italian Government in the decision-making process. “They use mainly the SIR model, that consists of three compartments: S for the number of susceptible, I for the number of infectious, and R for the number recovered (or immune) individuals. Any of those compartments can change during the epidemic, because of the local development. That’s why data collection is extremely important for modelling.” Italy had to face a challenge due to the regional nature of its health system: different regions used to collect data in different ways, using different templates. Regions like Lombardy, that were overwhelmed by the epidemic, had troubles in feeding the databases with all the details, like comorbidities. “Epidemiological analysis needs to be centralised and properly supported to help the decision makers” says Vineis.
Why it is difficult to have a reliable measure of lethality
At first glance, the lethality of COVID-19 in Italy appears to be much higher than it was in China, but according to experts, this is likely due to a combination of several factors, ranging from the testing strategy to the advanced age and comorbidities of most patients: “The average age of deceased patients is over 80 years, but when one looks at the age-stratified data the lethality is very similar to China” explains Giovanni Rezza, epidemiologist and Director of the Department of Infectious Diseases at the Higher Institute of Health in Rome, who sits in the scientific committee advising the Italian Government. Based on the analysis of medical records, the first 100 deceased patients had in average of 2.5 concomitant diseases. Still, in the Italian system they are accounted for when calculating the lethality of COVID-19. Another confounding factor is the testing strategy, which was concentrated on people with serious symptoms, worth being hospitalised. Those who had mild symptoms were recommended to stay at home, but were not systematically tested for SARS-CoV-2. “This has likely kept the denominator very low,” explains Rezza.
New and repurposed drugs are being tested
Italian doctors followed the suggestions from China also regarding the use of antiviral drugs that were already tested during the SARS epidemic, but are also working actively for new clinical trials. A phase III clinical trial with remdesivir, an investigational antiviral drug being developed by Gilead Sciences for the treatment of Ebola, is being conducted on patients recruited in the main hospitals like Spallanzani Hospital in Rome, Pavia Polyclinic, Padua and Parma University hospitals and Sacco Hospital in Milan. The drug is not yet approved for any indication globally but is provided for compassionate use. The US Food and Drug Administration (FDA) granted investigational new drug authorisation to study it in February 2020. The same hospitals will be involved in the trial using the antiviral combination lopinavir/ritonavir as COVID-19 treatment. Paolo Ascierto, from Fondazione Pascale Cancer Institute in Naples, announced on March 10 to have observed good results on two very critical patients receiving tocilizumab, a monoclonal antibody used in rheumatoid arthritis acting on IL6 cytokine and on the spike proteins of the virus. The drug is also used to reduce severe side effects in chemotherapies. After this anecdotal report, a proper clinical trial is being planned.
General practitioners and other diseases
General practitioners have been hit hard, acting as a first line asked to identify patients with symptoms suggesting COVID-19. And they are paying a high price for the lack of training, appropriate tools and a proper plan. Filippo Anelli, president of the National Federation of the Orders of Doctors and Dentists (FNOMCeO) sent a letter to prime minister Giuseppe Conte asking permission to stop all outpatient health activities. “By March 11, 50 doctors were infected by the virus and three of them died,” he wrote. General practitioners face the shortage of protective tools like gloves, masks and disposable scrubs. And even when they have them, they are not trained to properly manage potentially infected clothes and tools, lamented Claudio Cricelli, president of the Italian Society of General Practice (SIMG). Since the end of February, the hospitals in Northern Italy have been reorganised. Most of them have special areas for COVID-19 patients. In Milan, some hospitals are working as “hubs” to collect patients with the same disease. Most of the outpatient clinics have been closed and non-urgent visits are postponed, to make the hospitalists available for the most severe cases. This was a good strategy to increase the availability in hospitals wards but a very challenging and stressful burden on general practice. Protocols for patients with flu-like symptoms have been established by the Health Authorities. The first evaluation is done by telephone or e-mail. In case of symptoms suggesting a possible COVID-19 infection, the patient is invited to stay home, isolated from the rest of the family. The GP monitors the evolution of the symptoms while avoiding as much as possible direct contact with these patients. In case of respiratory distress, a special hotline number has been set up to dispatch a team that can transfer the patient to the hospital. “This is the only way to guarantee a proper care of the patients with other diseases” says Cricelli.
PTSD and psychiatric diseases
A lockdown like the one Italy is experiencing, together with the continuous flux of news on the epidemic risks, are not without effect on psychiatric patients. On February 26, the British journal Lancet published a paper by Samatha Brooks and colleagues from King’s College in London, reviewing studies on the psychological effects of quarantine and how to reduce it. “Most reviewed studies reported negative psychological effects including post-traumatic stress symptoms, confusion, and anger. Stressors included longer quarantine duration, infection fears, frustration, boredom, inadequate supplies, inadequate information, financial loss, and stigma,” states the review. “Some researchers have suggested long-lasting effects. In situations where quarantine is deemed necessary, officials should quarantine individuals for no longer than required, provide clear rationale for quarantine and information about protocols, and ensure sufficient supplies are provided. Appeals to altruism by reminding the public about the benefits of quarantine to wider society can be favourable.” Enrico Zanalda, president of the Italian Society of Psychiatry (SIP) confirms: “Patients with depression and obsessive–compulsive disorder tend to relapse,” he says. “And the general level of anxiety is very high.” Children and adolescents are particularly at risk of post-traumatic stress disorder, according to the review. “A proper planning for psychiatric support and for the diagnosis of PTSD is necessary.”
The impact on oncology
When the lockdown was extended to the whole country, the association of medical oncologists (AIOM, Associazione Italiana di Oncologia Medica) published a statement inviting specialists to reschedule all “non-urgent” activities, such as cancer screenings and follow-up visits for successfully-treated patients, and in some cases adjuvant therapy. “The rationale is to make sure that the oncology wards, especially in general hospitals that are also treating COVID-19-positive patients, can respect all the safety procedures, including social distancing, for cancer patients who are being treated or may need to start a new treatment,” explains vice-president of AIOM Saverio Cinieri, who is co-director of Milan’s European Institute of Oncology (IEO). “This also reduces the social interactions of immunocompromised persons who are at higher risk both of infection and of developing more serious symptoms.” AIOM recommended to contact patients via phone or e-mail, to verify which patients may need to be visited, and is developing an app that should facilitate video consultations.