key: cord-0693430-nbv5i1hv
authors: Camargo, Jose F.; Mendoza, Maria A.; Lin, Rick; Moroz, Ilona V.; Anderson, Anthony D.; Morris, Michelle I.; Natori, Yoichiro; Natori, Akina; Raja, Mohammed; Lekakis, Lazaros; Beitinjaneh, Amer; Jimenez, Antonio; Goodman, Mark; Wang, Trent; Komanduri, Krishna V.; Pereira, Denise
title: Clinical presentation and outcomes of COVID‐19 following hematopoietic cell transplantation and cellular therapy
date: 2021-05-02
journal: Transpl Infect Dis
DOI: 10.1111/tid.13625
sha: 1fb9cb73a4fbf7ca33c0102b1c495684bdd0ec0d
doc_id: 693430
cord_uid: nbv5i1hv

BACKGROUND: One year into the pandemic, published data on hematopoietic cell transplantation (HCT) recipients with coronavirus disease 2019 (COVID‐19) remain limited. METHODS: Single‐center retrospective cohort study of adult HCT recipients with polymerase chain reaction (PCR)‐confirmed severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. RESULTS: Twenty‐eight consecutive transplantation and cellular therapy patients (autologous, n = 12; allogeneic, n = 15; chimeric antigen receptor T‐cell therapy [CAR‐T], n = 1) with COVID‐19 were identified. The median age was 57 years. The median time from HCT to COVID‐19 diagnosis was 656 days (interquartile range [IQR], 33‐1274). Patients were followed for a median of 59 days (IQR, 40‐88). Among assessable patients (n = 19), 10 (53%) had documented virological clearance; median time to clearance was 34 days (range, 21‐56). Out of 28, 12 (43%), 6 (21%), and 10 (36%) patients had mild, moderate, and severe/critical disease, respectively. Overall mortality was 25%, nearly identical for autologous and allogeneic HCT, and exclusively seen in hospitalized patients, older than 50 years of age with severe COVID‐19. None of the patients with mild (n = 12) or moderate (n = 6) COVID‐19 died whereas 7/10 patients (70%) with severe/critical COVID‐19 died (P = .0001). Patients diagnosed with COVID‐19 within 12 months of HCT exhibited higher mortality (57% vs 14%; P = .04). All‐cause 30‐day mortality (n = 4) was 14%. A higher proportion of patients who died within 30 days of COVID‐19 diagnosis (3/4) were receiving ≥2 immunosuppressants, compared with patients who survived beyond 30 days after COVID‐19 diagnosis (2/24; 75% vs. 8%; P = .01). CONCLUSIONS: Mortality in COVID‐19 HCT patients is higher than that of the age‐comparable general population and largely dependent on age, disease severity, timing from HCT, and intensity of immunosuppression.

As of late March 2021, the World Health Organization (WHO) had reported more than 126 million people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and more than 2.7 million cumulative deaths due to coronavirus disease 2019 . 1 There are many established risk factors for severe COVID-19 disease and mortality, such as older age, diabetes, hypertension, obesity, or heart disease. 2 Additionally, immunosuppressed patients, such as those with malignancies 3 and solid organ transplant patients, 4 are at increased risk; likewise, hematopoietic cell transplantation (HCT) recipients might be at higher risk for severe illness from SARS-CoV-2 according to the Centers for Disease Control and Prevention (CDC). 5 This is likely a result of the effect of immunosuppressive therapy as well as the damped immune reconstitution that occurs following an HCT. 6 One year into the pandemic, published data on transplantation and cellular therapy (TCT) patients with COVID-19 are lim- 

We performed a single-center retrospective cohort study of adult TCT recipients with reverse transcription (RT) polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection, diagnosed from March 2020 to December 2020. The cohort included both hospitalized patients and those managed as outpatient. The study was approved by our institutional review board (IRB # 20080899) and conducted consistent with principles in the Declaration of Helsinki.

During the study period, multiple PCR platforms were used for SARS-CoV-2 detection: QIAstat-Dx COVID-19 assay, BD MAX RT-PCR, SARS-CoV-2 DiaSorin Simplexa, and Accula SARS-CoV-2. PCR was used for the qualitative detection of SARS-CoV-2 nucleic acid in nasopharyngeal (NP) swabs or bronchoalveolar lavage (BAL).

Routine swabbing until negativity was not done. 

Between March 2020 and December 2020, 28 

All but one of the 28 patients were diagnosed with COVID-19

through NP swab for SARS-CoV-2 RNA, including one patient tested at an outside hospital; one patient presented with diffuse alveolar Table 2 ). During the peak of illness, most common symptoms, similar to the initial presentation, were fever, cough, and SOB.

Laboratory tests were collected in 19 patients at the time of diagnosis. The median white blood cell count was 3.9 cells × 10 9 /L (IQR, 3.45-6.1). Median absolute lymphocyte count was 0.79 cells × 10 9 /L (IQR, 0.55-1.08), and lymphopenia defined as lymphocyte count <1000/µL was present in 60% of the patients.

The median neutrophil/lymphocyte ratio (NLR; normal range is 0.78-3.53) 8 

Among the 17 patients who had chest X-ray (CXR) done on admission, 14 (82%) patients had an abnormal CXR. Follow-up CXR was performed in 11 patients after a week, nine of them (82%) had abnormal findings. Computed tomography (CT) of the chest was done in nine patients; seven (78%) patients had findings compatible with organizing pneumonia and two had a normal CT.

Among the 11 patients receiving immunosuppressive therapy at time of COVID-19 diagnosis, five (45%) patients had their immunosuppression reduced or discontinued. Among 16 hospitalized patients, data regarding COVID-19-directed treatment were missing in one patient that was admitted to another hospital.

Among the remainder 15 patients, corticosteroids were given to 

Out of 28, 12 (43%), 6 (21%), and 10 (36%) patients had mild, moderate, and severe/critical disease (severe n = 3; critical n = 7), respectively. Among the 16 patients who were admitted, seven patients (44%) were admitted to intensive care unit (ICU; Table 2 ). Among hospitalized patients who survived (n = 9), five patients had documented full recovery after discharge, two continued to have oxygen dependency, and data were missing for two patients.

Regarding neurological sequelae, one patient had cognitive dysfunction and another patient developed aseptic meningitis with status migrainosus after SARS-CoV-2 infection. At the end of follow-up, one patient continued to have anosmia.

Overall mortality during follow-up period was 25% and exclusively seen in hospitalized patients, older than 50 years of age with severe COVID-19. None of the patients with mild (n = 12) or moderate (n = 6) COVID-19 died whereas 7/10 patients (70%) with severe/ critical COVID-19 died (P = .0001). Hospitalized patients (n = 16) had a higher mortality (n = 7; 44%) compared with patients who did not require admission (n = 12) all of whom survived (P = .01). Patients diagnosed with COVID-19 within 12 months of TCT exhibited higher mortality than those transplanted more than 12 months prior (4/7 

Here, we present a cohort of 28 TCT patients with COVID-19

infection with a near 2-month follow-up. Patients presented mostly with fever, cough, and SOB similar to other cohorts of general population, 2 solid organ transplant, 4,10 and HCT. 11, 12 Extrapulmonary manifestations and atypical presentations (eg, without fever or respiratory complaints) were also present, so it is important for transplant providers to have high index of clinical suspicion, particularly in areas of high COVID-19 activity.

Our patients were treated mainly with steroids (64%), remdesivir (50%), tocilizumab (29%), convalescent plasma (21%), and IVIG (7%). 

RECOVERY trial showed decreased mortality in patients with severe disease (ie, mechanical ventilation), 17 to antibiotic resistance, as evidenced by high incidence of MDR organisms seen in our cases; adverse side effects; and unnecessary impact in gut microbiome in COVID-19 patients, especially those infected early post-transplant, as there is a link between early antibiotic (particularly anaerobic coverage) use, disturbed microbiota, and increased risk of CMV reactivation, GVHD, and mortality in HCT recipients. [27] [28] [29] [30] [31] Limitations of our study include those inherent to a retrospective design. Furthermore, we did not have access to serial cycle threshold (Ct) data on SARS-CoV-2 PCR, precluding more detailed assessment of viral kinetics. We also do not have data on SARS-CoV-2 IgG and therefore were unable to comment on rates of seroconversion, which others have reported can occur in two thirds of HCT patients with COVID-19 despite profound lymphopenia. 12 Advantages of our study include the comprehensive report of data that includes not only clinical presentation and mortality but also important data on co-infections, shedding, and COVID-19-associated sequela, which has not been widely published in HCT population. To our knowledge, to the date, this is one of the largest single-center cohorts of HCT patients with COVID-19.

In conclusion, our study reveals that COVID-19 HCT patients had higher mortality than age-comparable general US population 32 but similar to other HCT cohorts, especially among hospitalized patients. 12, 19, 23, 33 Mortality varied by age, time from HCT, intensity of immunosuppression, and COVID-19 severity but was not influenced by transplant type. Lack of fever on presentation can occur; therefore, a high index of clinical suspicion is needed. Prolonged SARS-CoV-2

shedding is common, and antibiotics, although commonly prescribed, are only justified only in a minority of COVID-19 patients. Until public health efforts and massive vaccination against SARS-CoV-2 mitigate the impact of COVID-19 in transplant centers worldwide, further studies on this vulnerable TCT population, particularly aimed to understand immunological determinants of disease severity, are urgently needed.

World Health Organization. Weekly epidemiological update -19

Clinical characteristics of coronavirus disease 2019 in China

Epidemiological, clinical, and virological characteristics of 465 hospitalized cases of coronavirus disease 2019 (COVID-19) from Zhejiang province in China. Influenza Other Respir Viruses

COVID-19 in solid organ transplant recipients: a systematic review and meta-analysis of current literature

Coronavirus Disease 2019 -People of Any Age with Underlying Medical Conditions [press release

Immune reconstitution after allogeneic hematopoietic stem cell transplantation

European Society for Blood and Marrow Transplantation. Coronavirus disease COVID-19: EBMT recommendations

Version 13. Accessed

What is the normal value of the neutrophil-to-lymphocyte ratio?

Defining and managing COVID-19

ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis. 2020

COVID-19 in solid organ transplant: A multi-center cohort study

COVID-19 outcomes in patients with hematologic disease

Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation

Remdesivir for the Treatment of Covid-19 -Final Report

Remdesivir for 5 or 10 days in patients with severe Covid-19

Guidelines for COVID-19 management in hematopoietic cell transplantation and cellular therapy recipients

Tocilizumab in hospitalized patients with COVID-19: clinical outcomes, inflammatory marker kinetics, and safety

Dexamethasone in hospitalized patients with Covid-19 -preliminary report

COVID -19 post hematopoietic cell transplant, a report of 11 cases from a single center

Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study

COVID-19 in bone marrow transplant recipients: reflecting on a single centre experience

COVID-19 in hematopoietic cell transplant recipients

The outcome of hematopoietic stem cell transplantation patients with COVID-19 infection

COVID-19 infection in hematopoietic cell transplantation: age, time from transplant and steroids matter

Shedding of viable SARS-CoV-2 after immunosuppressive therapy for cancer

Empiric antibacterial therapy and community-onset bacterial co-infection in patients hospitalized with COVID-19: a multi-hospital cohort study

COVID-19 pneumonia and the appropriate use of antibiotics

Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation

Anaerobic antibiotics and the risk of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice

The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation

Early antibiotic use is associated with CMV risk and outcomes following allogeneic hematopoietic cell transplantation

COVID-19) -United States

The authors thank all the patients who participated in the study and Humberto Elejalde for assistance with data collection.

The authors declare no competing financial interests relevant to this manuscript.