After the acute phase of the SARS-CoV-2 infection, faded symptoms may last for weeks or months, or important symptoms may appear 14-110 days after infection, after the nasopharyngeal swab is negativized. The delay in standardizing even the terminology that the various studies use to indicate these sequelae is indicative of the pandemic confusion: we pass from post-acute Covid, to chronic Covid, to post Covid syndrome, before arriving at long-Covid; until, in February 2021, Anthony Fauci introduces the new denomination Post-Acute Sequelae of SARS-CoV-2 infection (PASC) to defuse the idea that they are rare, necessarily seamless with infection and related to the severity of Covid-19. Fauci cites, in this regard, the study by the University of Washington which found, in a cohort of 177 patients, mostly not hospitalized and followed for 9 months, 30% of subjects with post-infectious symptoms.
The first articles that warn the international scientific community about the existence of a long-Covid date back to summer 2020. In England and the United States, smartphone applications have been developed on which subjects with a confirmed diagnosis of Covid-19 enter the information requested: this tool leads to the collection of a large amount of data, but suffers from the limits linked to the subjectivity of the information recorded, the discontinuity of the collection and the uneven technological literacy of the participants, age-dependent. By February 2021, when there were already 175 million infected and 3.8 million dead worldwide, more than 18,000 descriptions of the long-term effects of Covid-19 had been published.
An international pool of authors selected the fifteen studies written in English that had recruited a minimum of 100 patients, thus coming to examine a total of 48,000 patients between 17 and 87 years of age in a meta-analysis, 80% of which still had, two weeks after the diagnosis of Covid-19, at least one symptom or sign or abnormal laboratory parameter. The latter could be C reactive protein, interleukin-6, D-dimer, ferritin or type B natriuretic peptide, while the most frequent clinical manifestations of long-Covid – from 58% to 25% of infected subjects – were fatigue (feeling of extreme physical, emotional and cognitive fatigue, not proportionate to the activity carried out and not relieved by rest), headache, hair loss and dyspnoea (difficulty in breathing). Lower frequency had symptoms of pulmonary fibrosis (persistent cough), myocarditis (chest pains, arrhythmias) and other generic (anosmia, tinnitus, night sweats). Nervous impairment (attention disorders such as brain foganxiety, depression, insomnia and obsessive-compulsive disorders) is particularly relevant and persists even after one year from the infection, as confirmed, in these days, a study on a very large number of observations by the US Department of Veterans Affairs.
The results of the meta-analysis are in line with the scientific knowledge already acquired regarding the post acute syndromes of the other two coronaviruses SARS and MERS and also of the Chikungunya and Ebola viruses.
Almost a year later, a new meta-analysis of 81 long-follow-up studies of Covid-19 patients found that 32% of them experienced fatigue and 22% cognitive impairment 12 weeks after diagnosis, with increased blood inflammatory indices in many cases. Doing the math, these prevalence data, transposed to the current 400 million confirmed (and documented) cases of Covid-19, lead to a total of about 100 million people who, in the world, live with long-Covid.
Despite the large number of studies that have plumbed every aspect of the syndrome, long-Covid (or PASC) remains a moving target and a continuing (bitter) surprise for doctors and patients: although more likely after severe illness, lasting deviations from the state physical and mental pre-infection also concern patients who have not undergone hospitalization or even asymptomatic patients. Furthermore, symptoms that were initially ignored, such as malaise after physical exercise, of very recent identification, appear to be independent of cardiac or pulmonary pathologies, but if anything caused by less blood flow to the muscles, due to vascular deficiency.
The demographic, social, ethnic, infectious, immunological or clinical risk factors of the long-Covid have not yet been clarified (if they exist). Finally, the mechanisms by which the virus creates long-term damage to the heart and vessels are still subject to debate: inflammation of the endothelium (the inner lining of the vessels), high levels of cytokines, a direct tissue damage by the pathogen or its persistence in sites secreted by the immune system. In general, older age, a higher BMI and being a woman (at least up to 60, when the risk becomes similar to that of men) appear to be risk factors for long-Covid and the autoimmune hypothesis. could justify this last observation: the stronger antibody response (for both genetic and hormonal factors), which makes the acute disease less severe for women, penalizes them with a higher incidence of autoimmunity.
A second study conducted on the same cohort of veterans already mentioned (more than 11 million, including controls), found that, in the more than 150,000 subjects who had contracted the SARS-CoV-2 infection, both the risk of developing cardio-cerebrovascular and thromboembolic diseases in the first 30 days, and the burden of disease one year later, for the same age, diabetic state or smoking habit. Eric Topol, director of the important Scripps Research Institute in La Jolla, California, has denounced the results of the investigation as the definitive denial of the equation of Covid-19 with a trivial flu.
Two characteristics of the study are worth noting: 90% of the veterans were male and, above all, 99.7% of those infected were not vaccinated. Regarding the hypothesis that the vaccine prevents long-Covid, the short compendium of the literature evidence updated to January 2022 of the UK Health Security Agency accounts for fifteen studies evaluating the effects of vaccination, practiced before the infection or a long-Covid already in progress, on the incidence or severity of the sequelae. Two doses of the vaccine reduce incapacitating post-infectious malaise, according to a large British study, and avoids it altogether according to a more recent Israeli study. A third study already assigns a preventive role to the single dose of vaccine, even if inoculated after contracting SARS-CoV-2 infection (15); however, a study of 10,000 vaccinated denies a decrease in the risk of sequelae in those infected over 60.
Studies on people vaccinated with long-Covid in progress give different results: some report a decrease in symptoms, one report a worsening, others an unchanged situation. The fear of ADE-like consequences is completely set aside (Antibody-Dependent Enhancement or antibody-dependent enhancement) of vaccination performed after infection: the facilitation of virus entry into the host cell, thanks to the binding with non-neutralizing antibodies, is, in fact, excluded not only from Pfizer’s authorization studies, but also from research which demonstrated how the immune response to a single vaccination dose of individuals with previous infection is overall better than that of non-infected after two doses of the vaccine.
It is not yet known what the prognosis of long-Covid is, because the available data come from the infection with the Delta variant. Furthermore, it is still premature to rule out that the virus in the now prevalent Omicron variant, which although it tends to cause a less serious disease, especially in vaccinated people, can still act slowly, to the detriment of organs and systems other than the respiratory system. Up to now, it has been seen that the organic deficit tends to resolve itself, albeit with different duration and completeness of the regression of symptoms. Even if it has partly overlapping symptoms, long-COVID must be distinguished from post-intensive care syndrome (Post-Intensive Care Syndrome, PICS), a term introduced in 2010 which defines “new or worsening impairments in the state of physical, cognitive or mental health that arise after a critical illness and persist beyond hospitalization for acute care”, precisely because it also follows forms of non-critical illness; however, the teachings derived from PICS are applicable to the new chronic syndrome, as long as the diagnosis is made promptly.
Therefore, patients with significant symptoms from Covid-19, frail, immunosuppressed, elderly or multi-pathological should be monitored by the general practitioner, even after the tampon has been negativized and the key word of any contact (including telephone) should be ” confident listening “(as opposed to suspicious) of the symptoms reported by the patient. The aim is to assist him directly, returning to outpatient visits, if not even increasing them, or referring the care to the appropriate structures.
The document 15/2021 of the Istituto Superiore di Sanità Interim indications on the management principles of Long-COVID reports the opening of “post-Covid” outpatient clinics and clinics, which provide multidisciplinary assistance. In reality, the current experiences of day-hospital or outpatient are, overturning the popular expression, “good but few”, so much so that, to count them, the fingers of both hands are too many: Post-COVID Day Hospital Foundation Policlinico Gemelli IRCCS From Rome; Clinic of Infectious and Pneumological Diseases of the University Hospital of Modena; Post-COVID ASST Monza Hospital S. Gerardo; post-Covid clinic of the San Martino Hospital in Genoa; Follow-up Outpatient Clinic COVID-19 ASST Grande Metropolitano Niguarda Hospital in Milan; Outpatient clinic and Day-hospital of the Bambino Gesù Pediatric Hospital in Rome; San Marco hospital in Catania: pediatric clinic.
All follow-up services are the responsibility of the NHS; the Sostegni bis decree-law also indicates the importance of defining targeted data collection studies on long-Covid, given that its understanding is relevant for coordinating the responses of the National Health Service. The therapy is mainly rehabilitative and supportive against organ damage. On the other hand, as Fauci said, “It is very difficult to treat something when you do not know what the objective of the treatment is.” Probably, for now, the right answer is, on an individual level, the adaptive one tailored to the needs of the person and , at the population level, the containment of the circulation of the virus.
Healthcare professionals who want to learn more about the topic can do so by following the Long COVID ECM distance training course