COVID-19 : Scientists are testing if convalescent plasma might also prevent infection

Survivors of COVID-19 are donating their blood plasma in droves in hopes it helps other patients recover from the coronavirus. And while the jury’s still out, now scientists are testing if the donations might also prevent infection in the first place.

Thousands of coronavirus patients in hospitals around the world have been treated with so-called convalescent plasma – including more than 20,000 in the U.S. – with little solid evidence so far that it makes a difference. One recent study from China was unclear while another from New York offered a hint of benefit.

“We have glimmers of hope,” said Dr. Shmuel Shoham of Johns Hopkins University.

With more rigorous testing of plasma treatment underway, Shoham is launching a nationwide study asking the next logical question: Could giving survivors plasma right after a high-risk exposure to the virus stave off illness?

To tell, researchers at Hopkins and 15 other sites will recruit health workers, spouses of the sick and residents of nursing homes where someone just fell ill and “they’re trying to nip it in the bud,” Shoham said.

It’s a strict study: The 150 volunteers will be randomly assigned to get either plasma from COVID-19 survivors that contains coronavirus-fighting antibodies or regular plasma, like is used daily in hospitals, that was frozen prior to the pandemic. Scientists will track if there’s a difference in who gets sick.

It if works, survivor plasma could have important ramifications until a vaccine arrives – raising the prospect of possibly protecting high-risk people with temporary immune-boosting infusions every so often.

“They’re a paramedic, they’re a police officer, they’re a poultry industry worker, they’re a submarine naval officer,” Shoham ticked off. “Can we blanket protect them?”

The new coronavirus has infected more than 7 million people worldwide and killed more than 400,000, according to official tallies believed to be an underestimate.

With no good treatments yet, researchers are frantically studying everything from drugs that tackle other viruses to survivor plasma – a century-old remedy used to fight infection before modern medicines came along.

The historical evidence is sketchy, but convalescent plasma’s most famous use was during the 1918 flu pandemic, and reports suggest that recipients were less likely to die.

Doctors still dust off the approach to tackle surprise outbreaks, like SARS, a cousin of COVID-19, in 2002 and the 2014 Ebola epidemic in West Africa, but even those recent uses lacked rigorous research.

When the body encounters a new germ, it makes proteins called antibodies that are specially targeted to fight the infection.

The antibodies float in plasma – the yellowish, liquid part of blood.

Because it takes a few weeks for antibodies to form, the hope is that transfusing someone else’s antibodies could help patients fight the virus before their own immune system kicks in. One donation is typically divided into two or three treatments.

And as more people survive COVID-19, there are increasing calls for them to donate plasma so there’s enough of a stockpile if it pans out. In addition to traditional infusions, donations can be combined into a high-dose product. Manufacturer Grifols is producing doses of that “hyperimmune globulin” for a study expected to start next month.

Convalescent plasma seems safe to use, Dr. Michael Joyner of the Mayo Clinic reported last month. His team tracked the first 5,000 plasma recipients in a Food and Drug Administration-sponsored program that helps hospitals use the experimental treatment, and found few serious side effects.

Does it help recovery?

A clue comes from the first 39 patients treated at New York’s Mount Sinai Hospital. Researchers compared each plasma recipient to four other COVID-19 patients who didn’t get plasma but were the same age, just as sick and being given the same amount of oxygen.

People who received plasma before needing a ventilator were less likely to die than non-plasma recipients, said Dr. Sean Liu, the study’s lead author.

“We really tried to target patients who were early in their course, preferably within the first one to two weeks of their disease,” Liu said.

“Being a doctor during this time, you just feel helpless,” Liu added, stressing that more rigorous study was needed but he was glad to have tried this first-step research. “Watching people die is, it’s heartbreaking. It’s scary and it’s heartbreaking.”

But results of the first strictly controlled study were disappointing. Hospitals in the hard-hit Chinese city of Wuhan were comparing severely ill patients randomly assigned to receive plasma or regular care, but ran out of new patients when the virus waned.

With only half of the 200 planned patients enrolled, more plasma recipients survived but researchers couldn’t tell if it was a real difference or coincidence, according to a report in the Journal of the American Medical Association last week.

The real proof will come from ongoing, strict studies that compare patients assigned to get either survivor plasma or a dummy treatment.

Further complicating the search for answers, COVID-19 survivors harbor widely varying levels of antibodies. And while researchers want to use what Hopkins’ Shoham calls “the high-octane stuff,” no one knows the best dose to test.

“About 20% of recovered patients and donors have very strong immunity,” estimated Dr. Michele Donato of Hackensack University Medical Center, who is studying how long they retain that level of protection.

Those are the people researchers want to become repeat donors.

“It’s, I think, our job as humans to step forward and help in society,” said Aubrie Cresswell, 24, of Bear, Delaware, who has donated three times and counting.

One donation was shipped to a hospitalized friend of a friend, and “it brought me to tears. I was like, overwhelmed with it just because the family was really thankful.”

---

Convalescent plasma (CP)

Given the lack of evidence for treatment of COVID-19 and vaccines, classical and historical interventions have remerged as options for the control of disease. That is the case of convalescent plasma (CP), a strategy of passive immunization that has been used in prevention and management of infectious diseases since early 20th century [18].

The CP is obtained using apheresis in survivors with prior infections caused by pathogens of interest in whom antibodies against the causal agent of disease are developed. The major target is to neutralize the pathogen for its eradication [19].

Given its rapid obtaining, CP has been considered as an emergency intervention in several pandemics, including the Spanish flu, SARS-CoV, West Nile virus, and more recently, Ebola virus [[20], [21], [22], [23], [24]].

CP early administered after symptoms onset showed a reduction in mortality compared with placebo or no therapy in severe acute respiratory infections of viral etiology like influenza and SARS-CoV, however, a similar response in Ebola virus disease was not observed [20,25].

During apheresis, in addition to neutralizing antibodies (NAbs), other proteins such as anti-inflammatory cytokines, clotting factors, natural antibodies, defensins, pentraxins and other undefined proteins are obtained from donors [26].

In this sense, transfusion of CP to infected patients may provide further benefits such as immunomodulation via amelioration of severe inflammatory response [27]. The latter could be the case of COVID-19 in which an over-activation of the immune system may come with systemic hyper-inflammation or “cytokine storm” driven by IL-1β, IL-2, IL-6, IL-17, IL-8, TNFα and CCL2.

This inflammatory reaction may perpetuate pulmonary damage entailing fibrosis and reduction of pulmonary capacity [28,29]. Herein, we propose the likely beneficial mechanisms of administering CP to patients with COVID-19 and provide a summary of evidence of this strategy in the current pandemic.

At the proof stage of this article there were 56 clinical trials registered at www.clinicaltrials.gov, including ours (NCT04332835, NCT04332380), in which the role of CP in COVID-19 will be evaluated.

Risks

Blood and plasma have been used to treat many other conditions, and they’re usually very safe. The risk of contracting COVID-19 infection from receiving convalescent plasma therapy hasn’t been tested yet. But researchers believe that the risk is very low because the plasma donor has fully recovered from the infection.

Convalescent plasma therapy carries the risk of:

• Allergic reactions
• Lung damage and difficulty breathing
• Transmission of infections, including HIV and hepatitis B and C

The risk of these infections is very low, because donated blood must meet certain requirements outlined by the FDA. Before donated blood can be used, it must be tested for safety. It then goes through a process to separate out blood cells so that all that’s left is plasma with antibodies.

Although many people experience no symptoms, others have mild to severe medical complications that lead to death in some people.

Production and composition
Historical perspective
The principle of CP infusion was established in 1880 when it was shown that immunity against diphtheria relied on existing antibodies in blood from animals intentionally immunized with non-lethal doses of toxins, that could be transferred to animals suffering from active infections [30,31].

Then, it was recognized that immune plasma not only neutralizes the pathogen, but also provides passive immunomodulatory properties that allow the recipient to control the excessive inflammatory cascade induced by several infectious agents or sepsis [26,31].

In the early 1950s, purification and concentration of immunoglobulins from healthy donors or recovered patients provided an option to treat serious infectious diseases as well as immune conditions including primary immunodeficiencies, allergies, and autoimmune diseases [30,32,33].

Several convalescent blood products such as intravenous immunoglobulins (IVIg) and polyclonal or monoclonal antibodies have been developed to treat infectious conditions [18].

However, in situations of emergency, they are difficult and expensive to produce, and may not yield an appropriate infectious control. Thus, the use of CP has been widely used in different outbreaks as the first therapeutic option given the lack of effective medications or vaccines, and often as last chance or experimental treatment [26].

From the Spanish influenza to the current pandemic caused by SARS-Cov-2, it has been observed that the use of CP significantly reduces the case fatality rates. That is the case of Influenza A (H1N1) pdm09, Spanish Influenza A (H1N1), and SARS-CoV infections in which the use of CP was associated to reduction in fatality rates, mortality (Table 1 ) [5,[34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45],111], and mild adverse events (Table 2 ) [25,[46], [47], [48], [49]].

Furthermore, the use of CP in other coronaviruses such as SARS-CoV, reduced days of hospital stay in critically ill patients [42,50]. In relation to the use of mechanical ventilation, in Influenza A (H1N1) pdm09, and avian influenza A (H5N1), administration of CP reduced the duration of invasive ventilation [47,51].

In addition, it has been described that the use of CP in SARS-CoV and avian influenza A (H5N1) decreased the viral load in the respiratory tract [46,49]. Currently, CP used in patients with COVID-19 demonstrated to reduce viral load and improve clinical condition [38,39].

However, it is necessary to conduct randomized controlled trials to confirm the usefulness of this intervention in both hospitalized patients with mild/severe symptoms and those in ICU.

Table 1

Convalescent plasma in patients with respiratory infection by Coronavirus (SARS, MERS, and COVID-19).

Author	Country	Study design	Viral Etiology	Diagnosis	Individuals included	Non-CP treatment	Previous clinical state CP	Dose protocol CP	Intervention	Outcomes	Mortality
Zhang et al. (2020) [111]	China	Case series	COVID-19	RT-PCR	Intervention: 4	Lopinavir/Ritonavir, Interferon alpha-2b, oseltamivir, Ribavirin	Clinical deterioration	Unknown	200–400 mL in one or two consecutive transfusions. A patient received 2,400 mL divided in eight consecutive transfusions	Clinical recovery and discharge from hospital	0% intervention group
Shen et al. (2020) [38]	China	Case series	COVID-19	RT-PCR	Intervention: 5	All patients received antiviral management during treatment.	Clinical deterioration	CP from the same donor	CP 200–250 mL two consecutive transfusions CP 200 mL single dose	Improvement in viral load and increase in antibodies	0% intervention group
Duan et al. (2020) [39]	China	Clinical trial	COVID-19	RT-PCR	Intervention: 19	Ribavirin, Cefoperazone, Levoflaxacin, Methylprednisolone, Interferon, Peramivir, Caspofungin.	Clinical deterioration	CP from the same donor	CP 200 mL single dose	Viral load improvement and lung imaging	Reduction of viral load and improvement in lung images
Ye et al. (2020) [37]	China	Case series	COVID-19	RT-PCR	Intervention: 6	Not reported	Clinical deterioration	Unknown	CP 200–250 mL two consecutive transfusions	Reduction of viral load and increase of SARS-CoV-2 IgG and IgM antibodies	0% intervention group
Anh et al. (2020) [34]	South Korea	Case report	COVID-19	RT-PCR	Intervention: 2	Lopinavir/Ritonavir, hydroxychloroquine and empirical antibiotics	Clinical deterioration	Unknown	Unknown	Reduction of viral load and increase of SARS-CoV-2 IgG and IgM antibodies	0% intervention group
Soo et al (2004) [40]	China	Retrospective comparison of cases	SARS-CoV	CDC Case Definition	Intervention: 19, control: 21	Intervention Group: Ribavirin, 3 doses Methylprednisolone (1 ∙ 5 g).	Clinical deterioration	Unknown	CP 200–400 mL days 11 and 42 after the onset of symptoms	Mortality, length of hospital stay, adverse events	23% reduction (p = .03)
Control group: Ribavirin, 4 or more doses of Methylprednisolone (1 ∙ 5 g).
Cheng et al (2005) [41]	China	Case series	SARS-CoV	CDC case definition and serology	Intervention: 80	Unknown	Clinical deterioration	Unknown	CP 279 mL per day 14	Mortality, length of hospital stay	12.5% intervention group
Nie et al. (2003) [5]	China	Case series	SARS-CoV	Unknown	Intervention: 40	Unknown	Unknown	Unknown	CP unknown dose	Mortality	0% intervention group
Yeh et al (2005) [42]	Taiwan	Case series	SARS-CoV	Serology	Intervention: 3	Ribavirin, Moxifloxacin, Methylprednisolone	Clinical deterioration	Unknown	CP unknown dose on day 11 of symptom onset	Mortality, antibodies, viral load, adverse events	0% intervention group
Zhou et al. (2003) [43]	China	Case series	SARS-CoV	CDC case definition	Intervention: 1 control: 28	All patients received Ribavirin, Azithromycin, Levofloxacin, Steroids, Mechanical ventilation.	Vulnerable or comorbid older adults	Unknown	CP 50 mL single dose on day 17 of symptom onset	Mortality, length of hospital stay	7% reduction (p = .93)
Kong (2003) [44]	China (Hong Kong)	Case report	SARS-CoV	Clinical Diagnosis	Intervention: 1	Antivirals, Steroids, Ventilation	Clinical deterioration	CP from the same donor	CP 250 mL 2 doses day 7 of the onset of symptoms	Mortality	0% intervention group
Wong et al (2003) [45]	China (Hong Kong)	Case report	SARS-CoV	WHO case definition	Intervention: 1	Ribavirin, Oseltamivir, Cefotaxime, Levofloxacin	Clinical deterioration	CP from the same donor	200 mL CP on day 14 of symptom onset	Mortality	0% intervention group
Ko et al. (2018) [35]	South Korea	Case series	MERS-CoV	RT-PCR	Intervention: 3	Steroids	Clinical deterioration	Unknown	CP unspecified dose	Antibody titers	0% intervention group

Table 2

Associated adverse events to convalescent plasma in different epidemics.

Author	Country	Viral etiology	Adverse events
Zhang; et al. (2020) [111]	China	COVID-19	None
Shen et al. (2020) [38]	China	COVID-19	None
Duan et al. (2020) [39]	China	COVID-19	Self-limited facial erythema in 2/10 patients. No major adverse events.
Ye et al. (2020) [37]	China	COVID-19	None
Anh et al. (2020) [34]	South Korea	COVID-19	None
Soo et al (2004) [40]	China	SARS-CoV	None
Cheng et al (2005) [41]	China	SARS-CoV	None
Nie et al. (2003) [5]	China	SARS-CoV	None
Yeh et al (2005) [42]	Taiwan	SARS-CoV	None
Zhou et al. (2003) [43]	China	SARS-CoV	None
Kong et al. (2003) [44]	China	SARS-CoV	None
Wong et al (2003) [45]	China	SARS-CoV	None
Ko et al. (2018) [35]	South Korea	MERS-CoV	None
Van Griensven et al. (2016) [25]	Guinea	Ebola	Nausea, skin erythema, fever. No major adverse events.
Hung et al. (2011) [46]	China	Influenza A(H1N1)	None
Chan et al. (2010) [47]	China	Influenza A(H1N1)	None
Yu et al. (2008) [48]	China	Influenza A(H5N1)	None
Kong et al. (2006) [49]	China	Influenza A(H5N1)	None

The safety of the use of CP is another issue that has been historically relevant in epidemics. Currently, evidence exists of the safety of CP in situations of emergency (Table 2). In epidemics of Influenza A (H1N1), SARS-CoV and MERS-CoV, studies did not find any adverse event associated to CP administration.

In the case of Ebola, CP administration was associated with mild adverse reactions such as nausea, skin erythema, and fever [25]. In COVID-19, reports have shown that administration of CP is safe, and it was not associated with major adverse events. Thus, due to tolerability and potential efficacy, CP is a good candidate to be evaluated as a therapeutic option to control the current pandemic.

Acquisition and plasma composition
The convalescent donors must undergo standard pre-donation assessment to ensure compliance with current regulations regarding plasma donation [52]. Currently, convalescent donors between 18 and 65 are considered as subjects without infectious symptomatology and a negative test for COVID-19 after 14 days of recovery.

These tests must be repeated 48 h later and at the moment of donation [39,52]. Donors from endemic areas for tropical diseases (e.g., malaria) should be excluded. In addition to molecular tests, it is critical to recognize the emotional situation, to explore susceptibilities, and guarantee not exploitation of donors [53].

Apheresis is the recommended procedure to obtain plasma. This procedure is based on a continuous centrifugation of blood from donor to allow a selective collection plasma.

The efficiency of this technique is around 400–800 mL from a single apheresis donation. This amount of plasma could be storage in units of 200 or 250 mL, and frozen within 24 h of collection to be used in further transfusions [54].

As CP production requires high quality standards, it must be free of any infection, so tests for human immunodeficiency virus (HIV), hepatitis B, hepatitis C, syphilis, human T-cell lymphotropic virus 1 and 2, and Trypanosoma cruzi (if living in an endemic area) should be carried out [52,55].

In this sense, the nucleic acid test for HIV and hepatitis viruses is mandatory to guarantee the safety of recipients [56]. Other protocols suggest the inactivation of pathogens with riboflavin or psoralen plus exposure to ultraviolet light to improve safety of CP [57].

There is not a standard transfusion dose of CP. In different studies for coronaviruses the administration of CP ranges between 200 and 500 mL in single or double scheme dosages (Table 1). Currently, the recommendation is to administrate 3 mL/kg per dose in two days [54]. This strategy facilitates the distribution of plasma units (250 mL per unit) and provide a standard option of delivery in public health strategies.

Composition of CP is variable and include a wide variety of blood derive components. Plasma contains a mixture of inorganic salts, organic compounds, water, and more than 1000 proteins.

In the latter we found albumin, immunoglobulins, complement, coagulation and antithrombotic factors among others [58] (Fig. 1A). Interestingly, it is supposed that plasma from healthy donors provides immunomodulatory effects via the infusion of anti-inflammatory cytokines and antibodies that blockade complement, inflammatory cytokines and autoantibodies [27].

These factors may influence the immunomodulatory effect of CP in patients with COVID-19 (see below for details).

Antiviral mechanisms
NAbs are crucial in virus clearance and have been considered essential in protecting against viral diseases. Passive immunity driven by CP can provide these NAbs that restrain the infection.

The efficacy of this therapy has been associated with the concentration of NAbs in plasma from recovered donors [25], [112]. In SARS-CoV and MERS was discovered that NAbs bind to spike1-receptor binding protein (S1-RBD), S1-N-terminal domain and S2, thus inhibiting their entry, limiting viral amplification [59]. Moreover, other antibody-mediated pathways such as complement activation, antibody-dependent cellular cytotoxicity and/or phagocytosis may also promote the therapeutic effect of CP.

Tian et al. [60], showed through ELISA and Biolayer Interferometry Binding that one SARS-CoV-specific antibody, CR3022, bind with COVID-19 RBD and more importantly this antibody did not show any competition with angiotensin converting enzyme-2 (ACE-2) for the binding to COVID-19 RBD.

The RBD of COVID-19 varies broadly from the SARS-CoV at the C-terminus residues. Although this difference does not enable COVID-19 to bind ACE-2 receptor, does influence the cross-reactivity of NAbs [60].

A pseudotyped-lentiviral-vector-based neutralization assay to measure specific NAbs in plasma from recovered patients with SARS-CoV-2 showed variations in NAbs titers, approximately 30% of patients did not develop high NAbs titers after infection [61].

These variations are associated with age, lymphocyte count, and C reactive protein levels in blood, suggesting that other components from plasma contribute to the recovery of these patients.

In plasma, in addition to NAbs, there are other protective antibodies, including immunoglobulin G (IgG) and immunoglobulin M (IgM). Non-NAbs that bind to the virus, but do not affect its capacity to replicate, might contribute to prophylaxis and/or recovery improvement [54] (Fig. 1B).

SARS-CoV infection induces IgG antibodies production against nucleoprotein (N) that can be detected at day 4 after the onset of disease and with seroconversion at day 14 [62]. In SARS infection 89% of the recovered patients, showed IgG-specific and NAbs 2 years post infection [63]. Moreover, the highest concentration of IgM was detected on the ninth day after the onset of disease and class switching to IgG occurred in the second week [64].

Shen et al. [38], showed that recovered donors from COVID-19 infection had SARS-CoV-2–specific antibody titers ranging between 1.800 and 16.200 and NAbs titers were between 80 and 480.

The plasma obtained from the donors and transfused in the recipients on the same day lead to viral load decreased. After transfusion of CP, the titers of IgG and IgM in the recipients increased in a time-dependent manner.

Moreover, presence of NAbs in the recipients played a vital role in the restriction of viral infection. Another study evaluated the kinetics of SARS-CoV-2-specific NAbs development during the course of the disease. The titers of NAbs in patients infected with SARS-CoV-2 were low before day 10 post-disease onset and then increased, with a peak 10 to 15 days after disease onset, remaining stable thereafter in all patients [61].

Immunomodulation
F(ab´)2 mechanisms
Historically, administration of IVIg has been one of the critical interventions in patients with autoimmune diseases as well as in autoinflammatory diseases, transplantation (i.e., chronic graft vs. host disease after marrow transplantation), primary and secondary immunodeficiency, hematologic malignancies among other conditions.

Preparation of IVIg includes anti-idiotypic antibodies that blockade autoreactive recipient antibodies [36,65]. This reaction is critical to control autoantibodies in patients with autoimmune diseases.

In this sense, a recent report in patients with COVID-19, showed that critically ill patients exhibited positivity for anti-cardiolipin IgA antibodies as well as for anti–β2-glycoprotein I IgA and IgG antibodies [66].

This evidence may suggest that CP-COVID-19 may neutralize this type of autoantibodies reducing the odds of suffering from thrombotic events (i.e., antiphospholipid syndrome-like disease), especially in critically ill patients. In the same line, a recent report of a patient with Sjögren’s syndrome and COVID-19 successfully treated with CP may suggest that this strategy is safe and effective in autoimmune conditions [37].

In addition, some antibodies inhibit complement cascade (i.e., C3a and C5a), and limit the formation of immune complexes (Fig. 1C) [67,68]. Complement-deficient mice with induced SARS-CoV infection showed high viral titers, secretion of inflammatory cytokines and chemokines, and immune cell infiltration within the lung.

These results suggest that complement activation largely contribute to systemic inflammation and migration of neutrophils to the lungs, perpetuating tissue damage [69]. Additional studies have shown that IgG transferred by plasma neutralize cytokines such as IL-1β and TNFα [70].

In this sense, passive immunity by infusion of CP-COVID-19 may limit the inflammatory cascade driven by pathogenic antibodies, as well as the cellular damage induced by the complement cascade activation in excessive inflammatory environments.

Antibody-dependent enhancement (ADE) is a mechanism in which the intensity of infection increases in the presence of preexisting poorly NAbs, favoring the replication of virus into macrophages and other cells through interaction with Fc and/or complement receptors [71]. This phenomenon is used by feline coronaviruses, HIV and dengue viruses to take advantage of prior anti-viral humoral immune response to effectively infect host target cells [72,73].

In vitro assays with human promonocyte cell lines demonstrated that SARS-CoV ADE was primarily mediated by antibodies against spike proteins, significantly increasing the rate of apoptosis in these cells [73].

This is of major interest in regions in which coronaviruses are endemic. Vaccines development should consider this phenomenon in patients with COVID-19, and administration of CP-COVID-19 in these areas should be conducted with caution since ADE may emerge as a harmful reaction in patients with active infection [74]. If one suspects of this phenomenon following CP-COVID-19 administration, clinicians must promptly notify the health authorities and evaluate the safety according to endemic coronaviruses in the region.

Fc mechanisms
FcRn is a critical regulator of IgG half-life. This receptor works by preventing degradation and clearance of IgG, by a pinocytotic mechanism that allow antibody circulation within the cell for its posterior excretion [65,75].

The FcRn inhibitor rozanolixizumab showed reduction of IgG concentrations in a phase 1 study [76], and it proved to be critical in IVIg catabolism in common variable immunodeficiency patients [77]. It has been demonstrated that saturation of this receptor by IVIg may account as the most likely mechanism to clear autoantibodies in autoimmune conditions by shortening their lifetime [[78], [79], [80]].

Whether antibodies play a critical role in COVID-19 pathogenesis stills remain to be elucidated, however, the saturation of FcRn may provide an additional immunomodulatory pathway in patients receiving CP.

Fcγ receptors are found in about all immune cells. These receptors are critical factors in modulating or inhibiting activity of immune cells, including lymphocytes [75]. Fcγ receptor activation by IgG induces the upregulation of FCγRIIB which has been associated with inhibitory effects.

This was demonstrated in B cells, where the upregulation of FCγRIIB was associated with treatment efficacy for acute rejection after kidney transplantation [81], and was a key determinant for IVIg response in patients with Kawasaki disease [82]. It has been suggested that sialylation of this receptor is critical for inhibitory effects in immune cells [83].

However, the study of Th17 cells in autoimmune encephalomyelitis model revealed that this process is dispensable for the immunomodulatory effect of IVIg treatment [84]. Despite these results, CP infusion may help the modulation of immune response via Fcγ receptors, and merits attention in the current management of COVID-19.

Dendritic cells
Dendritic cells (DCs) are key regulators of innate immunity and work as specialized antigen presenting cells. In vitro studies have shown that administration of IVIg may abrogate maturation of DCs, as well as a reduction in the production of IL-12. Interestingly, the production of IL-10 was enhanced [85].

In the study conducted by Sharma et al. [86], authors found that IVIg induced the production of IL-33 that subsequently expands IL-4-producing basophils. In this line, other study found that IVIg could promote the production of IL-4 and IL-13 which correlated with levels of IL-33 [87].

A Th2 cytokine-mediated downregulation of FcγRIIa and IFN-γR2 was suggested to be the most likely mechanisms for this phenomenon. Recently, it was found that IVIg activates β-catenin in an IgG-sialylation independent manner, which is critical for reducing inflammation [88].

Down regulation of HLA-II and costimulation molecules such CD86, CD80, and CD40 have been reported in DCs after stimulation with IVIg [85]. In patients with systemic lupus erythematosus, which show a high proinflammatory environment, administration of IVIg abrogated IFN-α-mediated maturation [89,90]. All together, data suggest that infusion of plasma from recovered COVID-19 donors may enhance anti-inflammatory properties of DCs, which could be critical in phases of excessive inflammatory stimuli in patients with COVID-19.

T cells
Despite the ability of enhancing Th2 via IL-33 in DCs [87], it has been described that IVIg modulates the balance between CD4+/CD8+ T cells, as well as promoting proliferation and survival of Tregs. Treatment with IVIg seems to reduce antigenic presentation of T cells via the modulation and inhibition of DCs. This process was independent of FCγRIIB [91], and other reports showed that reduced activation of T cells was independent of IgG sialylation, monocytes or B cells [92].

In addition, patients treated with IVIg showed a reduction in Th1 cells and low levels of IFNγ and TNFα with the increase of Th2 cytokines such as IL-4 and IL-10 [93]. Clinically, it has been demonstrated that patients with Influenza A (H1N1) treated with CP exhibited a reduction of IL-6 and TNFα [94], with an increase of IL-10 [46]. This support the notion of an anti-inflammatory effect of CP in subjects with acute viral infections.

Cytotoxicity is also regulated by administration of IVIg. In the study of Klehmet et al. [95], authors found that patients with chronic inflammatory demyelinating polyneuropathy treated with IVIg, showed reduction in CD8+ T cells with high levels of CD4+ T effector memory and T central memory cells. In another study, IVIg proved to reduce the activation of CD8+ T cells associated with a T-cell receptor blockade, thus reducing the interaction between effector and target cells [96]. In subjects with Kawasaki disease, a high proportion of CD8+ was associated with resistance to IVIg, thus suggesting that these cells could be considered a predictive factor for IVIg response [97].

Recent studies have shown that IVIg reduces the proliferation of Th17 cells, as well as decreases the production of IL-17A, IL-17F, IL-21, and CCL20 [98,99]. In other study, IVIg appeared to modulate the Th17/Treg ratio which is associated with recurrent pregnancy loss [100]. It is plausible that CP may act in a similar way in patients with COVID-19 [28,29] (Fig. 1C).

B cells
B cells are critical in adaptive immunity via production of antibodies and cytokines. In patients with demyelinating polyneuropathy, administration of IVIg was associated with overexpression of FcγRIIB receptors on B cells [101,102]. IVIg abrogated TLR-9-dependent B cell responses. This was associated with IVIg inhibitions of NF-κB signaling pathway, reduction of CD25 and CD40 expression, and reduction of IL-6 and IL-10 production by B cells. This process seems to be regulated by SH2 domain–containing phosphatase 1 [103].

Proliferation and survival of B cells is mediated by the B cell–activating factor (BAFF). In the study conducted by Le Pottier et al. [104], authors found that IVIg contained NAbs for BAFF. This could explain the reduction in proliferation, as well as the increased rates of apoptosis of B cells. Regarding the latter process, it was found that anti-Fas (anti-CD95) antibodies, present in IVIg preparations, induced apoptosis in B cells [105].

In DCs, downregulation of costimulatory molecules following administration of IVIg has been observed. This is similar to B cells which exhibited a reduction in antigen-presentation activity secondary to IgG internalization, in concordance with a reduced IL-2 production by T cells [106]. Moreover, IVIg administration modulates B-cell receptor (BCR) signaling. In the study of Séïté et al. [107], authors found that interaction between BCR and CD22 resulted in a down-regulation of tyrosine phosphorylation of Lyn and the B-cell linker proteins which resulted in a sustained activation of Erk 1/2 and arrest of the cell cycle at the G/1 phase.

These mechanisms may account for immunomodulation of the inflammatory response in COVID-19 secondary to CP administration. As showed above, recent reports suggest the production of antiphospholipid antibodies in patients with COVID-19 together with an antiphospholipid-like syndrome [66], and the regulation of this cascade could be critical to avoid deleterious outcomes in these group of patients (i.e., thrombosis, disseminated intravascular coagulopathy).

Other immune cells
The major immunological factor suspected to be associated with inflammation and lung damage in COVID-19 is the activation of macrophages. It has been suggested that patients with COVID-19 may suffer from a macrophage activation syndrome-like disease associated to innate immune migration to lung tissues [28]. In this context, the inhibition of this immunological pathway may help to control excessive cytokine production and prevent pulmonary damage (i.e., fibrosis). This was recently supported by the study of Blanco-Melo et al. [108] who described an up regulation of chemokines for innate immune cells in ferrets as well as in patients with COVID-19. Interestingly, results suggest that this scenario mainly occurred in the first 7 days post infection, whereas at day 14th, other cytokines such as IL-6 and IL-1 persisted activated [108]. These data have critical therapeutic consequences.

In the study conducted by Kozicky et al. [109], authors found that macrophages treated with IVIg showed an increased production of IL-10, with a reduction in IL-12/23p40, thus suggesting the promotion of an anti-inflammatory macrophage profile. Although there is no evidence of macrophage pulmonary migration inhibition by IVIg, a study on induced peripheral neurotoxicity showed that this treatment reduced nerve macrophage infiltration in rats [110].

These observations deserve attention in those patients treated with CP-COVID-19 since they may account for the positive results encountered in critically ill patients with COVID-19 [38,39]. In this line, we argue for CP-COVID-19 administration in early stages of diseases to prevent innate immune cells migration and avoid lung damage.

---

Journal information: Journal of the American Medical Association

References

1. Su S., Wong G., Shi W., Liu J., Lai A.C.K., Zhou J. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol. 2016;24:490–502. doi: 10.1016/j.tim.2016.03.003.

2. Cavanagh D. Coronavirus avian infectious bronchitis virus. Vet Res. 2007;38:281–297. doi: 10.1051/vetres:2006055.

3. Ismail M.M., Tang A.Y., Saif Y.M. Pathogenicity of turkey coronavirus in turkeys and chickens. Avian Dis. 2003;47:515–522. doi: 10.1637/5917.

4. Lu R., Zhao X., Li J., Niu P., Yang B., Wu H. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet. 2020;395:565–574. doi: 10.1016/S0140-6736(20)30251-8.

5. Nie Q.-H., Luo X.-D., Hui W.-L. Advances in clinical diagnosis and treatment of severe acute respiratory syndrome. World J Gastroenterol. 2003;9:1139–1143. doi: 10.3748/wjg.v9.i6.1139.

6. Zaki A.M., van Boheemen S., Bestebroer T.M., Osterhaus A.D.M.E., Fouchier R.A.M. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814–1820. doi: 10.1056/NEJMoa1211721.

7. Phua J., Weng L., Ling L., Egi M., Lim C.-M., Divatia J.V. Intensive care management of coronavirus disease 2019 (COVID-19): Challenges and recommendations. Lancet Respir Med. 2020 doi: 10.1016/S2213-2600(20)30161-2.

8. Zhu N., Zhang D., Wang W., Li X., Yang B., Song J. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733. doi: 10.1056/NEJMoa2001017.

9. Chan J.F.-W., Yuan S., Kok K.-H., To K.K.-W., Chu H., Yang J. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395:514–523. doi: 10.1016/S0140-6736(20)30154-9.

10. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5.

11. Shoenfeld Y. Corona (COVID-19) time musings: Our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning. Autoimmun Rev. 2020;102538 doi: 10.1016/j.autrev.2020.102538.

12. Kanduc D., Shoenfeld Y. On the molecular determinants and the mechanism of the SARS-CoV-2 attack 2020. Clin Immunol. 2020;215:108426. doi: 10.1016/j.clim.2020.108426.

13. Rojas M., Restrepo-Jiménez P., Monsalve D.M., Pacheco Y., Acosta-Ampudia Y., Ramírez-Santana C. Molecular mimicry and autoimmunity. J Autoimmun. 2018;95:100–123. doi: 10.1016/j.jaut.2018.10.012.

14. Cao B., Wang Y., Wen D., Liu W., Wang J., Fan G. A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19. N Engl J Med. 2020 doi: 10.1056/NEJMoa2001282.

15. Chen Z., Hu J., Zhang Z., Jiang S., Han S., Yan D. Efficacy of hydroxychloroquine in patients with COVID-19: Results of a randomized clinical trial. MedRxiv. 2020 doi: 10.1101/2020.03.22.20040758.

16. Gautret P., Lagier J.-C., Parola P., Hoang V.T., Meddeb L., Mailhe M. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;105949 doi: 10.1016/j.ijantimicag.2020.105949.

17. Borba M.G.S., Val F.F.A., Sampaio V.S., Alexandre M.A.A., Melo G.C., Brito M. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A randomized clinical trial. JAMA Netw Open. 2020;3 doi: 10.1001/jamanetworkopen.2020.8857.

18. Marano G., Vaglio S., Pupella S., Facco G., Catalano L., Liumbruno G.M. Convalescent plasma: New evidence for an old therapeutic tool? Blood Transfus. 2016;14:152–157. doi: 10.2450/2015.0131-15.

19. Burnouf T., Seghatchian J. Ebola virus convalescent blood products: Where we are now and where we may need to go. Transfus Apher Sci. 2014;51:120–125. doi: 10.1016/j.transci.2014.10.003.

20. Mair-Jenkins J., Saavedra-Campos M., Baillie J.K., Cleary P., Khaw F.-M., Lim W.S. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: A systematic review and exploratory meta-analysis. J Infect Dis. 2015;211:80–90. doi: 10.1093/infdis/jiu396.

21. Rojas M., Monsalve D.M., Pacheco Y., Acosta-Ampudia Y., Ramírez-Santana C., Ansari A.A. Ebola virus disease: An emerging and re-emerging viral threat. J Autoimmun. 2020;106:102375. doi: 10.1016/j.jaut.2019.102375.

22. Planitzer C.B., Modrof J., Kreil T.R. West Nile virus neutralization by US plasma-derived immunoglobulin products. J Infect Dis. 2007;196:435–440. doi: 10.1086/519392.

23. Haley M., Retter A.S., Fowler D., Gea-Banacloche J., O’Grady N.P. The role for intravenous immunoglobulin in the treatment of West Nile virus encephalitis. Clin Infect Dis. 2003;37:e88–e90. doi: 10.1086/377172.

24. Shimoni Z., Niven M.J., Pitlick S., Bulvik S. Treatment of West Nile virus encephalitis with intravenous immunoglobulin. Emerg Infect Dis. 2001;7:759. doi: 10.3201/eid0704.010432.

25. van Griensven J., Edwards T., de Lamballerie X., Semple M.G., Gallian P., Baize S. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med. 2016;374:33–42. doi: 10.1056/NEJMoa1511812.

26. Garraud O., Heshmati F., Pozzetto B., Lefrere F., Girot R., Saillol A. Plasma therapy against infectious pathogens, as of yesterday, today and tomorrow. Transfus Clin Biol. 2016;23:39–44. doi: 10.1016/j.tracli.2015.12.003.

27. Lünemann J.D., Nimmerjahn F., Dalakas M.C. Intravenous immunoglobulin in neurology–mode of action and clinical efficacy. Nat Rev Neurol. 2015;11:80–89. doi: 10.1038/nrneurol.2014.253.

28. McGonagle D., Sharif K., O’Regan A., Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev. 2020 doi: 10.1016/j.autrev.2020.102537. In press:102537.

29. Wan S., Yi Q., Fan S., Lv J., Zhang X., Guo L. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP) MedRxiv. 2020 doi: 10.1101/2020.02.10.20021832.

30. Shahani L., Singh S., Khardori N.M. Immunotherapy in clinical medicine: Historical perspective and current status. Med Clin North Am. 2012;96:421–431. doi: 10.1016/j.mcna.2012.04.001. ix.

31. Shakir E.M., Cheung D.S., Grayson M.H. Mechanisms of immunotherapy: A historical perspective. Ann Allergy Asthma Immunol. 2010;105:340–347. doi: 10.1016/j.anai.2010.09.012. quiz 348, 368.

32. Sherer Y., Levy Y., Shoenfeld Y. IVIG in autoimmunity and cancer–efficacy versus safety. Expert Opin Drug Saf. 2002;1:153–158. doi: 10.1517/14740338.1.2.153.

33. Katz U., Achiron A., Sherer Y., Shoenfeld Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev. 2007;6:257–259. doi: 10.1016/j.autrev.2006.08.011.

34. Ahn J.Y., Sohn Y., Lee S.H., Cho Y., Hyun J.H., Baek Y.J. Use of convalescent plasma therapy in two COVID-19 patients with acute respiratory distress syndrome in Korea. J Korean Med Sci. 2020;35 doi: 10.3346/jkms.2020.35.e149.

35. Ko J.-H., Seok H., Cho S.Y., Ha Y.E., Baek J.Y., Kim S.H. Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: A single centre experience. Antivir Ther. 2018;23:617–622. doi: 10.3851/IMP3243.

36. Spalter S.H., Kaveri S., Kazatchkine M.D. Anti-idiotypes to autoantibodies in therapeutic preparations of normal polyspecific human IgG (intravenous immunoglobulin, IVIg) In: Shoenfeld Y., Kennedy R.C., Ferrone Infection and Cancer SBT-I in MA, editors. Idiotypes Med. Autoimmun. Infect. Cancer. Elsevier; Amsterdam: 1997. pp. 217–225. editors.

37. Ye M., Fu D., Ren Y., Wang F., Wang D., Zhang F. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020 doi: 10.1002/jmv.25882.

38. Shen C., Wang Z., Zhao F., Yang Y., Li J., Yuan J. Treatment of 5 critically ill patients with Covid-19 with convalescent plasma. JAMA. 2020;323(16):1582–1589. doi: 10.1001/jama.2020.4783.

39. Duan K., Liu B., Li C., Zhang H., Yu T., Qu J. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020 doi: 10.1073/pnas.2004168117.

40. Soo Y.O.Y., Cheng Y., Wong R., Hui D.S., Lee C.K., Tsang K.K.S. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect. 2004;10:676–678. doi: 10.1111/j.1469-0691.2004.00956.x.

41. Cheng Y., Wong R., Soo Y.O.Y., Wong W.S., Lee C.K., Ng M.H.L. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24:44–46. doi: 10.1007/s10096-004-1271-9.

42. Yeh K.-M., Chiueh T.-S., Siu L.K., Lin J.-C., Chan P.K.S., Peng M.-Y. Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital. J Antimicrob Chemother. 2005;56:919–922. doi: 10.1093/jac/dki346.

43. Zhou X., Zhao M., Wang F., Jiang T., Li Y., Nie W. Epidemiologic features, clinical diagnosis and therapy of first cluster of patients with severe acute respiratory syndrome in Beijing area. Zhonghua Yi Xue Za Zhi. 2003;83:1018–1022.

44. Kong L. Letter to editor. Transfus Apher Sci. 2003;29:101. doi: 10.1016/S1473-0502(03)00109-5.

45. Wong V.W.S., Dai D., Wu A.K.L., Sung J.J.Y. Treatment of severe acute respiratory syndrome with convalescent plasma. Hong Kong Med J. 2003;9:199–201.

46. Hung I.F., To KK, Lee C.-K., Lee K.-L., Chan K., Yan W.-W. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52:447–456. doi: 10.1093/cid/ciq106.

47. Chan K.K.C., Lee K.L., Lam P.K.N., Law K.I., Joynt G.M., Yan W.W. Hong Kong’s experience on the use of extracorporeal membrane oxygenation for the treatment of influenza A (H1N1) Hong Kong Med J. 2010;16:447–454.

48. Yu H., Gao Z., Feng Z., Shu Y., Xiang N., Zhou L. Clinical characteristics of 26 human cases of highly pathogenic avian influenza A (H5N1) virus infection in China. PLoS One. 2008;3 doi: 10.1371/journal.pone.0002985.

49. Kong L.K., Zhou B.P. Successful treatment of avian influenza with convalescent plasma. Hong Kong Med J. 2006;12:489.

50. Wong S.S.Y., Yuen K.-Y. The management of coronavirus infections with particular reference to SARS. J Antimicrob Chemother. 2008;62:437–441. doi: 10.1093/jac/dkn243.

51. Zhang H., Zeng Y., Lin Z., Chen W., Liang J., Zhang H. Clinical characteristics and therapeutic experience of case of severe highly pathogenic A/H5N1 avian influenza with bronchopleural fistula. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese J Tuberc Respir Dis. 2009;32:356–359.

52. Tiberghien P., de Lambalerie X., Morel P., Gallian P., Lacombe K., Yazdanpanah Y. Collecting and evaluating convalescent plasma for COVID-19 treatment: Why and how. Vox Sang. 2020 doi: 10.1111/vox.12926.

53. Tissot J.-D., Garraud O. Ethics and blood donation: A marriage of convenience. Press Medicale. 2016;45:e247–e252. doi: 10.1016/j.lpm.2016.06.016.

54. Bloch E.M., Shoham S., Casadevall A., Sachais B.S., Shaz B., Winters J.L. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020 doi: 10.1172/JCI138745.

55. Dodd R.Y., Crowder L.A., Haynes J.M., Notari E.P., Stramer S.L., Steele W.R. Screening blood donors for HIV, HCV, and HBV at the American Red Cross: 10-year trends in prevalence, incidence, and residual risk, 2007 to 2016. Transfus Med Rev. 2020 doi: 10.1016/j.tmrv.2020.02.001.

56. Niazi S.K., Bhatti F.A., Salamat N., Ghani E., Tayyab M. Impact of nucleic acid amplification test on screening of blood donors in Northern Pakistan. Transfusion. 2015;55:1803–1811. doi: 10.1111/trf.13017.

57. Bello-López J.M., Delgado-Balbuena L., Rojas-Huidobro D., Rojo-Medina J. Treatment of platelet concentrates and plasma with riboflavin and UV light: Impact in bacterial reduction. Transfus Clin Biol. 2018;25:197–203. doi: 10.1016/j.tracli.2018.03.004.

58. Benjamin R.J., McLaughlin L.S. Plasma components: Properties, differences, and uses. Transfusion. 2012;52(Suppl. 1):9S–19S. doi: 10.1111/j.1537-2995.2012.03622.x.

59. Du L., He Y., Zhou Y., Liu S., Zheng B.-J., Jiang S. The spike protein of SARS-CoV–a target for vaccine and therapeutic development. Nat Rev Microbiol. 2009;7:226–236. doi: 10.1038/nrmicro2090.

60. Tian X., Li C., Huang A., Xia S., Lu S., Shi Z. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect. 2020;9:382–385. doi: 10.1080/22221751.2020.1729069.

61. Wu F., Wang A., Liu M., Wang Q., Chen J., Xia S. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. MedRxiv. 2020 doi: 10.1101/2020.03.30.20047365.

62. Hsueh P.-R., Huang L.-M., Chen P.-J., Kao C.-L., Yang P.-C. Chronological evolution of IgM, IgA, IgG and neutralisation antibodies after infection with SARS-associated coronavirus. Clin Microbiol Infect. 2004;10:1062–1066. doi: 10.1111/j.1469-0691.2004.01009.x.

63. Gorse G.J., Donovan M.M., Patel G.B. Antibodies to coronaviruses are higher in older compared with younger adults and binding antibodies are more sensitive than neutralizing antibodies in identifying coronavirus-associated illnesses. J Med Virol. 2020;92:512–517. doi: 10.1002/jmv.25715.

64. Rokni M., Ghasemi V., Tavakoli Z. Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: Comparison with SARS and MERS. Rev Med Virol. 2020 doi: 10.1002/rmv.2107.

65. Chaigne B., Mouthon L. Mechanisms of action of intravenous immunoglobulin. Transfus Apher Sci. 2017;56:45–49. doi: 10.1016/j.transci.2016.12.017.

66. Zhang Y., Xiao M., Zhang S., Xia P., Cao W., Jiang W. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020;382(17):e38. doi: 10.1056/NEJMc2007575. In press.

67. Lutz H.U., Späth P.J. Anti-inflammatory effect of intravenous immunoglobulin mediated through modulation of complement activation. Clin Rev Allergy Immunol. 2005;29:207–212. doi: 10.1385/CRIAI:29:3:207.

68. Basta M., Van Goor F., Luccioli S., Billings E.M., Vortmeyer A.O., Baranyi L. F(ab)’2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins. Nat Med. 2003;9:431–438. doi: 10.1038/nm836.

69. Gralinski L.E., Sheahan T.P., Morrison T.E., Menachery V.D., Jensen K., Leist S.R. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. MBio. 2018;9 doi: 10.1128/mBio.01753-18.

70. Abe Y., Horiuchi A., Miyake M., Kimura S. Anti-cytokine nature of natural human immunoglobulin: one possible mechanism of the clinical effect of intravenous immunoglobulin therapy. Immunol Rev. 1994;139:5–19. doi: 10.1111/j.1600-065x.1994.tb00854.x.

71. Kulkarni R. Antibody-dependent enhancement of viral infections BT – Dynamics of immune activation in viral diseases. In: Bramhachari P.V., editor. Dyn. Immune Act. Viral Dis. Springer Singapore; Singapore: 2020. pp. 9–41. editor.

72. Vatti A., Monsalve D.M., Pacheco Y., Chang C., Anaya J.-M., Gershwin M.E. Original antigenic sin: A comprehensive review. J Autoimmun. 2017;83:12–21. doi: 10.1016/j.jaut.2017.04.008.

73. Wang S.-F., Tseng S.-P., Yen C.-H., Yang J.-Y., Tsao C.-H., Shen C.-W. Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins. Biochem Biophys Res Commun. 2014;451:208–214. doi: 10.1016/j.bbrc.2014.07.090.

74. Casadevall A., Pirofski L. The convalescent sera option for containing COVID-19. J Clin Invest. 2020;130:1545–1548. doi: 10.1172/JCI138003.

75. Nimmerjahn F., Ravetch J.V. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol. 2008;26:513–533. doi: 10.1146/annurev.immunol.26.021607.090232.

76. Kiessling P., Lledo-Garcia R., Watanabe S., Langdon G., Tran D., Bari M. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017;9 doi: 10.1126/scitranslmed.aan1208.

77. Litzman J. Influence of FCRN expression on lung decline and intravenous immunoglobulin catabolism in common variable immunodeficiency patients. Clin Exp Immunol. 2014;178(Suppl):103–104. doi: 10.1111/cei.12529.

78. Akilesh S., Petkova S., Sproule T.J., Shaffer D.J., Christianson G.J., Roopenian D. The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J Clin Invest. 2004;113:1328–1333. doi: 10.1172/JCI18838.

79. Hansen R.J., Balthasar J.P. Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia. Blood. 2002;100:2087–2093.

80. Hansen R.J., Balthasar J.P. Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb Haemost. 2002;88:898–899.

81. Jin J., Gong J., Lin B., Li Y., He Q. FcγRIIb expression on B cells is associated with treatment efficacy for acute rejection after kidney transplantation. Mol Immunol. 2017;85:283–292. doi: 10.1016/j.molimm.2017.03.006.

82. Shrestha S., Wiener H., Shendre A., Kaslow R.A., Wu J., Olson A. Role of activating FcγR gene polymorphisms in Kawasaki disease susceptibility and intravenous immunoglobulin response. Circ Cardiovasc Genet. 2012;5:309–316. doi: 10.1161/CIRCGENETICS.111.962464.

83. Kaneko Y., Nimmerjahn F., Ravetch J.V. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313(80):670–673. doi: 10.1126/science.1129594.

84. Othy S., Topcu S., Saha C., Kothapalli P., Lacroix-Desmazes S., Kasermann F. Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin. Eur J Immunol. 2014;44:2059–2063. doi: 10.1002/eji.201444440.

85. Bayry J., Lacroix-Desmazes S., Carbonneil C., Misra N., Donkova V., Pashov A. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood. 2003;101:758–765. doi: 10.1182/blood-2002-05-1447.

86. Sharma M., Schoindre Y., Hegde P., Saha C., Maddur M.S., Stephen-Victor E. Intravenous immunoglobulin-induced IL-33 is insufficient to mediate basophil expansion in autoimmune patients. Sci Rep. 2014;4:5672. doi: 10.1038/srep05672.

87. Tjon A.S.W., van Gent R., Jaadar H., Martin van Hagen P., Mancham S., van der Laan L.J.W. Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production. J Immunol. 2014;192:5625–5634. doi: 10.4049/jimmunol.1301260.

88. Karnam A., Rambabu N., Das M., Bou-Jaoudeh M., Delignat S., Käsermann F. Therapeutic normal IgG intravenous immunoglobulin activates Wnt-β-catenin pathway in dendritic cells. Commun Biol. 2020;3:96. doi: 10.1038/s42003-020-0825-4.

89. Bayry J., Lacroix-Desmazes S., Delignat S., Mouthon L., Weill B., Kazatchkine M.D. Intravenous immunoglobulin abrogates dendritic cell differentiation induced by interferon-alpha present in serum from patients with systemic lupus erythematosus. Arthritis Rheum. 2003;48:3497–3502. doi: 10.1002/art.11346.

90. Sharma M., Saha C., Schoindre Y., Gilardin L., Benveniste O., Kaveri S.V. Interferon-α inhibition by intravenous immunoglobulin is independent of modulation of the plasmacytoid dendritic cell population in the circulation: Comment on the article by Wiedeman et al. Arthritis Rheumatol. 2014;66:2308–2309. doi: 10.1002/art.38683.

91. Aubin E., Lemieux R., Bazin R. Indirect inhibition of in vivo and in vitro T-cell responses by intravenous immunoglobulins due to impaired antigen presentation. Blood. 2010;115:1727–1734. doi: 10.1182/blood-2009-06-225417.

92. Issekutz A.C., Rowter D., Miescher S., Käsermann F. Intravenous IgG (IVIG) and subcutaneous IgG (SCIG) preparations have comparable inhibitory effect on T cell activation, which is not dependent on IgG sialylation, monocytes or B cells. Clin Immunol. 2015;160:123–132. doi: 10.1016/j.clim.2015.05.003.

93. Ahmadi M., Abdolmohammadi-Vahid S., Ghaebi M., Aghebati-Maleki L., Afkham A., Danaii S. Effect of intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL) Biomed Pharmacother. 2017;92:1095–1102. doi: 10.1016/j.biopha.2017.06.001.

94. Hung I.F.N., KKW To, Lee C.-K., Lee K.-L., Yan W.-W., Chan K. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013;144:464–473. doi: 10.1378/chest.12-2907.

95. Klehmet J., Goehler J., Ulm L., Kohler S., Meisel C., Meisel A. Effective treatment with intravenous immunoglobulins reduces autoreactive T-cell response in patients with CIDP. J Neurol Neurosurg Psychiatry. 2015;86:686–691. doi: 10.1136/jnnp-2014-307708.

96. Trépanier P., Chabot D., Bazin R. Intravenous immunoglobulin modulates the expansion and cytotoxicity of CD8+ T cells. Immunology. 2014;141:233–241. doi: 10.1111/imm.12189.

97. Ye Q., Gong F.-Q., Shang S.-Q., Hu J. Intravenous immunoglobulin treatment responsiveness depends on the degree of CD8+ T cell activation in Kawasaki disease. Clin Immunol. 2016;171:25–31. doi: 10.1016/j.clim.2016.08.012.

98. Maddur M.S., Vani J., Hegde P., Lacroix-Desmazes S., Kaveri S.V., Bayry J. Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin. J Allergy Clin Immunol. 2011;127:823–827. doi: 10.1016/j.jaci.2010.12.1102.

99. Maddur M.S., Kaveri S.V., Bayry J. Comparison of different IVIg preparations on IL-17 production by human Th17 cells. Autoimmun Rev. 2011;10:809–810. doi: 10.1016/j.autrev.2011.02.007.

100. Kim D.J., Lee S.K., Kim J.Y., Na B.J., Hur S.E., Lee M. Intravenous immunoglobulin G modulates peripheral blood Th17 and Foxp3(+) regulatory T cells in pregnant women with recurrent pregnancy loss. Am J Reprod Immunol. 2014;71:441–450. doi: 10.1111/aji.12208.

101. Tackenberg B., Jelcic I., Baerenwaldt A., Oertel W.H., Sommer N., Nimmerjahn F. Impaired inhibitory Fc gamma receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy. Proc Natl Acad Sci U S A. 2009;106:4788–4792. doi: 10.1073/pnas.0807319106.

102. Nikolova K.A., Tchorbanov A.I., Djoumerska-Alexieva I.K., Nikolova M., Vassilev T.L. Intravenous immunoglobulin up-regulates the expression of the inhibitory Fc gamma IIB receptor on B cells. Immunol Cell Biol. 2009;87:529–533. doi: 10.1038/icb.2009.36.

103. Séité J.-F., Guerrier T., Cornec D., Jamin C., Youinou P., Hillion S. TLR9 responses of B cells are repressed by intravenous immunoglobulin through the recruitment of phosphatase. J Autoimmun. 2011;37:190–197. doi: 10.1016/j.jaut.2011.05.014.

104. Le Pottier L., Bendaoud B., Dueymes M., Daridon C., Youinou P., Shoenfeld Y. BAFF, a new target for intravenous immunoglobulin in autoimmunity and cancer. J Clin Immunol. 2007;27:257–265. doi: 10.1007/s10875-007-9082-2.

105. Prasad N.K., Papoff G., Zeuner A., Bonnin E., Kazatchkine M.D., Ruberti G. Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVIg involving the Fas apoptotic pathway. J Immunol. 1998;161:3781–3790.

106. Paquin Proulx D., Aubin E., Lemieux R., Bazin R. Inhibition of B cell-mediated antigen presentation by intravenous immunoglobulins (IVIg) Clin Immunol. 2010;135:422–429. doi: 10.1016/j.clim.2010.01.001.

107. Séïté J.-F., Cornec D., Renaudineau Y., Youinou P., Mageed R.A., Hillion S. IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes. Blood. 2010;116:1698–1704. doi: 10.1182/blood-2009-12-261461.

108. Blanco-Melo D., Nilsson-Payant B.E., Chun Liu W., Uhl S., Hoagland D., Møller R. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020 doi: 10.1016/j.cell.2020.04.026. In press.

109. Kozicky L.K., Zhao Z.Y., Menzies S.C., Fidanza M., Reid G.S.D., Wilhelmsen K. Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state. J Leukoc Biol. 2015;98:983–994. doi: 10.1189/jlb.3VMA0315-078R.

110. Meregalli C., Marjanovic I., Scali C., Monza L., Spinoni N., Galliani C. High-dose intravenous immunoglobulins reduce nerve macrophage infiltration and the severity of bortezomib-induced peripheral neurotoxicity in rats. J Neuroinflammation. 2018;15:232. doi: 10.1186/s12974-018-1270-x.

111. Zhang Bin, Liu Shuyi, Tan Tan, Huang Wenhui, Dong Yuhao, Chen Luyan. Treatment With Convalescent Plasma for Critically Ill Patients With SARS-CoV-2 Infection. Chest. 2020 doi: 10.1016/j.chest.2020.03.039. In press.

112. Rajendran Karthick, Narayanasamy Krishnasamy, Rangarajan Jayanthi, Rathinam Jeyalalitha, Natarajan Murugan, Ramachandran Arunkumar. Convalescent plasma transfusion for the treatment of COVID‐19: Systematic review. J Med Virol. 2020 doi: 10.1002/jmv.25961. In press.