Due to the lack of effective drugs in the treatment of COVID-19, several authors [1,2,3] have proposed the use of CP and HP. Passive immunization proved variable efficacy in several infectious diseases, such as Spanish flu, Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS) and Ebola [7, 8, 10,11,12], all linked by a similar physiopathology of the lung damage.
To date, more than 100 trials have been registered worldwide, but only few data have been published [5, 6], providing conflicting data in terms of mortality, duration and progression of disease in hospitalized, critically ill, subjects treated with CP [5, 6, 13]. Moreover, all these studies, as well as the other ones stopped or still ongoing, are affected by a notable variety of the sample and by the uncertainty of the serological status of the patients, since many of them had anti-SARS-CoV-2 antibodies.
HP improved radiological findings and reduced mortality, markers of inflammation and viral load in an Italian cohort of moderate-to-severe COVID-19 patients , but, due to the lack of a control group, these findings still have to be confirmed in larger controlled studies. Indeed, no RCT investigating the efficacy of HP in COVID-19 has been published yet .
On the other hand, CP and HP appear to be quite safe, with no serious or unexpected adverse events (AEs) in the majority of patients who underwent this treatment [14, 15]. Nevertheless, no clear-cut-conclusion can be drawn about the safety of CP and HP, due to the limited information about grade 3 and 4 adverse events (AEs) .
Moreover, as previously mentioned, a profound uncertainty exists about what subset of COVID-19 patients may benefit from passive immunization and when the treatment is more efficacious during the course of the disease. Data from the currently available literature seem to suggest that, in case of severe COVID-19 infection, the highest efficacy of the treatment is achieved when CP is infused within the first 7 days .
Conversely, in our experience, we chose to administer HP in 3 patients affected by different conditions (hematological malignancies and organ transplant) leading to prolonged immunodeficiency, with a marked reduction in number and functionality of B lymphocytes. All these patients had been previously treated with intravenous and/or oral steroids and, due to their comorbidities, they were not considered eligible for further pharmacological treatments.
HP was effective in reducing viral load in all patients and led to their hospital discharge, with no further complications, AEs or need to invasive ventilation.
It is well known that the major complication of severe COVID-19 infection is an acute respiratory distress syndrome (ARDS), presumably mediated by an aberrant and exaggerate response of immune system. On the other hand, immunodeficient patients probably lack those immune stimuli leading to ARDS  but, conversely, they also lack defense mechanisms involved in viral clearance and antibodies production and associated to a higher viral load and a lower viral clearance [18, 19].
For these reasons, if a combined treatment of both antiviral and immunosuppressive drugs may represent a promising option for the first and more common subtype of COVID-19 patients, CP or HP should be administered to all those subjects whose immune system is impaired by concomitant treatments or diseases. Indeed, passive immunization, whose antiviral activity may probably not provide substantial benefits in severely ill patients, may be conversely more indicated in those subjects at risk for a sudden worsening, due to an impaired viral clearance .
A growing number of evidence is currently witnessing the potential role of passive immunization in patients affected by different conditions, such as malignancies, congenital and acquired immunodeficiencies and organ transplants, all with an impaired immune humoral response .. Nevertheless, these data only rely on case reports or case series, and no RCT has currently included immunocompromised subjects. At the same time, the vast majority of papers focuses on CP, while only a few of them have reported the use of HP. ).
In conclusion, our findings, although limited by the small number of patients, provide some interesting insights: first, HP also proved to be effective and safe in fragile and compromised subjects, burdened by severe comorbidities, low life expectancy and prolonged duration of disease; secondly, our paper may help paving the way in defining a tailored therapy for particular subsets of patients.
Due to the limited number of patients, we cannot exclude the risk of re-infection in these patients connected with their persistent immunosuppression; however, the HP treatment was successful to make them COVID-free. The patients were followed-up after discharge and they did not show persistence of the virus three months later. Nevertheless, the recent emergence of variants is underscoring the need to use HP more wisely, particularly taking into account the epidemiological picture and considering the circulating viral variants in specific geographic areas. This aspect is aiming to use only HP having antibodies which can cross-neutralize the viral variant.