Table 2.
Summary of original clinical studies of CP therapy for COVID-19. The studies were stratified according to the study design.
| Study design and studies | Population | Details of CPa | Interventions and comparisons | Outcomes/main findings | Adverse events related to CP therapy | |
| Case report | ||||||
|
|
Al Helali et al 2020 [65] | A previously healthy male 55 years of age with severe COVID-19 | Not reported | About 300 mL CP was transfused over 1 h in addition to other therapeutics: favipiravir, hydroxychloroquine, enoxaparin, paracetamol, diphenhydramine | A significant radiological and clinical improvement in a few days after CP transfusion and negative PCRb test for COVID-19 in <48 h and discharged 12 days post transfusion | No significant adverse effects |
|
|
Anderson et al 2020 [66] | A pregnant critically ill female 35 years of age with COVID-19 and past medical history for type 2 diabetes mellitus, asthma, and class III obesity | Not reported | One unit of CP on the day of admission at ICUc and supportive care and therapeutic agents | Discharged on day 14 with no further issues afterward and continuing antenatal care with both primary obstetric office and maternal fetal medicine specialists | Not reported |
|
|
Bao et al 2020 [67] | A critically ill man 38 years of age infected by SARS-CoV-2 and had cerebral hemorrhage | Not reported | 150-200 ml CP of type A Rh positive was given twice 9 days after hospital admission in addition to antiviral and antibacterial treatment | Both SARS-CoV-2 nucleic acid tests were negative (24 h interval) 2 days after the transfusion, and the patient’s symptoms gradually stabilized | Not reported |
|
|
Cinar et al 2020 [68] | A male patient 55 years of age with severe COVID-19 and active myeloid malignancy, disseminated tuberculosis, and kidney failure | Collected using Trima Accel Automated Blood Collection System from a donor who had previously recovered from COVID-19 and met universal donation criteria, anti–SARS-CoV-2 IgG titer 6.6 | 200 mL of CP on fifth day of symptom onset and another 200 mL of CP at ICU, in combination with antiviral and anticytokine drugs | SARS-CoV-2 was negative, discharged from the hospital with full recovery | No adverse reaction or complication |
|
|
Clark et al 2020 [69] | Immunocompromised woman 76 years of age with persisting COVID‐19 following therapeutic lymphocyte depletion | Not reported | CP transfused at day 50 after symptom onset over 2 days (200 mL/day) in addition to treatment with lopinavir/ritonavir and prednisone | Rapid improvement in health condition, allowing definitively withdrawing oxygen, apyrexia ensued, and negative SARS-CoV-2 test; discharged on day 69 | No adverse events |
|
|
Figlerowicz et al 2020 [70] | A girl 6 years of age with severe COVID-19 | CP inactivated using methylene blue with anti–SARS-CoV-2 IgG at a titer of 1:700 | CP transfused once in a 200-mL dose at 5 weeks from the beginning of the disease and treatment with antiviral drugs and immune modulators, antibiotics, and antifungal drugs | SARS-CoV-2 was negative for the next 3 weeks after CP therapy. The hematologic parameters did not improve after SARS-CoV-2 elimination. | No adverse events |
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|
Grisolia et al 2020 [71] | A woman 29 years of age at 24 2/7 weeks of gestation | Not reported | The patient was transfused with 300 mL of CP on day 7 from onset of symptoms and another 300 mL of CP on day 12, and treated with antibiotics, low-molecular-weight heparin, hydroxychloroquine, and methylprednisolone | The patient’s clinical condition rapidly improved as shown by normalization of laboratory tests, body temperature, O2 saturation, and vital signs within 3 days of the second CP transfusion, discharged 13 days after admission | No adverse effects |
|
|
Hahn et al 2020 [72] | A previously healthy man in his 70s with severe COVID-19 admitted to ICU | Obtained from two blood donors with one being diagnosed with high-level anti–SARS-CoV-2 IgG antibody | A total of 900 ml of CP was transfused at a slow infusion rate on day 31 after admission and treatment with a respirator, muscle relaxants, and antibiotics | The patient became afebrile and was tested negative for SARS-CoV-2 the following day after CP therapy, gradually improved and was weaned from the ventilator and discharged alive from the ICU on day 63 | Not reported |
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|
Hartman et al 2020 [73] | A man 62 years of age with a history of moderate persistent asthma, sinus bradycardia, chronic obstructive pulmonary disease, and newly diagnosed COVID-19 | Not reported | The patient received 217 mL of CP with no other interventions at the time estimated 7 days after onset of symptoms (cough and shortness of breath) | The patient showed rapid improvement in symptoms and electrocardiogram findings, and was discharged 36 hours after the transfusion | Not reported |
|
|
Im et al 2020 [74] | A man 68 years of age with severe COVID-19 | A donor with ABO blood group A (Rh-positive) incompatible with the patient ABO blood group B (Rh-positive) | 250 mL of CP at 16 days after symptom onset for 2 consecutive days with mechanical ventilation and ECMOd, steroid, heparinization, and antibiotic treatment | The patient showed clear improvement in respiratory distress and fever symptoms for 3 days after the CP transfusion; discharged without any detectable virus or other complications | No evident acute adverse effect |
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Jafari et al 2020 [75] | A woman 26 years of age with a twin pregnancy at 36 weeks and 1 day gestation with confirmed COVID-19 | Not reported | One unit of CP was transfused on the sixth day after hospital admission in addition to favipiravir and oxytocine | The patient showed dramatic clinical and radiologic improvements and was discharged 2 weeks after admission with no infection of the newborns | Not reported |
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|
Jiang et al 2020 [76] | A kidney transplant female recipient 70 years of age with immunosuppression; severe COVID-19; and a history of chronic bronchitis, hypertension, and hyperlipidemia | Collected by apheresis from a donor who had recovered from SARS-CoV-2 infection for >14 days, with an ELISAe antibody titer >1:1000 | 200 mL CP was administered at day 4 and 11 after admission in addition to treatment with moxifloxacin, piperacillin, methylprednisolone, tienam, and fluconazole | The patient’s body temperature became normal and chest CTf was significantly better than at admission, and the patient was discharged on day 30 | Not reported |
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Karataş et al 2020 [77] | A man 61 years of age with a history of ASCTg for lymphoma with persistent positive tests for SARS-CoV-2 RT-PCRh and fever | Obtained using Trima Accel Automated Blood Collection System from a donor satisfying universal donation criteria and recovered from COVID-19 disease; ELISA IgG titer 13.3 | CP transfusion on the 40th day of the infection (dose not specified) | After the CP transfusion, his fever resolved after 3 days. He was discharged from the hospital on the 78th day of hospitalization; viral shedding remained positive as demonstrated by RT-PCR | Not reported |
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|
Kong et al 2020 [79] | A mild COVID-19 male 100 years of age with a 30-year record of hypertension, abdominal aortic aneurysm, cerebral infarction, prostate hyperplasia, and complete loss of cognitive function for the preceding 3 years | Collected via plasmapheresis from a donor who had recovered from COVID-19 for more than 2 weeks and had a SARS-CoV-2 S-RBDi–specific IgG titer >1:640 | The patient received CP twice: 200 ml on the seventh day of hospitalization and 100 ml on the 11th day of hospitalization | Patient’s viral load decreased significantly, by a factor of ~18, 24 h after the first transfusion of convalescent plasma and then became undetectable after the second, discharged on day 13 of hospitalization | Not reported |
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Mira et al 2020 [80] | A male patient 39 years of age with severe COVID-19 and XLAj, receiving monthly immunoglobulin replacement therapy | IgG antibodies against either the spike or nucleocapside viral proteins with a titer ≥1:320 | 200 mL, single dose, on day 23 after admission | After 24 h of infusion, fever ceased without subsequent reappearance and with progressive improvement of asthenia. After 48 h of infusion, no detectable virus in qPCRk from nasopharyngeal exudate | Not reported |
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|
Soleimani and Soleimani 2020 [82] | A woman 30 years of age (gravid 3, parity 2) at her 21 and 2/7 weeks gestation with ARDSl caused by SARS-CoV-2 infection | Not reported | CP was administered in addition to lopinavir/ritonavir and azithromycin and early methyl prednisolone therapy | A mild clinical improvement and decrease in inflammatory markers; normal growth of the fetus | Not reported |
|
|
Xu et al 2020 [83] | A man 65 years of age with severe COVID-19 | Collected from two convalescent patients; no details provided | CP was given at a 400-mL dose on day 1 and 2 after admission, and hydroxychloroquine was orally administrated for a week | On day 11 after CP transfusion, temperature returned to normal and mechanical ventilation was withdrawn, the RNA test remained positive in throat swab, and CT revealed severe pulmonary lesions | No apparent side effects |
|
|
Zhang et al 2020 [84] | A critically ill female 64 years of age with hypertension and diabetes | Collected by apheresis from a male 37 years of age with blood type O at 36 days after symptom onset and 17 days after discharge; CP IgG titer >1:320 by ELISA | 200 mL CP on day 17 of hospitalization while receiving invasive mechanical ventilation | The patient did not require mechanical ventilation 11 days after plasma transfusion and was transferred from ICU to a general ward | No adverse event |
| Case series | ||||||
|
|
Ahn et al 2020 [85] | A previously healthy man 71 years of age and a woman 67 years of age with a medical history of hypertension, both diagnosed with severe COVID-19 | Obtained with Spectra Optia apheresis system from a male donor in his 20s who had recovered from COVID-19 for 21 and 18 days, respectively, and met the blood donor eligibility criteria for plasma donation. ELISA optical density ratio for anti–SARS-CoV-2 IgG was 0.586 and 0.532 (cutoff value 0.22) | A total 500 mL of CP was divided into two doses and given over 1 hour for each dose at 12-hour intervals after 22 days from the onset of symptoms in case 1 and 7 days in case 2 | SARS-CoV-2 became negative in both cases: case 1 underwent a tracheostomy and currently was successfully weaned from the mechanical ventilator; case 2 was successfully extubated and discharged from the hospital on day 24 | No adverse reaction occurred after the administration of CP |
|
|
Abdullah et al 2020 [86] | A male 46 years of age and a male 56 years of age, both with hypertension and severe COVID-19 | Collected from a recovered moderate COVID-19 patient after performing necessary investigations for donor plasma (hemoglobin level and viral screen) but not antibody tests | Deteriorated despite supportive care and antiviral therapy: 200 mL of CP at day 3 of hospitalization (day 7 after symptom onset) in case 1; day 10 of hospitalization (day 13 after symptom onset) in case 2 | Improve clinically 4 days and 70 h after CP, discharged from the hospital 16 and 21 days after admission with three consecutive negative RT-PCR tests each with at least 24 h apart | Not reported |
|
|
Bradfute et al 2020 [87] | 12 hospitalized COVID-19 patients (8 males and 4 females) with a median age of 52 (range 39-91) years, 9 obese patients, 10 patients in the ICU, and 2 on the general ward | Collected by apheresis from donors ≥28 days after positive PCR test, with complete recovery from COVID-19 and a median of neutralizing antibody titer of 1:40 (range, undetectable to 1:160) | Patients received one unit (200 mL) CP at a median of 8.5 (range 6-16) days after the onset of symptoms and a median 3.5 (range 1-10) days after hospitalization | Temporal increases in neutralizing antibody titers and IgG/IgM levels, gradual decreases in viral loads, with two deaths within 14 days after CP transfusion | No serious adverse events |
|
|
Diorio et al 2020 [88] | Four critically ill children with COVID-19; 14-18 years; female; varied antibody titer levels pretransfusion | Collected from donors proven positive for SARS‐CoV‐2 by a laboratory test; and either ≥14 days from symptom resolution with a repeat negative test for SARS‐CoV‐2 or ≥28 days from symptom resolution without the repeat test. RBD-specific IgG titer <1:160 to >1:6000 | 200-220 mL of CP at 7-14 days after symptom onset | 1 died; 2 showed no clinical improvement; 1 recovered | No emergent adverse events related to CP infusion |
|
|
Enzmann et al 2020 [89] | 16 critically ill COVID-19 patients with most (12 patients) underlying cardiovascular disease | Not reported | Not reported | In-hospital mortality rate was 31% and median length of hospital stay was 19 (8-36) days | No apparent adverse effects |
|
|
Erkurt et al 2020 [90] | 26 (8 females and 18 males) severe COVID-19 patients (mean age 67.4, SD 15.5 years) | Collected via apheresis ≥14 days after complete recovery from the eligible blood donors who had mild or moderate COVID-19 with positive antibodies | 200 mL of CP was administered at a mean 13.87 (SD 6.5) days after admission in addition to supportive treatment, hydroxychloroquine, azithromycin, and favipiravir | The patients who did not need mechanical ventilation improved with CP treatment, while 6 of 17 patients on mechanical ventilation were dead | No severe adverse reactions |
|
|
Fung et al 2020 [56] | 4 immune-suppressed patients (males: two were aged 42 years and one was aged 62 years; female: one aged 65 years) with or at risk of progression to severe or life-threatening COVID-19 | Collected per FDAm guidance from donors with confirmed COVID-19 and resolution of symptoms within 14-28 days and a negative PCR test or >28 days without a PCR test; ELISA anti–SARS-CoV-2 spike protein IgG titer >1:400 | Approximately 200 mL of CP was transfused at 4-27 days following symptom onset | All patients were clinically improved, with 2 discharged home and fully recovered, and 2 discharged to skilled nursing facilities | No adverse reactions |
|
|
Gemici et al 2020 [91] | 40 consecutive patients (median age 57.5 years and 72.5% male) with severe COVID-19 | Collected from eligible blood donors recovered from COVID-19 with negative laboratory results and symptom free for ≥14 days | Patients received a median of 2 (range 1-3) units of CP at median time of 5 days from the diagnosis in addition to antiviral therapy | 90% of patients who received CP outside ICU totally recovered at a median of 9 days after the transfusion, and half of the patients treated in ICU were free of mechanical ventilation | No TRALIn or severe allergic reactions |
|
|
Hartman et al 2020 [63] | 16 (7 female) severe and 15 (3 female) life-threatened patients | Collected from a local donor recruitment and referral program | Dose and timing not reported | Respiratory support requirements began on or about day 7 following CP transfusion, especially in the severe patients | Not reported |
|
|
Ibrahim et al 2020 [92] | 38 hospitalized, severely (n=16) or critically ill patients (n=22) with confirmed COVID-19 (mean age 63, SD 12 years; 18 female); 31.5% had three or more comorbidities, with 68% having hypertension and 47% having diabetes | Collected by apheresis from adults who were confirmed positive and had recovered from SARS-CoV-2 with negative PCT test for the virus and had total anti–SARS-CoV-2 titer >1:320 | ABO-compatible CP was given in two consecutive 200-mL infusions (mean 18.7, SD 9.0) days following symptom onset. Another unit of CP was given to those with undetectable anti–SARS-CoV-2 antibodies. | 24 (63%) recovered and were discharged from the hospital, and 14 (37%) died. The survival patients received CP earlier in their course of disease (mean 15.3, SD 6.9 days) and hospital stay (mean 8.4, SD 6.8 days) compared to those who died with mean durations of 24.5 (SD 9.6) days and 16.6 (SD 9.5) days, respectively. | No adverse effects except for a transient transfusion reaction (fever and hematuria) within 2 h of CP infusion in 1 patient |
|
|
Bobek et al 2020 [93] | 2 critically ill Hungarian patients (males 59 and 72 years of age) with COVID-19, hypertension, and cardiovascular disease | Collected by plasmapheresis from recovered COVID-19 patients who had been asymptomatic for at least 2 weeks, negative PCR tests, and IgG-type antibody detectable by ELISA | 3 × 200 mL of CP with the first dose administered on the fourth day of the patient’s ICU mechanical ventilation | Both showed improved oxygenation and inflammatory decreased markers, and were weaned from mechanical ventilation within 2 weeks | No severe adverse effects |
|
|
Jin et al 2020 [94] | 3 patients (males 10, 24, and 40 years of age) with XLA, hospitalized for COVID-19 | CP containing antispike protein titer 1≥:320 | Two units of 200 mL ABO-compatible CP were given on days 16, 22, or 44 of illness when there was minimal improvement on other therapies | Various clinical and laboratory improvements including increases in antibody titers; discharged within days after CP transfusion | Not reported |
|
|
Joyner et al 2020 [95] | 5000 hospitalized adults (median age of 62) with 81% having severe or life-threatening COVID-19 and 66% admitted to ICU | ABO-compatible CP | CP dose of 200-500 mL | The incidence of SAEso was less than 1%, and the mortality rate at the seventh day after CP transfusion was 14.9% | Of 36 SAEs, 7 and 11 incidents of TACOp and TRALI, respectively, were judged as related to CP transfusion |
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Joyner et al 2020 [96] | 20,000 hospitalized adults (aged 20-80 years) with severe or life-threatening COVID-19 | ABO-compatible CP with no minimum neutralizing antibody titer level donated by recently recovered COVID-19 survivors | CP dose of 200-500 mL | 141 SAEs classified as transfusion reactions were reported (<1% of all transfusions); 38 thromboembolic or thrombotic events and cardiac events were related to the transfusion. The mortality rate at the seventh day after transfusion was 13.0%. | Of 141 SAEs, there were 36 reports of TACO, 21 reports of TRALI, and 21 reports of severe allergic transfusion reaction |
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Joyner et al 2020 [97] | 35,322 hospitalized patients with (or at risk of) severe or life- threatening acute COVID-19 and a diverse representation of gender, age, weight status, race, and ethnicity | Collected from recently recovered COVID-19 survivors without symptoms for ≥14 days, and the antibody levels in the units collected were unknown at the time. | All patients were treated with at least one unit (~200 mL) of CP with the option to administer additional doses if clinically justified in addition to adjunctive COVID-19 medications | A gradient of 7- and 30–day mortality associated with higher IgG levels in CP and early CP transfusion within 3 days of COVID-19 diagnosis | Reported in Joyner et al 2020 [96] |
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Liu et al 2020 [117] | 3 critically ill male patients with COVID‐19 (42, 56, and 58 years of age; two healthy; one with hypertension) | Collected from COVID-19 survivors who had fully recovered and tested negative for the virus and a total anti–SARS-CoV‐2 IgG titer of 160 | Patients were transfused with 200-225 mL CP between 20 and 30 days after disease onset at the critical illness stage in addition to standard care | No therapeutic effect of CP was observed in any of the patients | Not reported |
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Maor et al 2020 [99] | 49 patients (median age 64.0, IQR 50.5-76.0 years; 35 males) with moderate and severe COVID-19 and comorbidities (diabetes and hypertension) in one-third of the patients | Collected by apheresis procedure from recovered COVID-19 patients eligible for plasma donation and >14 days since the last negative PCR test; neutralizing antibody titer 1:20-1:2560 | The first dose of 200 mL CP was transfused at a median of 10.0 (IQR 4.0-14.0) days after PCR diagnosis, followed by a second unit of 200 mL 24 h later, in addition to various standard of care | At day 14 after the first CP dose, 24 patients improved, 9 died, and 13 were ventilated. More patients improved when treated with CP containing higher antibody levels or earlier. | No serious adverse events except that one developed a rash that responded to antihistamine therapy |
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Naeem et al 2020 [100] | 3 kidney transplant recipients with COVID‐19 treated with CP (1 female 65 years of age admitted to the general medicine service and a female aged 35 years and a male 36 years of age in the ICU) | Collected from donors at local and regional blood centers | One or two units of CP were given on day 2, 4, or 7 after hospital admission, in addition to immunosuppressant/ antiviral/antibiotic | All showed clinical improvement and were discharged 9, 16, and 25 days after hospital admission with no evident infectious complications | 1 patient experienced acute chest pain and dyspnea but improved over the following 12-24 h. |
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Olivares-Gazca et al 2020 [101] | 10 male severe COVID-19 patients with a median age of 53 (range 27-72) years and comorbidities (diabetes, hypertension) | Obtained by apheresis from 5 donors (2 females) with a median age of 35 (range 24-52) years and two negative PCR tests in a 24-h interval 10 days after the resolution of COVID-19 symptoms | Each patient received 200 mL of ABO-compatible CP and other therapies (eg, steroids or hydroxychloroquine) | Improvement in overall respiratory function and clinical condition over a period of 8 days, with 6 discharged and 2 died | No side effects |
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Pal et al 2020 [102] | 17 critically ill patients (mean age 56, range 24-81 years; 10 males) with COVID‐19 and most patients had multiple medical comorbidities, including 6 with hematological malignancies | Collected from donors 18-56 days following full recovery from COVID-19 with anti–SARS-CoV-2 spike protein IgG titers 1:400-1:6400 as measured by ELISA | A single unit of 200 mL CP was given at an average time of 12 (range 4‐41) days from illness; 3 patients received two units roughly 8 days apart in addition to other COVID-19 treatment and chemotherapy as required | All patients showed a decline in oxygen needs and ventilatory support with most effects seen in patients when CP was administered early in their disease course | No adverse events except a fever during transfusion in 1 patient, resulting in infusion of only 100 mL |
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Rahman et al 2020 [103] | 13 SOTq recipients (median age 51, range 20‐75 years; 8 males) with severe COVID-19 and comorbidities (eg, hypertension and diabetes) | Collected from eligible blood donors with anti–SARS-CoV‐2 spike protein antibody titers ≥1:320 as measured by ELISA | All patients received two ABO-compatible units of CP, for a total of 500 mL, at a median time of 8 days from symptom onset and additional therapies (hydroxychloroquine alone or in combination with azithromycin, steroids, anticoagulation, and immunosuppression) | 8 patients had de-escalating oxygenation support by day 7 post CP. 9 patients were discharged, 1 still hospitalized, and 3 patients died ~3 months after the CP transfusion. | No apparent transfusion-related adverse reactions |
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Salazar et al 2020 [104] | 25 patients (median age 51 years) with severe or life-threatening COVID-19 and one or more underlying chronic conditions | Obtained from donors eligible according to standard blood donor criteria, confirmed SARS-CoV-2 infection and symptom free for 14 days, and tested negative for SARS-CoV-2 by RT-PCR; ELISA IgG titer ranged from 0 to 1350 | One 300-mL dose of CP at a median time of 10 days from symptom onset and concomitant anti-inflammatory and antiviral treatments, and 1 patient received a second dose 6 days after the initial transfusion | By day 14 of CP transfusion, 19 (76%) patients had clinical improvement and 11 were discharged | No adverse events within 24 h after transfusion. 1 patient developed a morbilliform rash 1 day after transfusion that lasted for several days. |
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Shen et al 2020 [105] | 5 critically ill patients (age range 36-65 years; 2 female) with laboratory-confirmed COVID-19, rapid progression, and continuously high viral load despite antiviral treatment | Obtained from 5 patients who recovered from COVID-19; anti–SARS-CoV-2 IgG titer >1:1000 as determined by ELISA and a neutralization titer >40 | ABO-compatible CP was administered at a dose of 200-250 twice (400 mL in total) between 10 and 22 days after admission | Improvement in their clinical status as indicated by declined viral load, body temperature reduction, improved PaO2 /FiO2, and chest imaging | Not reported |
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Tremblay et al 2020 [106] | 24 patients with cancer and severe or life-threatening COVID-19 (median age 69, range 31-88 years; 14 males), some having other comorbidities (eg, hypertension in 15 patients) | Collected via plasmapheresis, spike protein-directed ELISA antibody titers ≥1:320 | Two units (250 mL) of ABO-compatible CP were transfused at 3 (IQR 2-7) days from admission in addition to cancer‐directed treatment and COVID-19–specific therapies (hydroxychloroquine, azithromycin, remdesivir, and tocilizumab) | Marked variability in both the timing and degree of improvement or worsening of oxygen requirement; 13 discharged; 10 deaths | 3 patients experienced febrile nonhemolytic transfusion reactions |
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Wang et al 2020 [108] | 5 critically ill COVID-19 patients (median age 56, IQR 50-62 years) admitted to ICU with a persistent (>30 days) positive nucleic acid test for SARS-CoV-2 and underlying chronic comorbidities, including hypertension and diabetes | Collected from the recently cured patients whose antibody titers were above 1:640 | 200 mL of cross-matching CP was transfused over 15 min initiated at a median of 37 (IQR 34-44) days from the onset of symptoms. In total, 3 patients received 400 mL and the other 2 received 1200 mL; all received antibiotics, antiviral, and anti-inflammatory agents. | Within 6 days after CP therapy, all patients became negative for two consecutive nucleic acid tests. Additionally, 4-9 days following the CP, 3 patients showed resolution of pulmonary lesion. 2 recovered and 3 died. | No adverse reactions |
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Wei et al 2020 [107] | 2 COVID-19 patients (males aged 50 and 81 years, the latter with type 2 diabetes mellitus, hypertension, and aortic dissection) with long-term positive viral infection | Not reported | One or two 200-mL doses of CP were administered >8 weeks after symptom onset; other therapeutics: interferon, arbidol, chloroquine phosphate, and ritonavir-boosted danoprevir | Substantial improvement as confirmed by CT scan and discharged after three consecutive negative nucleic acid tests | Not reported |
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Wu et al 2020 [109] | 27 adult patients with prolonged infection for a median of 44 (IQR 30-47) days between symptom onset and last positive test of SARS-CoV-2 before CP therapy (median age 64, IQR 57-72 years; 55.5% males), some with chronic diseases | Collected from donors (without transfusion-related infectious diseases who recovered from COVID-19) >3 weeks after symptom onset and >10 days after discharge; neutralizing antibody titer >1:160 | The patients were treated with a median of 400 (IQR 200-600) mL CP at a median of 45 (IQR 3549) days after symptom onset and other therapeutics: antivirals, antibiotics, corticoid, or immunoglobulin | The patients showed pulmonary imaging improvement (within 5-8 days) and viral clearance (18 patients) 15 days after the CP transfusion, and 3 died within 60 days | No transfusion-related adverse reactions |
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Xi et al 2020 [110] | 3 severe COVID-19 patients with comorbidities (hypertension, liver injury, and hepatitis B) | Collected from 2 recovered patients with high levels of IgG (>30 AU/mL) and IgG titer >1:80 | 50 mL twice with a 2-day interval and other treatments with noninvasive mechanical ventilation and antiviral, antibacterial drugs, and traditional Chinese medicine | The CT images, blood gas analysis, and symptoms improved after CP therapy. All recovered after 16-18 days of hospitalization. | No adverse event |
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Ye et al 2020 [111] | 6 laboratory‐confirmed critically ill COVID‐19 patients (mean age 58, SD 16.4 years; 3 male) | Collected from patients at least 3 weeks following disease onset, two consecutive negative RT-PCR tests, and seropositive for anti–SARS‐CoV-2 IgG and IgM | One to three doses of ABO-compatible CP (200 mL/dose) at 6-31 days after admission. Each transfusion was administered over a 30‐minute period. | A resolution of ground‐glass opacities and consolidation in 5 out of 6 patients and an elimination of the virus in 2 in the following days of CP therapy | No adverse events |
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Zhang et al 2020 [112] | 4 critically ill patients infected with SARS-CoV-2 (age: 31-73 years; 2 male) | Prepared from recovered patients without details | One to eight doses of CP (200-2400 mL in total) 11-41 days after admission in addition to antiviral therapy | The time from transfusion to negative RT-PCR test results ranged from 3 to 22 days. 3 were discharged from the hospital, and 1 remained in ICU up to the time of this writing | No adverse events |
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Zeng et al 2020 [113] | 8 patients (4 males, median age 65 years) with severe or critical COVID-19; 5 patients had coexisting chronic diseases | Collected from seven donors (median age of 37 years) who had mild or moderate COVID-19 with no comorbidities and were at a median day of 11 from discharge; neutralizing antibody titer 1:255-1:1576 | ABO-compatible and cross-matched CP were administered at one (3 patients) or two doses of 100-200 mL of CP within 24 h between 9 and 34 days following the onset of symptoms | 6 of 8 patients showed an improvement in oxygen support status within 5 days from CP treatment, partial resolution of pulmonary lesions, and decreased viral load | No adverse events |
| Observational (cohort, case-control) studies | ||||||
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Abolghasemi et al 2020 [114] | 115 CP treatment group with an average age of 54.4 years, and 74 control group– matched by age, gender, underlying diseases (hypertension and diabetes), and COVID-19 severity | Selected from clinically and laboratory-confirmed recovered patients of COVID-19 who were between the ages of 18-60 years and had no remaining symptoms of COVID-19 infection for at least 14 days; ELISA antibody titer cutoff index >1.1 | One unit of 500 mL was infused in <3 days of hospital admission (≤7 days since illness onset), followed by another unit if the patient did not show any improvement after 24 h | More discharged patients (98.2 % vs 78.7 %), shorter hospital stay (9.54 vs 12.88 days), and less requirement for intubation (7% vs 20%) in the CP group than the control group | No adverse effect |
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Duan et al 2020 [115] | 10 severe COVID-19 patients (6 males and 4 females) with a median age of 52.5 years in comparison with a historic control group of 10 patients matched by age, gender, and severity of the diseases | Collected by apheresis using a Baxter CS 300 cell separator from 10 donor patients who recovered from COVID-19 at 3 weeks after illness and 4 days after discharge and two consecutively negative results of sputum SARS-CoV-2 by RT-PCR assay (1-day sampling interval) neutralization activity of >1:640 | One dose (200 mL) of CP at the median time of 16 days from onset of illness in combination with antiviral, antibiotic or antifungal treatment, or glucocorticoid therapy | Improved clinical symptoms and paraclinical criteria within 3 days after CP, varying degrees of absorption of lung lesions for all patients within 7 days, as compared to 3 deaths, 6 cases in stabilized status, and 1 case of improvement in the control group (P<.001) | No SAEs or safety events; 1 patient showed an evanescent facial red spot |
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Hegerova et al 2020 [116] | 20 patients (median age 60, range 29-95 years) with severe or critical COVID-19 treated with CP under an expanded access protocol, as compared with 20 matched controls with regard to age, number of comorbidities, and severity of illness | Collected from patients aged from 29 to 79 years who recovered from COVID-19 (symptom free) for >28 days without hospitalization, most showing anti–SARS-CoV-2 IgG | One unit of ABO-compatible CP was administered early at the median time of 2 (IQR 1-4.3) days from hospitalization and additional therapies (eg, azithromycin and hydroxychloroquine) | Improved laboratory and respiratory parameters in patients following CP infusion, similar to those in controls but with lower mortality (2 vs 6 deaths) | No adverse events |
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Liu et al 2020 [117] | 39 hospitalized patients (mean age 55, SD 13 years; 25 males) with severe to life-threatening COVID-19 received CP transfusion in comparison with a cohort of retrospectively matched controls (n=156) | Collected by plasmapheresis from donors with antispike antibody titers ≥1:320 as measured by ELISA | Two units (250 mL each unit) of ABO-type matched were infused over 1-2 hours at the median time of 4 days after admission in addition to a variety of inpatient pharmacotherapies | More likely improvements in supplemental oxygen requirements by posttransfusion day 14, improved survival, compared to control patients, especially for nonintubated patients | No significant transfusion-related morbidity or mortality |
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Perotti et al 2020 [118] | 46 moderate to severe COVID-19 patients (mean age 63, SD 12 years), with 19 (41%) having two or more comorbidities, in comparison with a control cohort of 23 consecutive patients | Collected using a Trima Accel blood collection device from eligible COVID-19 recovered patients with 2 consecutive negative tests for SARS‐CoV‐2, followed by pathogen reduction; neutralization titers ≥1:80 | 24 patients received one unit of plasma, 21 received two units, and 1 patient received 3 units after having symptoms for 2 weeks, with most having been treated with antibiotics, hydroxychloroquine, and anticoagulants | 3 out of 46 patients (6.5%) died within 7 days (at 1, 4, and 6 days), lower than 30% in the control, and showed improved respiratory function (PaO2 /FiO2), chest radiogram, laboratory parameters (CRPr, Ferritin, LDHs, viral load), and weaning from mechanical ventilation | Five serious adverse events occurred in 4 patients. |
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Rasheed et al 2020 [119] | 49 early-stage (no more than 3 days in ICU) critically ill COVID-19 patients randomized to receive CP or not (21 and 28 patients, respectively, matched in terms of age, sex, and comorbidities) | Collected from healthy donors younger than 50 years who recovered from moderate COVID-19 and had a IgG index ≥1.25 as measured by ELISA | 400 mL of CP were transfused over 2 hours in addition to standard of care in the control group | CP-treated patients showed reduced duration of infection in about 4 days, a lower death rate (1/21 vs 8/28), and higher levels of SARS-CoV-2 IgG and IgM 3 days after CP transfusion compared to the control group | No adverse events except that 1 patient developed mild skin redness and itching that lasted for 1 hour after CP; resolved by antihistamine injection |
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Roger et al 2020 [120] | 64 patients with symptom onset ≤10 days prior to admission and supplemental oxygen (but not invasive ventilation) within 48 h of hospitalization versus a matched control group of 177 patients for all cause in-hospital mortality and rate of hospital discharge at day 28 | The SARS-CoV-2 antibody content in CP was assessed retrospectively with 13% of the units below the cutoff for a positive antibody index | 3 of 64 patients received one and the remainder received two units of CP at a median of 7 (IQR 5-9) days after symptom onset | No significant difference in the risk of in-hospital mortality or overall rate of hospital discharge between the two groups, except for a significantly increased hospital discharge rate among patients 65 years or older | 2 patients had TRALI reactions associated with the first unit of CP, and 1 had TACO approximately 3 h after transfusion of the second unit of CP |
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Salazar et al 2020 [121] | 136 severe or life-threatening COVID-19 patients treated with CP versus 215 propensity score-matched patients to assess the efficacy of CP transfusion compared to standard of care | Collected from donors who had been asymptomatic for more than 14 days and had negative SARS-CoV-2 RT-PCR tests at the time of plasmapheresis; antispike IgG antibody titers ≥1:1350 as measured by ELISA | The majority of patients received one and some patients reviewed two units of CP due to worsening COVID-19 conditions | Patients treated by CP with IgG titer ≥1:1350 within 72 h of hospital admission had decreased mortality within 28 days | Reported in Joyner et al 2020 [95] |
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Xia et al 2020 [122] | 1568 severe or critical COVID-19 patients, most with comorbidities, among whom 1430 patients (median age of 63 years; 50% male) only received standard treatment and 138 patients (median age of 65 years; 56% male) also received ABO-compatible CP | Not reported | 200-1200 mL of CP were transfused at a median of 45 days of symptom onset (1 week to ≥8 weeks from symptom onset to CP therapy) | Compared to that in the standard treatment group, there was a reduced mortality rate (2.2% vs 4.1%), lower admission to ICU (2.4% vs 5.1%), and improved respiratory symptoms of severe patients as evaluated by SCSSt | No significant differences in cardiac, liver, and renal functions before and after CP therapy, except for a decrease in total bilirubin and 3 patients with minor allergic reactions (pruritus or erythema) during the transfusion |
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Xiao et al 2020 [123] | 18 patients with severe and critical COVID-19 divided into two groups with no significant differences in age, gender, and basic clinical data: one with CP transfusion (n=6) and the other without CP transfusion (n=12) | Collected from donors between age 18-55 years who had fully recovered from COVID-19 without symptoms for 2 weeks and ≥4 weeks from symptom onset; anti–SARS-CoV-2 IgG titers >1:160 | 200~500 mL (4~5 mL/kg body weight) of CP were transfused | No difference between the two groups of patients in terms of ventilator and ECMO weaning time, time for viral clearance, and hospitalization | Not reported |
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Zeng et al 2020 [124] | 21 critically ill patients with COVID-19 and respiratory failure: 6 patients (median age of 61.5 years; 5 males) in the CP group versus 15 patients (median age of 73 years; 11 males) in a control group with no significant differences in demographic and clinical features | 200-400 mL obtained from each young adult individual who had recovered from COVID-19 for 1-2 weeks and was negative for SARS-CoV-2 RNA and IgM testing, and positive for IgG testing before donation | A median volume of 300 mL CP was transfused at a median of 21.5 days after viral shedding was first detected | All CP-treated patients tested negative for SARS-CoV-2 RNA within 3 days after infusion versus 26.7% in the control group, but 5 patients eventually died with a longer survival period, suggesting treatment should be initiated earlier | No immediate or noticeable adverse effects |
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Gharbharan et al 2020 [125] | 86 hospitalized patients (median age of 63 years; 72% male) randomized at 1:1 for standard of care therapy with and without CP | Collected from donors confirmed with an RT-PCR SARS-CoV-2 infection and were asymptomatic for at least 14 days; neutralizing antibodies titer ≥1:80 determined by a SARS-CoV-2 plaque reduction neutralization test | One unit of 300 mL ABO-compatible CP was transfused on the day of inclusion followed with the second plasma unit after 5 days for patients with persistent positive RT-PCR tests | There was no difference in day-60 mortality, hospital stay (P=.68), or day-15 disease severity (P=.58) between CP-treated patients and patients on standard care. The study was discontinued due to high neutralizing antibody titers at hospital admission in the majority of the study population. | No plasma-related serious adverse events were observed |
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Li et al 2020 [126] | 103 patients (median age 70 years; 60 males, 58.3%) with severe and life-threatening COVID-19 randomized to receive CP in addition to standard treatment (n=52) or standard treatment (antiviral medications, antibacterial medications, steroids, human immunoglobulin, Chinese herbal medicines, and other medications) alone (control; n = 51) | Collected based on routine plasma collection procedures via plasmapheresis from adults aged 18-55 years that were suitable for blood donation, initially diagnosed with COVID-19 but with 2 negative PCR results from nasopharyngeal swabs (at least 24 h apart) prior to hospital discharge, discharged for ≥2 weeks from the hospital, and had no persisting COVID-19 symptoms. CP S-RBD–specific IgG titer ≥1:640 correlating to serum neutralization titre of 1:80 | ABO-compatible CP was transfused at approximately 4-13 mL/kg of recipient body weight and at approximately 10 mL for the first 15 minutes, which was then increased to approximately 100 mL per hour with close monitoring | More clinical improvement occurred within 28 days in the CP group than in the control group among those with severe disease (91.3% vs 68.2%; P=.03) but not for those with life-threatening disease (20.7% vs 24.1%; P=.83). There was a higher negative conversion rate of viral PCR at 72 hours in the CP group than in the control group (87.2% vs 37.5%; P<.001). | 2 patients in the CP group experienced adverse events within hours after transfusion that improved with supportive care |
aCP: convalescent plasma.
bPCR: polymerase chain reaction.
cICU: intensive care unit.
dECMO: extracorporeal membranous oxygenation.
eELISA: enzyme-linked immunosorbent assay.
fCT: computed tomography.
gASCT: autologous stem cell transplantation.
hRT-PCR: real-time polymerase chain reaction.
iS-RBD: spike protein receptor-binding domain.
jXLA: X-linked agammagloblulinemia.
kqPCR: quantitative polymerase chain reaction.
lARDS: acute respiratory distress syndrome.
mFDA: Food and Drug Administration.
nTRALI: transfusion-related acute lung injury.
oSAE: serious adverse event.
pTACO: transfusion-associated circulatory overload.
qSOT: solid organ transplant.
rCRP: C-reactive protein.
sLDH: lactate dehydrogenase.
tSCSS: six-category scale score.
uRCT: randomized controlled trial.