Background: The emergence and rapid global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents a major challenge to health services, and has disrupted social and economic activities worldwide. In Spain, the first pandemic wave started in mid-March 2020 and lasted for 3 months, requiring home confinement and strict lockdown. Following relaxation of the measures during the summer, a second wave commenced in mid-September 2020 and extended until Christmas 2020. Methods: The two pandemic waves were compared using information collected from rapid diagnostic tests and polymerase chain reaction assays at one university clinic in Madrid, the epicentre of the pandemic in Spain. Results: In total, 1569 individuals (968 during the first wave and 601 during the second wave) were tested for SARS-CoV-2-specific antibodies using fingerprick capillary blood. In addition, during the second wave, 346 individuals were tested for SARS-CoV-2-specific antigen using either oral swabs or saliva. The overall seroprevalence of first-time-tested individuals was 12.6% during the first wave and 7.7% during the second wave (P < 0.01). Seroconversions and seroreversions within 6 months occurred at low rates, both below 5%. During the second wave, 3.5% of tested individuals were SARS-CoV-2 antigen positive, with two cases considered as re-infections. Severe clinical symptoms occurred in a greater proportion of cases during the first wave compared with the second wave (27.8% vs 10.6%, respectively; P = 0.03). Conclusion:The cumulative seroprevalence of SARS-CoV-2 antibodies in Madrid at the end of 2020 was approximately 20%. Seroreversions within 6 months occurred in 4% of cases. Seroconversions and reinfections were clinically less severe during the second wave than during the first wave. Hypothetically, a lower viral inoculum as a result of social distancing, increased use of face masks, promotion of outdoor activities and restrictions on gatherings may have contributed to this lower pathogenicity.

The clinical spectrum of "Severe Acute Respiratory Syndrome Coronavirus type 2" (SARS-CoV-2) infection is wider than initially thought. The coronavirus does not establish a chronic cellular infection, in contrast with HIV or the hepatitis B virus, that keeps their genomes, respectively, as proviruses integrated within the chromosomes or as episomes (Soriano et al. J Antimicrob Chemother 2014). SARS-CoV-2 replicates within the cellular cytosol and generally only produces self-limited illness. Once the immune response develops, viral clearance occurs (Kato et al. J Infect Chemother 2020). Despite this being the rule, post-coronavirus disease (COVID) complications and reports of persistent infections are of increased concern and are attracting much attention.Centers for Disease Control and Prevention Researchers have recently proposed a new staging for the natural history of SARS-CoV-2 infection (Datta et al. JAMA 2020). Three phases are distinguished: Acute (active viral replication), post-acute hyperinflammatory (antibody positive after 2 weeks), and late sequelae (i.e., cardiovascular and/or neurological/psychological damage after 4 weeks), as shown in Table 1.The last two phases represent complications that may occur beyond COVID-19, which strictly applies only to the typical symptomatic acute phase of SARS-CoV-2 infection (fever, cough, breath shortness, anosmia, dysgeusia, diarrhea, nausea/vomiting, etc.). Checking acute phase reactants (fibrinogen, C reactive protein, haptoglobin, complement, etc.) may assist in recognition of the hyper-inflammatory phase that surge as a cytokine storm in some individuals. Beyond that stage, diagnostic procedures become less reliable.