key: cord-0813150-p1htlm97 authors: Malek, Alexandre E.; Adachi, Javier A.; Mulanovich, Victor E.; Sassine, Joseph; Raad, Issam I.; McConn, Kelly; Seiler, Garret T.; Dhal, Udit; Khawaja, Fareed; Chemaly, Roy F. title: Immune reconstitution and severity of COVID‐19 among hematopoietic cell transplant recipients date: 2021-04-03 journal: Transpl Infect Dis DOI: 10.1111/tid.13606 sha: ffbef9dc1d0f6ad6b7d6ec27ba96b95ab4679378 doc_id: 813150 cord_uid: p1htlm97 Severe acute respiratory syndrome coronavirus 2 can lead to life‐threatening coronavirus disease 2019 (COVID‐19) infections in patients with hematologic malignancies, particularly among hematopoietic cell transplant (HCT) recipients. We describe two patients with COVID‐19 during the pre‐engraftment period after HCT and review previous reports of COVID‐19 in HCT recipients. Because of significant mortality from COVID‐19, primarily after allogeneic HCT, early, preemptive, and optimal directed therapy may improve outcomes and reduce the mortality rate but still needs to be established in clinical trials. A 61-year-old man with multiple myeloma had an autologous HCT after a conditioning regimen consisting of busulfan and melphalan. On admission, the patient was asymptomatic, and a nasopharyngeal (NP) swab yielded negative real-time reversetranscription polymerase chain reaction (rRT-PCR) results for SARS-CoV-2. On day +3 post-HCT and as part of an investigation of an employees' cluster of cases, the patient, still asymptomatic, had a NP swab that was positive for COVID- 19 . Computed tomography (CT) of the chest on day +4 showed no evidence of pneumonia ( Figure 1A ). On day +7, the patient had fevers up to 102°F (38.8°C) and diarrhea that prompted initiation of empiric antibiotics for febrile neutropenia. Further diagnostic workup, including blood cultures, was negative for infectious causes. Repeat chest CT on day +8 revealed new ground-glass opacities (GGOs) suggestive of COVID-19 pneumonia ( Figure 1B ). Although the patient had persistent fever and positive lung abnormalities, he was not short of breath or hypoxic and did not qualify for remdesivir therapy. He received one dose of tocilizumab (400 mg) on day +10 and a 4-day course of dexamethasone (8 mg daily) starting on day +11 during engraftment for concerns of exuberant inflammatory reaction and engraftment syndrome that could lead to respiratory failure. The patient had a satisfactory clinical recovery with no further complications and was discharged home in stable condition on day +14 after HCT. The salient laboratory studies and clinical course are summarized in Figure 2 (top panel). A 69-year-old man with chronic lymphocytic leukemia underwent an allogeneic HCT with a reduced-intensity conditioning regimen (fludarabine and melphalan) and received post-transplant cyclophosphamide for graft-versus-host disease (GvHD) prophylaxis. On admission, the patient was asymptomatic and a NP swab yielded negative rRT-PCR results for SARS-CoV-2. On day +11 after HCT, he developed fever associated with non-productive cough that prompted further diagnostic workup, which included blood cultures that showed Enterococcus faecalis bacteremia, which was likely secondary to mucosal-related bloodstream infection and was treated with vancomycin. A plain X-ray of the chest showed no evidence of pneumonia ( Figure 1C ). However, in light of persistent fever after 48h of appropriate antibacterial therapy, new onset of cough, and given the concern for a nosocomial acquisition of SARS-CoV 2 infection in the setting of a cluster of employees diagnosed with COVID-19 in the same location, a repeated NP swab on day +13, yielded a positive rRT-PCR results for SARS-CoV-2. A CT scan of the chest showed new bilateral GGOs ( Figure 1D ). The patient required oxygen supplementation and received convalescent plasma, two doses of tocilizumab (400 mg) on days +16 and +17, methylprednisolone (1 mg/kg) started on day +16, anakinra (100 mg daily) started on day +18, and a 5-day course of remdesivir started on day +19 (day +6 after COVID-19 diagnosis, when it became available at our institution). At day +15 when the patient started engrafting, he required a rapid increase in oxygen supplementation and showed increased bilateral pulmonary opacities ( Figure 1E ) that led to en- Severe COVID-19 infection has been reported among patients with underlying medical comorbidities such as cardiovascular diseases, hypertension, diabetes mellitus, or cancer and in the elderly people. 14, 15 The spectrum of infection among those with hematologic malignancies and particularly patients who have undergone HCT F I G U R E 1 Chest imaging for the two cases. (A, B) Case 1. Panel A: CT scan obtained within 24h of COVID-19 diagnosis showed no evidence of pneumonia. Panel B: CT scan at day+8 after HCT revealed new nodular ground-glass opacities in the mid and lower lungs. (C-F) Case 2. Panel C: Plain X-ray at day+11 post HCT showed a clear lung field. Panel D: CT scan at day + 13 after HCT showed bilateral ground-glass opacities with a peripheral predominance with focal scattered regions of consolidation. Panel E: X-ray at the time of engraftment showed bilateral patchy multifocal interstitial and airspace opacities. Panel F: X-ray at day + 19 after HCT with endotracheal tube in place showed progressive multilobar lung opacity is not well described, and such patients are likely at greater risk of morbidity and mortality from COVID-19, underscoring the need for effective preventive and therapeutic strategies. To date, there is a paucity of data on the impact of COVID-19 on HCT recipients, and the reported cases have mainly described patients who developed COVID-19 after engraftment. [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Overall, 276 HCT recipients with COVID-19 have been reported in the medical literature ( (1) Yes (1) CCP (1) Alive (1), Dead (1) NR (7) Yes (7) NR (7) NR (2) Yes ( Yes (1) CG (1) Alive (5) be affected by many factors, such as the source of stem cells, the degree of human leukocyte antigen match, and the use of immunosuppressant drugs, including corticosteroids, that could affect the immune reconstitution. Recovery of the immune system occurs gradually over the post-transplantation period. 16 The first immune cells to engraft are monocytes, followed by granulocytes, platelets, and natural killer cells, which together constitute the innate immunity. In contrast, adaptive immunity, consisting of B and T lymphocytes, may take 1-2 y to full recover. 16 All authors declare no conflict of interest. Data sharing not applicable -no new data generated. Alexandre E. Malek https://orcid.org/0000-0002-7867-4502 World Health Organization. Novel coronavirus-China COVID-19 infection: the perspectives on immune responses Attenuated Novel SARS Coronavirus 2 Infection in an Allogeneic Hematopoietic Stem Cell Transplant Patient on Ruxolitinib COVID-19 in bone marrow transplant recipients: reflecting on a single centre experience Severe COVID-19 in a patient with chronic graft-versus-host disease after hematopoietic stem cell transplant successfully treated with ruxolitinib COVID-19 in allogeneic stem cell transplant: high false-negative probability and role of CRISPR and convalescent plasma COVID-19 outcomes in patients with hematologic disease COVID-19 infection in hematopoietic cell transplantation: age, time from transplant and steroids matter Response to "COVID-19 in persons with haematological cancers Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation COVID-19 in transplant recipients: The Spanish experience COVID-19 in hematopoietic cell transplant recipients. Bone Marrow Transplant The outcome of hematopoietic stem cell transplantation patients with COVID-19 infection Clinical characteristics of coronavirus disease 2019 in China Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Reconstitution of the immune system after hematopoietic stem cell transplantation in humans Engraftment syndrome: Double-edged sword of hematopoietic cell transplants Engraftment syndrome after allogeneic hematopoietic cell transplantation predicts poor outcomes The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study Real estimates of mortality following COVID-19 infection Immune reconstitution and severity of COVID-19 among hematopoietic cell transplant recipients