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Id Subject Object Predicate Lexical cue
T1 0-109 Sentence denotes Use of Convalescent Plasma Therapy in Two COVID-19 Patients with Acute Respiratory Distress Syndrome in Korea
T2 111-119 Sentence denotes Abstract
T3 120-374 Sentence denotes Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 not yet has established its treatment, but convalescent plasma has been expected to increase survival rates as in the case with other emerging viral infections.
T4 375-451 Sentence denotes We describe two cases of COVID-19 treated with convalescent plasma infusion.
T5 452-641 Sentence denotes Both patients presented severe pneumonia with acute respiratory distress syndrome and showed a favorable outcome after the use of convalescent plasma in addition to systemic corticosteroid.
T6 642-749 Sentence denotes To our knowledge, this is the first report of the use of convalescent plasma therapy for COVID-19 in Korea.
T7 751-769 Sentence denotes Graphical Abstract
T8 771-783 Sentence denotes INTRODUCTION
T9 784-952 Sentence denotes An outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, which began in Wuhan, China, has emerged as a primary concern all over the world.
T10 953-1125 Sentence denotes The World Health Organization announced the risk assessment of coronavirus disease 2019 (COVID-19) as very high at the global level, and fatal cases are rapidly increasing.
T11 1126-1219 Sentence denotes By March 24, 2020, more than 9,000 people were infected, and 126 people died, in South Korea.
T12 1220-1330 Sentence denotes Without specific treatments for the virus, treatment options are being studied in addition to supportive care.
T13 1331-1706 Sentence denotes Evidence shows that the use of convalescent plasma to treat emerging viral infections, including SARS, Middle East respiratory syndrome (MERS), Ebola virus disease or avian flu, can improve survival rates in patients whose condition worsens even with conventional treatment.12 However, the safety and efficacy of convalescent plasma treatment in COVID-19 have not been known.
T14 1707-1894 Sentence denotes Here, we report two cases of severe COVID-19 patients presenting acute respiratory distress syndrome (ARDS), who showed a favorable clinical course after the convalescent plasma infusion.
T15 1895-2002 Sentence denotes This is the first report of the use of convalescent plasma to treat cases of SARS-CoV-2 infection in Korea.
T16 2004-2020 Sentence denotes CASE DESCRIPTION
T17 2022-2028 Sentence denotes Case 1
T18 2029-2156 Sentence denotes A previously healthy 71-year-old man visited the Community Health Center on February 22, presenting 12 days of fever and cough.
T19 2157-2297 Sentence denotes He underwent an examination of SARS-CoV-2 via real-time reverse transcription polymerase chain reaction (rRT-PCR) and diagnosed as COVID-19.
T20 2298-2401 Sentence denotes He admitted to the local public medical center and 400 mg of hydroxychloroquine once daily was started.
T21 2402-2542 Sentence denotes A chest radiograph obtained on day 2 showed mild opacities in the right lower lung, lopinavir/ritonavir 400 mg/100 mg twice daily was added.
T22 2543-2635 Sentence denotes However, on day 3, oxygen demand increased, so he transferred to the tertiary-care hospital.
T23 2636-2797 Sentence denotes At the time of arrival, the patient had no subjective dyspnea under 4 L/min oxygen flow via nasal cannula, but the respiratory rate was over 30 times per minute.
T24 2798-2871 Sentence denotes Chest radiographs demonstrated rapidly aggravated bilateral infiltration.
T25 2872-2978 Sentence denotes Routine blood tests found white blood cell (WBC) count at 3.53 × 103/µL, with lymphopenia of 0.4 × 103/µL.
T26 2979-3073 Sentence denotes C-reactive protein (CRP) and lactic dehydrogenase (LDH) elevated up to 59.7 mg/L and 814 IU/L.
T27 3074-3206 Sentence denotes Routine chemistry, electrolyte, and blood coagulation tests revealed no abnormalities except mildly elevated aspartate transaminase.
T28 3207-3270 Sentence denotes The level of interleukin 6 (IL-6) was increased as 101.3 pg/mL.
T29 3271-3380 Sentence denotes Serial bacterial culture and polymerase chain reaction (PCR) for other respiratory viruses were all negative.
T30 3381-3472 Sentence denotes Intubation and mechanical ventilator care were started according to the management of ARDS.
T31 3473-3644 Sentence denotes Despite the continuous use of lopinavir/ritonavir, hydroxychloroquine and empirical antibiotics, he remained febrile with aggravated oxygenation profiles and chest images.
T32 3645-3726 Sentence denotes Laboratory test showed further elevation of CRP (172.6 mg/L), IL-6 (208.2 pg/mL).
T33 3727-3821 Sentence denotes On day 9, the arterial blood gas analysis showed PaO2/FiO2 of 86, consistent with severe ARDS.
T34 3822-3885 Sentence denotes Intravenous methylprednisolone (1 mg/kg/day daily) was started.
T35 3886-4003 Sentence denotes On day 10, convalescent plasma was obtained from a male donor in his 20s who had recovered from COVID-19 for 21 days.
T36 4004-4165 Sentence denotes He was diagnosed as COVID-19 presenting fever, cough and pneumonia, however, showed complete recovery and didn’t have any symptom at the time of plasma donation.
T37 4166-4293 Sentence denotes He has met the blood donor eligibility criteria for plasma donation, including age, weight, reasonable-sized antecubital veins.
T38 4294-4433 Sentence denotes Also, allogeneic donor screening tests, defined by enforcement rules of the Blood Management Act in Korea, were acceptable for transfusion.
T39 4434-4622 Sentence denotes Donor apheresis was performed with Spectra Optia apheresis system (CMNC software; Spectra Optia IDL Tubing set; Terumo BCT, Lakewood, CO, USA), 500 mL of convalescent plasma was collected.
T40 4623-4874 Sentence denotes Anti-SARS-CoV-2 IgG antibody in plasma was measured by enzyme-linked immunosorbent assay (ELISA) (Novel Coronavirus COVID-19 IgG ELISA kit; Epitope Diagnostics, San Diego, CA, USA) and optical density (OD) ratio for IgG was 0.586 (cut-off value 0.22).
T41 4875-4966 Sentence denotes The plasma was divided into two doses and administered to the patient at 12 hours interval.
T42 4967-5003 Sentence denotes Each dose was given over for 1 hour.
T43 5004-5081 Sentence denotes No adverse reaction occurred after the administration of convalescent plasma.
T44 5082-5143 Sentence denotes The fever subsided, and oxygen demand decreased since day 11.
T45 5144-5322 Sentence denotes The patient's condition much improved with decreased CRP and IL-6 to normal range (5.7 mg/L and < 1.5 pg/mL, respectively), and on day 18, PaO2/FiO2 increased up to 300 (Fig. 1).
T46 5323-5399 Sentence denotes A chest X-ray revealed further resolution of both lung infiltrates (Fig. 2).
T47 5400-5625 Sentence denotes SARS-CoV-2 was quantified by detection of the RNA-dependent RNA polymerase region of the ORF1b gene on rRT-PCR, the value of cycle threshold (Ct) changed from 24.98 on day 10 to 33.96 on day 20 after plasma infusion (Fig. 1).
T48 5626-5663 Sentence denotes SARS-CoV-2 was negative after day 26.
T49 5664-5770 Sentence denotes The patient underwent a tracheostomy and currently, is successfully weaned from the mechanical ventilator.
T50 5771-6117 Sentence denotes Fig. 1 Case 1, responses to treatment. (A) Timelines of changes in PaO2/FiO2 and CRP during hospitalization. (B) Timelines of detection of the RNA-dependent RNA polymerase region of the ORF1b gene of severe acute respiratory syndrome coronavirus-2 in sputum by real-time reverse transcription polymerase chain reaction; cycle threshold is shown.
T51 6118-6143 Sentence denotes CRP = C-reactive protein.
T52 6144-6227 Sentence denotes Fig. 2 Chest X-rays of Case 1 taken before and after convalescent plasma infusion.
T53 6228-6296 Sentence denotes Taken on day 7, just before the convalescent plasma infusion (left).
T54 6297-6373 Sentence denotes Taken on day 13 shows marked improvement of bilateral infiltrations (right).
T55 6374-6430 Sentence denotes The images are published under agreement of the patient.
T56 6432-6438 Sentence denotes Case 2
T57 6439-6586 Sentence denotes A 67-year-old woman with a medical history of hypertension developed fever and myalgia and diagnosed as COVID-19 via SARS-CoV-2 rRT-PCR on March 6.
T58 6587-6778 Sentence denotes The next day, she was admitted to a local public medical center and received hydroxychloroquine 400 mg once daily and lopinavir/ritonavir 400 mg/100 mg twice daily with empirical antibiotics.
T59 6779-6937 Sentence denotes However, on day 3, she was transferred to the tertiary-care hospital due to increased oxygen demand and worsening infiltrative shadows in the left lower lung.
T60 6938-7074 Sentence denotes At that time, her oxygen saturation checked 93% on 4 L/min oxygen flow via nasal cannula with a respiratory rate of 24 times per minute.
T61 7075-7332 Sentence denotes Routine blood tests showed mild leukocytosis (12.67 × 103/µL) with lymphopenia (0.7 × 103/µL), elevated CRP, IL-6 and LDH. (131.1 mg/L, 474.7 pg/mL, 344 IU/L, respectively) Routine chemistry, electrolyte, and blood coagulation tests showed no abnormalities.
T62 7333-7412 Sentence denotes Bacterial cultures and the PCR for other respiratory viruses were all negative.
T63 7413-7575 Sentence denotes She received high flow oxygen therapy but bilateral infiltration and oxygenation were deteriorated, so intubation and mechanical ventilator care started on day 4.
T64 7576-7644 Sentence denotes Intravenous methylprednisolone (0.5 mg/kg/day daily) was also added.
T65 7645-7778 Sentence denotes She had sustained high fever with rapidly increasing CRP (314 mg/L), WBC (21.79 × 103/µL), and persistent lymphopenia (0.5 × 103/µL).
T66 7779-7829 Sentence denotes PaO2/FiO2 fell to 76, consistent with severe ARDS.
T67 7830-7986 Sentence denotes After applying for the prone position according to the management of ARDS with the use of steroids, chest images and the oxygen demand began to be improved.
T68 7987-8103 Sentence denotes On day 6, convalescent plasma was obtained from a male donor in his 20s who had recovered from COVID-19 for 18 days.
T69 8104-8279 Sentence denotes He was diagnosed as COVID-19 presenting fever, cough and pneumonia however, showed complete recovery and serial PCRs for SARS-CoV-2 were all negative after hospital discharge.
T70 8280-8366 Sentence denotes Donor screening and plasma collection were performed as mentioned above in the Case 1.
T71 8367-8467 Sentence denotes OD ratio for IgG was 0.532 and the plasma was administered to the patient in the same way as Case 1.
T72 8468-8528 Sentence denotes There was no adverse reaction during the plasma transfusion.
T73 8529-8620 Sentence denotes Leukocytosis and lymphopenia were immediately recovered after convalescent plasma infusion.
T74 8621-8730 Sentence denotes On day 9, the density of bilateral infiltration on chest X-ray much improved with increased PaO2/FiO2 to 230.
T75 8731-8798 Sentence denotes The level of CRP and IL-6 also recovered to the normal range (Figs.
T76 8799-8808 Sentence denotes 3 and 4).
T77 8809-8940 Sentence denotes SARS-CoV-2 was quantified by rRT-PCR; the value of Ct changed from 20.51 on day 5 to 36.33 on day 9 after plasma infusion (Fig. 3).
T78 8941-9022 Sentence denotes The patient is successfully extubated and discharged from the hospital on day 24.
T79 9023-9060 Sentence denotes SARS-CoV-2 was negative after day 20.
T80 9061-9407 Sentence denotes Fig. 3 Case 2, responses to treatment. (A) Timelines of changes in PaO2/FiO2 and CRP during hospitalization. (B) Timelines of detection of the RNA-dependent RNA polymerase region of the ORF1b gene of severe acute respiratory syndrome coronavirus-2 in sputum by real-time reverse transcription polymerase chain reaction; cycle threshold is shown.
T81 9408-9433 Sentence denotes CRP = C-reactive protein.
T82 9434-9517 Sentence denotes Fig. 4 Chest X-rays of Case 2 taken before and after convalescent plasma infusion.
T83 9518-9581 Sentence denotes Taken on day 2, before the convalescent plasma infusion (left).
T84 9582-9657 Sentence denotes Taken on day 6 shows marked improvement of bilateral infiltrations (right).
T85 9658-9714 Sentence denotes The images are published under agreement of the patient.
T86 9716-9732 Sentence denotes Ethics statement
T87 9733-9827 Sentence denotes This study was approved by the Institutional Review Board (IRB) of Severance Hospital (IRB No.
T88 9828-9889 Sentence denotes 4-2020-0076) and with participants' written informed consent.
T89 9890-9947 Sentence denotes The images are published under agreement of the patients.
T90 9949-9959 Sentence denotes DISCUSSION
T91 9960-10746 Sentence denotes The study of the therapeutic benefits of plasma transfusion of a cured person from infectious diseases began in the 20th century.2 As new antibiotics, antiviral agents, and vaccines are developed, administration of convalescent plasma is not a common treatment, but it can be still an important treatment in the absence of specific treatment of new infectious diseases.3 Over the decades, convalescent plasma has proved its effectiveness as a potential treatment in patients with MERS-CoV,4 H1N15 and H5N1 avian flu,5 and SARS-CoV.6 A systemic review and meta-analysis to evaluate the clinical effects of convalescent plasma shows a statistically significant reduction of mortality.1 In this context, convalescent plasma can be a promising treatment option for severe COVID-19 patients.
T92 10747-10982 Sentence denotes As can be seen in the two cases, both received lopinavir/ritonavir and hydroxychloroquine but showed persistent fever, rapidly aggravated hypoxemia and progressive bilateral infiltrations in accordance with the criteria of severe ARDS.
T93 10983-11129 Sentence denotes After convalescent plasma infusion, the patients showed improved oxygenation and chest X-rays with decreased inflammatory markers and viral loads.
T94 11130-11232 Sentence denotes Intravenous methylprednisolone was started just before the convalescent plasma infusion in both cases.
T95 11233-11306 Sentence denotes We did not use corticosteroids from the beginning as a routine treatment.
T96 11307-11608 Sentence denotes Current guidelines recommend that systemic corticosteroids should not be given routinely for the treatment of COVID-19 due to the lack of evidence of its clinical efficacy on mortality reduction.78 However, we decided to start corticosteroids when the patients' condition rapidly deteriorated to ARDS.
T97 11609-11728 Sentence denotes Methylprednisolone was administered one day and two days before the plasma infusion in case 1 and case 2, respectively.
T98 11729-11890 Sentence denotes Serial laboratory and oxygenation parameters showed rapid improvement right after the corticosteroid administration even before the convalescent plasma infusion.
T99 11891-12591 Sentence denotes ARDS is partly caused by cytokine storm and host immune responses.7 Autopsy of patients dying from COVID-19 shows diffuse alveolar damage with exudate and inflammation very similar to those seen in SARS and MERS-CoV infections.9 Theoretically, systemic corticosteroids may have a role to dampen excessive lung damage due to inflammatory responses.10 The recent article about risk factors associated with ARDS and death among COVID-19 patients showed that treatment with methylprednisolone might be beneficial to reduce the risk of death for patients developing ARDS.11 However, corticosteroids are also thought to inhibit proper immune responses and viral clearance and delay antibody production.1213
T100 12592-12705 Sentence denotes Convalescent plasma infusion might play a role in the coexistence of benefits and concerns of corticosteroid use.
T101 12706-13003 Sentence denotes Antibodies contained in the convalescent plasma will suppress viruses.14 In an animal study, passively transferred antibodies can provide total protection as well as the maintenance of high levels of antibody titer until the host's immune responses could be increased to clear the viral infection.
T102 13004-13182 Sentence denotes Besides, in vivo studies showed that the effects of neutralizing antibodies were not only limited to viral clearance, but also included acceleration of infected cell clearance.15
T103 13183-13355 Sentence denotes In our cases, the viral load estimated by Ct values showed an increasing trend just before plasma infusion but began to decrease right after the use of convalescent plasma.
T104 13356-13591 Sentence denotes Although improvement of inflammatory marker and oxygenation could be contributed to the combined use of corticosteroid, decreased viral load of SARS-CoV-2 might mean the effectiveness of convalescent plasma in the treatment of COVID-2.
T105 13592-13716 Sentence denotes Convalescent plasma was administered after 22 days from the onset of symptoms in Case 1, and 7 days in Case 2, respectively.
T106 13717-13930 Sentence denotes Because these are not in the early phase of the disease, it is difficult to determine clearly that the decrease in the viral load shown in both cases is due to convalescent plasma or natural pathology of COVID-19.
T107 13931-14388 Sentence denotes Other studies about viral kinetics of COVID-19 show naturally reducing viral titers after 7–10 days from onset in most patients.1617 However, Liu and colleagues reported that severe patients requiring intensive care unit admission due to COVID-19 had high viral load for a longer period than in mild patients.16 Both our cases presented severe ARDS and the viral loads were in increasing trend at the time of plasma infusion regardless of the date of onset.
T108 14389-14516 Sentence denotes In Case 2, the patient showed lymphopenia from day 1, and it persisted even after clinical improvement with corticosteroid use.
T109 14517-14699 Sentence denotes When the convalescent plasma was administered on day 6, lymphocyte count immediately rose to normal level (from 0.52 × 103/µL to 1.21 × 103/µL) and then remained in the normal range.
T110 14700-15197 Sentence denotes Patients with severe COVID-19 pneumonia and ARDS also presented with lymphopenia in other studies.11 Some authors hypothesized that continuous and gradual increases in lymphocyte count might be required for immunity against SARS-CoV-2 infection.11 In SARS patients, lymphopenia existed at the onset of illness and persisted until the recovery period.1819 These findings were consistent with the recovery of lymphocyte count with clinical improvement of Case 2 after the use of convalescent plasma.
T111 15198-15276 Sentence denotes We could not assess neutralizing antibody titers from the convalescent plasma.
T112 15277-15550 Sentence denotes Plasma with high neutralizing antibody titers is likely to be available from the patients in the convalescent phase recovered from severe infection.20 To use plasma for treatment, a neutralization test is suggested as the optimal assay for assessing proper donor or plasma.
T113 15551-15870 Sentence denotes However, some studies showed that ELISA IgG correlates well with neutralization titers in MERS cases so that it might be a suitable screening test for plasma donation.2021 In our cases, donors presented bilateral pneumonia in the course of COVID-19 and both showed positive results in the ELISA IgG test for SARS-CoV-2.
T114 15871-15934 Sentence denotes There are still limitations for the use of convalescent plasma.
T115 15935-16071 Sentence denotes Scientific evidence is insufficient due to the lack of large-scale clinical trials that may be representative of the target populations.
T116 16072-16155 Sentence denotes Second, the number of antibodies administered to each patient was not standardized.
T117 16156-16364 Sentence denotes Finally, convalescent plasma usually proceeds with other treatments, such as antiviral agents and steroids, which can affect the relationship between convalescent plasma and antibody, confounding the results.
T118 16365-16581 Sentence denotes Despite the limitations, our cases suggest that convalescent plasma from patients who have recovered from COVID-19 infection might be an additional option to treat patients without causing any severe adverse effects.
T119 16582-16812 Sentence denotes Also, when used with systemic corticosteroids, we might expect the possibility of reducing excessive inflammatory response by corticosteroids as well as promoting the reduction of viral loads by convalescent plasma simultaneously.
T120 16813-16949 Sentence denotes Further well-designed studies are needed to demonstrate the efficacy and safety of convalescent plasma transfusion in COVID-19 patients.
T121 16951-16959 Sentence denotes Funding:
T122 16960-17212 Sentence denotes This study was supported by research grants for deriving the major clinical and epidemiological indicators of people with HIV (Korea HIV/AIDS Cohort Study, 2019-ER5101-00), and a grant from the Ministry of Health & Welfare, Republic of Korea (grant No.
T123 17213-17224 Sentence denotes HI14C1324).
T124 17225-17236 Sentence denotes Disclosure:
T125 17237-17301 Sentence denotes The authors have no potential conflicts of interest to disclose.
T126 17302-17323 Sentence denotes Author Contributions:
T127 17324-17340 Sentence denotes Formal analysis:
T128 17341-17349 Sentence denotes Hyun JH.
T129 17350-17364 Sentence denotes Investigation:
T130 17365-17427 Sentence denotes Lee SH, Cho Y, Baek YJ, Kim JH, Kim YS, Lee H, Yong D, Kim HO.
T131 17428-17440 Sentence denotes Methodology:
T132 17441-17450 Sentence denotes Jeong SJ.
T133 17451-17461 Sentence denotes Resources:
T134 17462-17502 Sentence denotes Lee SH, Yeom JS, Roh J, Ahn MY, Chin BS.
T135 17503-17515 Sentence denotes Supervision:
T136 17516-17538 Sentence denotes Ku NS, Kim S, Choi JY.
T137 17539-17564 Sentence denotes Writing - original draft:
T138 17565-17580 Sentence denotes Ahn JY, Sohn Y.
T139 17581-17608 Sentence denotes Writing - review & editing:
T140 17609-17615 Sentence denotes Kim S.