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Abstract
A 39-year-old woman with systemic lupus erythematosus treated with anti-CD20 monoclonal
antibody rituximab was admitted to our hospital with COVID-19 pneumonia. Despite receiving
dexamethasone, she developed hypoxaemia and persistent lung opacities. As bronchoalveolar
lavage was suggestive of cryptogenic organising pneumonia, high-dose corticosteroid
was administered, and she received antimicrobial therapy for opportunistic infections
without improvement. Reverse transcription PCR was repeatedly positive for SARS-CoV-2,
and virus replication was confirmed in cell cultures. As no anti-SARS-CoV-2 antibodies
were detected more than 100 days after symptom onset, she was treated with convalescent
plasma with fast clinical improvement, returning home days later. Our case shows that
persistent SARS-CoV-2 infection in an immunocompromised patient may be overturned
with the appropriate treatment.
Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed.
To the Editor: A 45-year-old man with severe antiphospholipid syndrome complicated by diffuse alveolar hemorrhage, 1 who was receiving anticoagulation therapy, glucocorticoids, cyclophosphamide, and intermittent rituximab and eculizumab, was admitted to the hospital with fever (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). On day 0, Covid-19 was diagnosed by SARS-CoV-2 reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of a nasopharyngeal swab specimen, and the patient received a 5-day course of remdesivir (Fig. S2). Glucocorticoid doses were increased because of suspected diffuse alveolar hemorrhage. He was discharged on day 5 without a need for supplemental oxygen. From day 6 through day 68, the patient quarantined alone at home, but during the quarantine period, he was hospitalized three times for abdominal pain and once for fatigue and dyspnea. The admissions were complicated by hypoxemia that caused concern for recurrent diffuse alveolar hemorrhage and was treated with increased doses of glucocorticoids. SARS-CoV-2 RT-PCR cycle threshold (Ct) values increased to 37.8 on day 39, which suggested resolving infection (Table S1). 2,3 On day 72 (4 days into another hospital admission for hypoxemia), RT-PCR assay of a nasopharyngeal swab was positive, with a Ct value of 27.6, causing concern for a recurrence of Covid-19. The patient again received remdesivir (a 10-day course), and subsequent RT-PCR assays were negative. On day 105, the patient was admitted for cellulitis. On day 111, hypoxemia developed, ultimately requiring treatment with high-flow oxygen. Given the concern for recurrent diffuse alveolar hemorrhage, the patient’s immunosuppression was escalated (Figs. S1 through S3). On day 128, the RT-PCR Ct value was 32.7, which caused concern for a second Covid-19 recurrence, and the patient was given another 5-day course of remdesivir. A subsequent RT-PCR assay was negative. Given continued respiratory decline and concern for ongoing diffuse alveolar hemorrhage, the patient was treated with intravenous immunoglobulin, intravenous cyclophosphamide, and daily ruxolitinib, in addition to glucocorticoids. On day 143, the RT-PCR Ct value was 15.6, which caused concern for a third recurrence of Covid-19. The patient received a SARS-CoV-2 antibody cocktail against the SARS-CoV-2 spike protein (Regeneron). 4 On day 150, he underwent endotracheal intubation because of hypoxemia. A bronchoalveolar-lavage specimen on day 151 revealed an RT-PCR Ct value of 15.8 and grew Aspergillus fumigatus. The patient received remdesivir and antifungal agents. On day 154, he died from shock and respiratory failure. We performed quantitative SARS-CoV-2 viral load assays in respiratory samples (nasopharyngeal and sputum) and in plasma, and the results were concordant with RT-PCR Ct values, peaking at 8.9 log10 copies per milliliter (Fig. S2 and Table S1). Tissue studies showed the highest SARS-CoV-2 RNA levels in the lungs and spleen (Figs. S4 and S5). Phylogenetic analysis was consistent with persistent infection and accelerated viral evolution (Figures 1A and S6). Amino acid changes were predominantly in the spike gene and the receptor-binding domain, which make up 13% and 2% of the viral genome, respectively, but harbored 57% and 38% of the observed changes (Figure 1B). Viral infectivity studies confirmed infectious virus in nasopharyngeal samples from days 75 and 143 (Fig. S7). Immunophenotyping and SARS-CoV-2–specific B-cell and T-cell responses are shown in Table S2 and Figures S8 through S11. Although most immunocompromised persons effectively clear SARS-CoV-2 infection, this case highlights the potential for persistent infection 5 and accelerated viral evolution associated with an immunocompromised state.
Abstract Background Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness. Methods We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible. Results A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. Conclusions Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.)
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