What world can learn from Italy COVID-19 case

The firstcase of COVID-19 appeared in Italy on January 30^th. 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 20th 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 coronavirus. He had not travelled to China nor had any contact with people coming from Asia. He was tested only because a young anaesthesiologist, 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 2 weeks. But it was too late.

As of March 12th, Italy has 15,113 official cases, 1016 deaths and 1258 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 3 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, the virus which causes COVID-19.

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 a 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 Pressure

The COVID-19 outbreak is a stress test for 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 6000 beds for intensive care, which the government plans to increase to 9000 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 10 times the current availability: "The number of hospitalised patients expected by March 26th, in 2 weeks, is 18,000 just in Lombardy. Between 2700 and 3200 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 ventilation support that seems to be very useful for patients who can manage without invasive ventilation. "We need such tools because 33% of the people in intensive care are between 50 and 64 years old: they are fit people who do not have pre-existing conditions. If we put them in invasive ventilation, they occupy an intensive care unit for 2-3 weeks," says Pesenti. "Any alternative is useful to relieve ICUs."

Doctors also had to deal with ethical issues. The Italian College of Anaesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) published guidelines for triage when there's a shortage of ventilators to help with decision making 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," the document says.

Epidemiology and Data Collection

Epidemiological curves are the new weather forecast for citizens 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 mainly use 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 components 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 trouble 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.

How Lethal is COVID-19?

At first glance, the death rate from COVID-19 in Italy appears to be much higher than it was in China, but according to experts, this is likely to be 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 on the scientific committee advising the Italian Government. Based on the analysis of medical records, the first 100 deceased patients had an average of 2.5 concurrent 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 Being Tested

Italian doctors followed the suggestions from China on 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 to treat 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 10th 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.

Risks for GPs

General practitioners have been hit hard, acting as a first line 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 11th, 50 doctors were infected by the virus and three of them died," he wrote. General practitioners face a 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, said 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 resources available for the most severe cases. This was a good strategy to increase the availability in hospital 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 direct contact as possible 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 continuous news coverage on the epidemic risks, are not without mental health risks. On February 26th, the Lancet published a paper by Samantha 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," the review said. "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 OCD 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 contacting patients via phone or e-mail, to verify which patients may need to be visited, and is developing an app for video consultations.