Guidelines for COVID-19 Management in Hematopoietic Cell Transplantation and Cellular Therapy Recipients



## Scope
This document is intended as a guide for diagnosis and management of Coronavirus Disease 2019 , caused by the SARS-CoV-2 virus, in adult and pediatric hematopoietic cell transplantation (HCT) and cellular therapy recipients. This document was prepared using available data and with expert opinion provided by members of the American Society for Transplantation and Cellular Therapy (ASTCT) Infectious Diseases Special Interest Group. The information provided herein may change as new information becomes available, including more data on epidemiology, clinical outcomes, and the efficacy of drug therapies, including clinical trial outcomes of novel therapeutics, especially data pertaining to transplant recipients or other immunocompromised patients. Updates may be available through the ASTCT website (www.astct.org). Additional guidance can be found in recent publications from the European Society for Blood and Marrow Transplantationand the CAR T Cell Consortium [bib_ref] Chimeric antigen receptor T cell therapy during the COVID-19 pandemic, Bachanova [/bib_ref].

## Diagnostic considerations in hct and cellular therapy recipients
In the setting of known high community prevalence of COVID-19 or exposure to a known case of COVID-19, the following evaluations should be performed.
A. In any patient with upper or lower respiratory symptoms, perform PCR testing for SARS-CoV-2 in addition to multiplex PCR testing for other respiratory viruses from any respiratory sample obtained. Follow Centers for Disease Control and Prevention (CDC) recommendations for swab collection (https://www.cdc.gov/coronavirus/2019-ncov/ lab/guidelines-clinical-specimens.html). 1. Nasopharyngeal (NP) sampling should be performed preferentially over oropharyngeal sampling given preliminary data suggesting higher viral loads in nasal samples in early stages of illness. In certain circumstances, other sample types, including anterior nasal, midturbinate nasal, oropharyngeal, or saliva, can be considered, and collection may be better tolerated. 2. Nasal washes are discouraged; however, in centers that use this method or if swabs are unavailable, washes can be done with appropriate personal protective equipment (PPE) in accordance with guidelines. B. In patients without SARS-CoV-2 detected in the upper respiratory tract but with clinical symptoms of lower respiratory tract infection (LRTI; shortness of breath, hypoxia, tachypnea), chest imaging to evaluate for LRTI should be considered.. Preliminary reports suggest the possibility of discrepancy between upper and lower respiratory tract specimen positivity, as has been reported with other respiratory viruses [bib_ref] Predictive value of respiratory viral detection in the upper respiratory tract for..., Boonyaratanakornkit [/bib_ref] , and a longer time from symptom onset to clinical presentation. 2. A single negative test in the setting of high clinical suspicion should be interpreted with caution, and repeat testing of a lower respiratory sample, such as sputum, can be considered. C. Routine bronchoalveolar lavage (BAL) is not recommended in patients testing positive for SARS-CoV-2 given the risk of transmission among health care workers (HCWs), unless a coinfection is suspected. If chest imaging is abnormal and in patients for whom it is clinically indicated (eg, those receiving invasive mechanical ventilation), a lower respiratory tract endotracheal tube aspirate or BAL sample should be collected and tested for SARS-CoV-2. Copathogens should be evaluated and treated. D. See testing recommendations below for HCT and cellular immunotherapy candidates and donors below. E. Prolonged viral shedding: Patients with hematologic malignancies and HCT recipients may exhibit different viral dynamics and can remain positive for SARS-CoV-2 by PCR longer than the general population [bib_ref] Temporal dynamics in viral shedding and transmissibility of COVID-19, He [/bib_ref]. Prolonged RT-PCR positivity does not necessarily translate into ongoing active infection or presence of viable virus. Although prolonged PCR positivity has been reported in healthy individuals (30% positive at 4 weeks), viable virus was recovered for only up to 9 days after symptom onset in mild to severe illness [bib_ref] Virological assessment of hospitalized patients with COVID-2019, W Olfel [/bib_ref] [bib_ref] Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility, Arons [/bib_ref]. Among 108 individuals who tested positive by PCR after being negative, none had culturable virus present. Data on how long immunosuppressed patients shed viable virus has not been evaluated but is expected to be prolonged compared with immunocompetent individuals. Information on SARS-CoV-2 viability in COVID-19Ainfected transplant recipients will be critical to develop recommendations for the duration of isolation precautions (see below). F. COVID-19 serology: Several serologic assays are available to assess IgG/IgM responses to SARS-CoV-2 and identify current or past infection. Patients with hematologic malignancy and those undergoing HCT or chimeric antigen receptor (CAR) T cell therapy might not mount effective humoral immunity, and any serology results should be interpreted with caution. The US Food and Drug Administration (FDA) does not recommend serology as the sole basis of diagnosis of acute infection; however, serology can be used to supplement PCR testing in situations with high clinical suspicion. Cross-reactivity with other commonly circulating coronaviruses might occur with some commercial serologic tests. False-positive results also may occur from passive immunity transfer in patients receiving intravenous immunoglobulin (IVIG) therapy. Protective titers, waning of antibody response and durability of immunity remain unknown. The Infectious Diseases Society of America (IDSA) recently released a primer on COVID-19 serology addressing some of these concerns in general population. Antibody testing should not be used for pretransplantation clearance or to guide isolation decisions, and routine serology testing is not recommended. G. Routine serial PCR testing of asymptomatic inpatients and/ or outpatients has been implemented at some centers and could be considered based on local epidemiology or in the evaluation of outbreaks. Recommendations may be updated as more data become available.

## Considerations for evaluation before hct or cellular therapy
Though data are limited regarding the impact of COVID-19 in HCT candidates, donors, and cellular therapy recipients, there is concern that COVID-19 could have a significant impact on posttransplantation or post-therapy outcomes. The following should be considered while weighing the risk of delaying or altering therapy against the risk of underlying disease progression. [fig_ref] Figure 1: Evaluation of HCT and cellular therapy candidates [/fig_ref] provides an overview of general principles to evaluate HCT and cellular therapy candidates.

## Hct and cellular therapy candidates
A. HCT and cellular therapy candidates with symptoms of an acute respiratory tract infection should be tested for respiratory viruses, preferably by multiplex respiratory viral PCR, including SARS-CoV-2. If symptoms continue despite negative PCR results, consider repeat testing by multiplex respiratory viral PCR, including for SARS-CoV-2. B. If SARS-CoV-2 is detected by PCR, HCT or cellular therapy procedures should be deferred. In patients with high-risk underlying malignancies, procedures including peripheral blood stem cell mobilization, bone marrow harvest, T cell collections, and conditioning/lymphodepletion should be deferred (14 days minimum) until the patient is asymptomatic and has at least 2 consecutive negative PCR tests 24 hours apart. RNA detection by PCR can outlast the presence of replication competent virus; therefore, the requirement for PCR clearance before treatment should be balanced against the urgency of proceeding with HCT in clinically recovered individuals. C. In HCT and cellular therapy candidates with household SARS-CoV-2 exposure, procedures including peripheral blood stem cell mobilization, bone marrow harvest, T cell collections, and conditioning/lymphodepletion should be deferred for 14 days from the date of last contact. Exposed patients should be closely monitored for the development of symptoms, and if none, they should have 2 consecutive negative PCR tests 24 hours apart before proceeding with required procedures. D. HCT and cellular therapy candidates should refrain from nonessential travel; practice good hygiene, social distancing, and mask-wearing in public; and avoid crowds and large group gatherings. E. All HCT and cellular therapy candidates should undergo screening for SARS-CoV-2 infection by PCR in respiratory specimens before procedures and no more than 2 to 3 days before conditioning/lymphodepletion. Test turnaround time should be considered. F. Interim treatment and/or longer deferral of definite therapy should be considered when feasible (eg, in multiple myeloma, germ cell tumors, consolidative transplants). G. Consider pretransplantation evaluation by infectious disease, cardiology, and pulmonary consultants to assess cardiopulmonary status. Cardiac imaging, chest computed tomography scan and pulmonary function tests are recommended for patients recovered from COVID-19. Whether recovered patients are at increased risk for post-transplantation cardiopulmonary complications is unknown, and these patients should be carefully monitored.
HCT Donors SARS-CoV and MERS-CoV have been detected in blood; however, there are no reported cases of transmission of these viruses through transfusion of blood products or cellular therapies [bib_ref] Coronavirus disease 2019: coronaviruses and blood safety, Chang [/bib_ref]. SARS-CoV-2 has been detected in blood, but the duration of detection in the blood and clinical correlations are unclear [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref]. A single case of a asymptomatic SARS-CoV-2Apositive stem cell donor has been reported, with no adverse infection-related outcome in the recipient. Current American Association of Blood Banks guidelines and FDA guidelines do not recommend screening for SARS-CoV-2 in blood products. considering a donor eligible earlier than 28 days should be evaluated on a case-by-case basis. C. Current recommendations for unrelated donors from the National Marrow Donor Program (NMDP) are available at https://network.bethematchclinical.org/news/nmdp/bethe-match-response-to-COVID-19/updates-for-transplantcenters-and-cooperative-registries/ Please refer to the NMDP guidelines for updated guidance. D. If possible, ensure that an alternative stem cell source will be available. If multiple possible donors are available, choose a donor without risk. E. During the 28 days before donation, donors should practice good hygiene, social distancing, and mask-wearing in public and avoid crowded places and large group gatherings.

## Infection prevention considerations for hct and cellular therapy recipients
The IDSA has developed national guidelines for infection prevention of COVID-19 in healthcare systems. HCT and cellular therapy recipients are unique populations that are at increased risk for complications from SARS-CoV-2 and for outbreaks within units and clinics in which cohorting of high-risk populations is common. Standard efforts to prevent transmission are key to prevention and include appropriate use of PPE among staff; symptom screening of patients, HCWs, and visitors and early isolation of symptomatic individuals; and high testing capacity. Efforts to prevent transmission should focus on all key domains, with recommendations that take into consideration the level of regional community spread and the risk of transmission from presymptomatic or asymptomatic individuals. The CDC recommends that when available, respirators (instead of facemasks) are preferred; they should be prioritized for situations where respiratory protection is most important and the care of patients with pathogens requiring Airborne Precautions. https://www.cdc.gov/coronavirus/ 2019-ncov/hcp/infection-control-recommendations.htm. World Health Organization and Canadian Health Department guidelines note that SARS-CoV-2 is transmitted primarily by respiratory droplets. Regardless, PPE decisions are dependent on local supply, availability, and options for reprocessing. [fig_ref] Figure 2: Suggested infection prevention practices for bone marrow transplant units [/fig_ref] outlines general principles to consider.

## Center readiness
Centers should be ready to screen, evaluate, test, triage, isolate, and care for persons under investigation (PUI) or those with documented COVID-19 infection, with a focus on protecting clinical teams. Local planning to address outbreaks and hospital surge capacity are essential preparation efforts. Centers should use a hospital incident command structure to consolidate and communicate the work of individual groups, address shifts in local epidemiology, streamline organizational change, deal with workforce concerns, and communicate with patients, staff, and the community during the pandemic.

## Administrative controls
Transplantation and cellular therapy clinics and units should already have important administrative controls in place to protect against transmission of respiratory viruses. Owing to the unique characteristics of SARS-CoV-2, such as asymptomatic/presymptomatic transmission, prevention should be treated differently than other common community respiratory pathogens. The key recommendations are as follows:

## Staff
Prevention Screening and Testing Recommendations for Staff.
A. All staff who enter clinics or units should undergo active screening for respiratory viral symptoms (for typical and atypical COVID-19 symptoms), and symptomatic staff should be sent home. If feasible, symptom screening should be performed at single entry points before entry in person or using web-based tools. B. Limit entry points on the unit to facilitate screening. C. Onsite SARS-CoV-2 testing for symptomatic staff should be available, with policies for return to work based on current CDC or local health department guidelines. D. Asymptomatic testing of staff is not recommended unless an individual has a high-risk COVID-19 exposure or as part of an outbreak investigation. Routine testing of HCWs should be considered in the setting of widespread community transmission.

## Environmental controls
Transplant and cellular therapy units have additional measures in place to prevent transmission of respiratory pathogens, including invasive mold infections. National policies recommend single rooms for these high-risk patients, and positive pressurization primarily to prevent fungal infections. Highefficiency particulate air systems are the standard for transplant and cellular therapy units. Some of these policies may conflict with efforts to limit transmission on units. Moreover, clinical spaces, workrooms, and hospital units are not ideally suited for social distancing.

## Air systems
Positive pressure on units is considered a potential but asyet undefined risk for transmission. Centers must balance the risk of other major pathogens (eg, invasive mold) against the risk of COVID-19 when deciding whether unit air flows should be modified. Most centers do not have the capacity to modify unit air systems, and most have limited negative-pressure rooms in clinic and hospital environments. To limit transmission and conserve PPE, dedicated units are encouraged with widespread community spread. Available negative-pressure rooms should be used for COVID-19 positive patients whenever possible. Consider cohorting positive patients and staff providing care to COVID-19-positive patients within the unit to limit exposures if a dedicated unit is not available or feasible. Options to modify individual rooms with portable negative-pressure systems, mobile HEPA filtration equipment, and external ventilation can be considered, but only with input from infection prevention and hospital engineering teams.

## Physical distancing
Staff work rooms should be reconfigured however possible to allow for more physical distancing (eg, removing chairs, creating mobile workstations). Where physical distancing is not possible, extended-use masks must be used appropriately and limited to only essential staff. Waiting areas should be modified to prevent close contact where possible. Strongly consider modification or closure of community spaces (eg, conference rooms) in ambulatory areas or repurpose them to increase waiting room space. Masking policies should target areas where physical distancing is not possible.

## Environmental cleaning
Policies to ensure appropriate room cleaning and agents used in cleaning rooms are considered sufficient to disinfect high-touch areas. Additional efforts to disinfect frequently touched surfaces may be considered, especially in high-traffic areas, such as waiting rooms, cafeterias, elevators, and other common spaces with EPAregistered hospital-grade disinfectants. Supplementary disinfection with UV-C light or with hydrogen peroxide misters if available may be considered, particularly for inpatient locations, procedure suites, and designated COVID-19 units.

## High-risk procedures
Efforts to limit aerosol-generating procedures should be considered for patients who have known COVID-19 or are PUI. Policies for nebulized medications, diagnostic bronchoscopy, and pulmonary function testing should be developed in conjunction with subspecialty services, intensive care units, and infection prevention teams to both limit potential exposures and ensure patient and staff safety.

## Treatment considerations for hct and cellular therapy patients
Recently published guidelines are available from the IDSA (https://www.idsociety.org/Covid19guidelines) and the National Institutes of Health (NIH) (https://www.Covid19treat mentguidelines.nih.gov/). Given the lack of data on HCT and immunotherapy patients, treatment should be considered after careful consideration of drug interactions, drug toxicities, and overall level of immunosuppression. Additional information on drug toxicities and drug-drug interactions can be found in the ASTCT Pharmacy Special Interest Group guidance [bib_ref] American Society for Transplantation and Cellular Therapy pharmacy special interest group position..., Mahmoudjafari [/bib_ref]. Toxicity may be enhanced with combination therapy.
Treatment recommendations continue to change as additional data become available, and current guidelines should be consulted for up-to-date recommendations. HCT and cellular therapy recipients should be considered for COVID-19 treatment clinical trials if appropriate. Data from adult populations should be interpreted with caution given the overall lower incidence of severe disease in children. Drug availability is another important consideration. An overview of treatment recommendations at various disease stages is outlined in. agents may be added as combination therapy as severity increases. 7. Infectious diseases consultation is recommended. C. Extrapulmonary manifestations: COVID-19 primarily causes respiratory tract disease; however, patients may also experience cardiac, central nervous system, hepatic, and renal disease (reviewed in [fig_ref] Table 1: Extrapulmonary Manifestations of COVID-19 Described in Mostly Nonimmunocompromised Hosts [/fig_ref]. The frequency of these manifestations in recipients of HCT or cellular therapy is unknown.

## General principles

## Rationale for use of selected agents

## Antiviral agents

## Remdesivir
The efficacy of remdesivir against coronaviruses was first demonstrated in in vitro and mouse studies of MERS-CoV and SARS-CoV [bib_ref] Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta..., Sheahan [/bib_ref] [bib_ref] Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses, Sheahan [/bib_ref] and in in vitro models of SARS-CoV-2 [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref].
Data from 2 randomized placebo-controlled trials have been published. In 237 hospitalized adults with SARS-CoV-2, there was no difference in time to clinical improvement, 28-day mortality, or rate of viral clearance between the remdesivir and placebo groups [bib_ref] Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial, Wang [/bib_ref]. Limitations of the study included early termination, resulting in inadequate power, and coadministration of multiple agents that may have affected the outcomes.
Data from a multinational randomized, placebo-controlled trial (Adaptive COVID-19 Treatment Trial [ACTT]) of hospitalized patients (n =1063) with COVID-19 showed that patients who received remdesivir had a significant reduction in time to clinical recovery (11 days versus 15 days for placebo) and a nonsignificant decrease in mortality (8% for remdesivir versus 11.6% for placebo). Based on these data, recently published NIH guidelinesrecommend the use of remdesivir for the management of severe COVID-19 disease in hospitalized patients. Currently, remdesivir has not been approved by the FDA, but it is available through emergency use authorization for treatment of hospitalized patients with COVID-19. Remdesivir is not recommended for mild or moderate COVID-19 outside the setting of a clinical trial. In mostly immunocompetent adults with severe COVID-19, 5 days of therapy was equivalent to 10 days of therapy for clinical improvement by day 14. Compassionate use is available only for pregnant women and children aged 18 years with severe disease. The optimal duration of therapy in HCT and immunotherapy recipients is not known.
Adverse events most often reported in available clinical data include transient elevations in transaminases, anemia or decreased hemoglobin, acute kidney injury, pyrexia, and hyperglycemia. In the ACTT trial, these adverse events were not significantly different between the remdesivir and placebo groups. There are no known major drug-drug interactions with remdesivir [bib_ref] American Society for Transplantation and Cellular Therapy pharmacy special interest group position..., Mahmoudjafari [/bib_ref]. Recent reports showed that agents that inhibit P-glycoprotein substrate, such as amiodarone and chloroquine, can confer drug interactions. Physicians should be vigilant for any emerging toxicities from unanticipated drug interactions.
Chloroquine/hydroxychloroquine Large observational studies among hospitalized patients with COVID-19 have not demonstrated any benefit with hydroxychloroquine alone [bib_ref] Observational study of hydroxychloroquine in hospitalized patients with COVID-19, Geleris [/bib_ref] or in combination with azithromycin [bib_ref] Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients..., Rosenberg [/bib_ref]. In a randomized controlled trial of hydroxychloroquine for mild to moderate COVID-19, there was no effect on viral clearance by day 28 [bib_ref] Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open-label,..., Tang [/bib_ref]. Moreover, in a randomized controlled trial of hydroxychloroquine for postexposure prophylaxis, there was no effect on development of illness compatible with COVID-19.
Adverse reactions include nausea and diarrhea, hypoglycemia, agranulocytosis, liver function test abnormalities, and QTc prolongation. High dose hydroxychloroquine (600 mg twice daily for 10 days), in combination with azithromycin, was associated with higher rates of mortality and QTc prolongation [bib_ref] Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy..., Borba [/bib_ref]. Concomitant medications that cause QTc prolongation should be avoided. Given the data suggesting limited efficacy and potential for toxicity, hydroxychloroquine is not recommended outside of a clinical trial. Combination therapy with azithromycin is not recommended. Cardiac disease Underlying cardiovascular disease (coronary artery disease, heart failure, cardiac arrhythmias) is associated with an increased risk of in-hospital death among patients with COVID-19 [bib_ref] Cardiovascular disease, drug therapy, and mortality in COVID-19, Mehra [/bib_ref]. Cardiac dysfunction, including myocarditis, pericarditis, acute cardiac injury, and arrhythmias, have been described. Myocardial injury is reported in >25% of critical cases and may present as acute myocardial injury and dysfunction on initial presentation, or myocardial injury that develops as COVID-19 disease intensifies [bib_ref] COVID-19 and cardiovascular disease, Clerkin [/bib_ref].

## Central nervous system manifestations
Encephalitis, acute polyradiculitis, stroke, and central venous sinus thrombosis have been described. The postulated mechanisms for the neurologic complications are thought to be from direct viral invasion, inflammation-induced coagulopathy, or postinfectious autoimmune reactions.
Renal and hepatic dysfunction Renal and hepatic dysfunction have been described in severe COVID-19 disease, with the need for continuous renal replacement therapy described in >15% of cases in 1 series [bib_ref] Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington..., Arentz [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref].
Thromboembolic events Severe COVID-19Aassociated infection is associated with coagulopathy that is prognostic of poor outcomes [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref]. Although some laboratory findings resemble sepsis-associated disseminated intravascular coagulopathy, COVID-19 associated coagulopathy appears to be more thrombotic rather than hemorrhagic. The most common coagulopathy presentations are characterized by thrombocytopenia and elevated serum D-dimer levels [bib_ref] Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis, Lippi [/bib_ref] [bib_ref] D-dimer is associated with severity of coronavirus disease 2019: a pooled analysis, Lippi [/bib_ref]. There are reports of both venous and arterial thromboembolic events in these critically ill patients [bib_ref] Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of..., Hung [/bib_ref] , but it remains unclear whether they are unique to COVID-19 disease or simply part of the sepsis, cytokine storm, and impending multiorgan failure.
Multisystem inflammatory syndrome in children Several case series have described a severe systemic inflammatory syndrome associated with SARS-CoV-2 PCR or serology positivity in children and adolescents. Clinical manifestations include fever, shock, severe abdominal pain, and myocardial dysfunction with marked elevation in cardiac damage markers. The syndrome has not been described in HCT or immunotherapy patients. Antibody Therapy

## Convalescent plasma
Passive antibody transfer with convalescent plasma has been used in the treatment of or prophylaxis against other viral pathogens, including respiratory viruses. The experience with COVID-19 is limited to small case series comprising patients on concomitant antiviral therapies and corticosteroids, with suggestion of faster viral clearance and clinical recovery with early treatment, but no clear mortality benefit [bib_ref] Treatment of 5 critically ill patients with COVID-19 with convalescent plasma, Shen [/bib_ref] [bib_ref] Treatment with convalescent plasma for critically ill patients with severe acute respiratory..., Zhang [/bib_ref] [bib_ref] Effectiveness of convalescent plasma therapy in severe COVID-19 patients, Duan [/bib_ref] [bib_ref] Effect of convalescent plasma therapy on viral shedding and survival in patients..., Zeng [/bib_ref]. Limited experience from the SARS-CoV-1 epidemic also indicated potential benefit with convalescent plasma when used in the first 2 weeks of illness rather than in the late hyperimmune phase [bib_ref] Use of convalescent plasma therapy in SARS patients in Hong Kong, Cheng [/bib_ref]. The FDA recently provided guidance for the use of COVID-19 convalescent plasma under an emergency Investigational New Drug request. In the United States, more than 20,000 patients with COVID-19 have received convalescent plasma through an expanded access protocol (https://ccpp19.org/; https://www.usCovidplasma. org/; https://clinicaltrials.gov/ct2/show/NCT04338360). In an open-label randomized study of patients with severe or lifethreatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant decrease in the time to clinical improvement within 28 days. Interpretation was limited by early termination of the trial, which might have been underpowered to detect a clinically important difference. Additional randomized clinical trials are ongoing. At present, the type and concentration of antibodies against SARS-CoV-2 in the convalescent plasma used for treatment is not standardized. Furthermore, the optimal timing and dosing schedule are not established. If COVID-19 convalescent plasma is pursued, it should be in the context of a clinical trial. No recommendation can be made for or against the use of convalescent plasma at this time.
Potential adverse reactions associated with convalescent plasma infusion include transfusion-related acute lung injury, transfusion-associated circulatory overload, and other allergic transfusion reactions. Early safety indicators from 5000 treated patients in the United States suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19. Another theoretical concern is the risk of antibody-dependent enhancement that may occur in in patients with preexisting nonneutralizing SARS-CoV-2 antibodies [bib_ref] Anti-severe acute respiratory syndrome coronavirus spike antibodies trigger infection of human immune..., Jaume [/bib_ref] [bib_ref] Is antibody-dependent enhancement playing a role in COVID-19 pathogenesis, Negro [/bib_ref]. Whether these observations translate to clinical settings is unclear.

## Monoclonal antibodies
Monoclonal antibodies directed against the receptor-binding domain (RBD) and other epitopes of the viral spike protein have the potential to provide a standardized and scalable option for the treatment and prevention of COVID-19. As of June 26, 2020, 2 anti-SARS-CoV-2 monoclonal antibodies are in early-phase clinical trials: JS S016 (Junshi Biosciences) and combination therapy with REGN10933 + REGN1087 (Regeneron Pharmaceuticals).

## Adjunctive therapies

## Immunomodulatory and anti-inflammatory agents
A subset of patients with severe COVID-19 display a unique pattern of inflammatory response with multiorgan dysfunction. Variable presentations, such as hyperinflammatory response, immune dysregulation, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, and cytokine release syndrome, have been described. Other aspects of innate, adaptive immunity response signaling cascade and complement pathway activation also might be implicated in the pathogenesis of COVID-19 disease [bib_ref] Will complement inhibition be the new target in treating COVID-19Arelated systemic thrombosis?, Campbell [/bib_ref]. The role of anti-inflammatory drugs, such as tocilizumab (anti-IL-6), sarilumab (anti-IL-6), anakinra (anti-IL1), baricitinib (anti-JAK), and ruxolitinib (JAK inhibitor) are being explored [fig_ref] Table 3: Immunomodulatory and Anti-Inflammatory Agents Under Investigation for COVID-19 Drug/Mechanism Proposed Concept Published... [/fig_ref]. Given the absence of concrete data showing clinical efficacy, no recommendation either for or against the use of these agents can be made at this time. Given their broad immunosuppressive effect, these agents should be used only in the context of a clinical trial. Patients with uncontrolled infection bacterial or fungal infections should not receive these agents.

## Corticosteroids
In SARS-CoV-1, steroid therapy was associated with an increased need for ICU admission and mortality [bib_ref] The use of corticosteroid as treatment in SARS was associated with adverse..., Auyeung [/bib_ref] , although lower mortality and shorter hospitalization was seen among critical cases [bib_ref] Treatment of severe acute respiratory syndrome with glucosteroids: the Guangzhou experience, Chen [/bib_ref] , and the use of pulsed steroids resulted in lower oxygen requirements and better radiographic outcomes compared with nonpulsed steroids [bib_ref] High-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome, Ho [/bib_ref]. In MERS-CoV-2, however, steroid therapy was evaluated by both dose and duration, and no effect was seen on mortality; however, increased time to RNA clearance was observed [bib_ref] Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome, Arabi [/bib_ref]. One study of SARS-CoV-2 suggested that delayed use of steroids may increase the risk of death in the ICU [bib_ref] Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref]. In another COVID-19 cohort, the use of methylprednisolone in patients who developed ARDS was associated with decreased risk of death [bib_ref] Risk factors associated with acute respiratory distress syndrome and death in patients..., Wu [/bib_ref] ; short courses of low-to moderate-dose steroids has also been recommended in critically ill patients [bib_ref] On the use of corticosteroids for 2019-nCoV pneumonia, Shang [/bib_ref].
Preliminary results from a large randomized controlled trial of dexamethasone (n = 2104) compared with usual care (n = 4321) demonstrated reduced 28-day mortality in the dexamethasone group (22.9% versus 25.7.%; adjusted rate ratio, .83; 95% confidence interval, .75 to .93) [bib_ref] Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report, The Recovery Collaborative Group [/bib_ref]. The effect was most pronounced in patients on mechanical ventilation at the time of randomization (n = 1007), although an effect was also seen in patients on supplemental oxygen alone.
The use of steroids in patients with severe disease (requiring oxygen support or mechanical ventilation) should be considered, although there are currently no data on key questions, including whether there is antagonistic effect of dexamethasone given concomitantly with antiviral agents, what steroid equivalents can be equally effective, and outcomes and/or adverse events associated with dexamethasone in immunocompromised patients. The routine use of steroids is not recommended in patients with mild disease.

## Ivig
Currently available IVIG products are unlikely to contain specific antibodies to SARS-CoV-2 and thus are unlikely to improve clinical disease via a direct neutralizing antibody effect. IVIG has been suggested to have anti-inflammatory or immunomodulatory effects; however, given the lack of conclusive clinical data for treatment of coronaviruses and national shortage of IVIG products, the routine use of IVIG is not recommended at this time. There are no data on the use of hyperimmune immunoglobulin for SARS-CoV-2.

## Antimicrobials
Data on coinfection with bacterial and fungal pathogens in patients with COVID-19 are scant [bib_ref] COVID-19Aassociated pulmonary aspergillosis, Koehler [/bib_ref] [bib_ref] COVID-19Aassociated pulmonary aspergillosis, Van Arkel [/bib_ref]. We do not recommend routine antibiotic use in patients with SAR-CoV-2 limited to the upper respiratory tract, unless indicated for other reasons according to local protocols (ie, management of febrile neutropenia). Physicians should be vigilant for emerging nosocomial and opportunistic infections, because typical signs of infection might be masked secondary to iatrogenic and inherent immunosuppression. Antimicrobial prophylaxis should be continued in patients who are currently receiving it. It may be reasonable to restart antimicrobial prophylaxis for those in whom it was recently discontinued if they are started on an immunomodulatory agent.

## Anticoagulation therapy
No official guidelines addressing the optimal management of COVID-19-associated coagulopathy (CIC) have been published to date. A recent expert opinion review suggests using venous thromboembolism prophylaxis for these patients during hospitalization [bib_ref] Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from..., Barnes [/bib_ref]. The American Society of Hematology and NIH have also published general guidance on management of CIC on their respective websites.

## Other agents not currently recommended
Several other agents have been used in the treatment of SARS-CoV-2, including lopinavir/ritonavir, ribavirin, and interferons. These agents are not currently recommended for HCT and cellular therapy recipients. A full discussion of the rationale against this recommendation are outlined in the Supplementary Material.

## Survivorship
The estimated current number of HCT survivors in the United States is~250,000, and it will continue to increase [bib_ref] Prevalence of hematopoietic cell transplant survivors in the United States, Majhail [/bib_ref]. The Center of International Blood and Marrow Transplant Research is currently gathering data on HCT recipients with SARS-CoV-2 infection. There is no guidance available specifically addressing the needs of HCT survivors as the country plans to reopen. Patients in this group are diverse and may vary in their net state of immunosuppression. Our panel suggests that they continue to practice caution during social interactions, encourage the use of face masks, and practicing hand hygiene. Because community spread will differ among geographic areas, it is important to follow local trends and guidance provided by local departments and the CDC. HCT survivors should discuss returning to work with their treating physicians and should take necessary precautions at their workplace. Acknowledging the physical and psychological needs for HCT survivors and seeking help for their physical and mental health needs, especially during the pandemic phase, is of utmost importance [bib_ref] National Institutes of Health hematopoietic cell transplantation late effects initiative: the Patient-Centered..., Bevans [/bib_ref].

# Acknowledgments
The author thank the following colleagues for their valuable input: Ella Ariza-Heredia Multiple reports showed improved oxygen requirement, normalization in CRP, and resolution of fever, and increased the lymphocyte count to normal [bib_ref] Risk of serious infections in tocilizumab versus other biologic drugs in patients..., Pawar [/bib_ref] [bib_ref] Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and..., Toniati [/bib_ref] [bib_ref] Impact of low-dose tocilizumab on mortality rate in patients with COVID-19Arelated pneumonia, Capra [/bib_ref].
The optimal timing and dosing schedule of tocilizumab are not established.
Others showed tocilizumab failed to prevent ICU admission or impact disease progression and mortality [bib_ref] Use of tocilizumab for COVID-19-induced cytokine release syndrome: a cautionary case report, Radbel [/bib_ref].
Monitor for hepatic function abnormalities, local injection site reactions, and possible inducible effects on drugs metabolized by CYP450 given the drug's long half-life. FDA black box warnings for the risk of severe infections that can lead to hospitalization and death [bib_ref] Effective treatment of severe COVID-19 patients with tocilizumab, Xu [/bib_ref].
IL-6 levels normally increase after tocilizumab administration from inhibited cytokine/receptor catabolism. Post-tocilizumab IL-6 levels should not be used as a surrogate marker for clinical response [bib_ref] Tocilizumab treatment in COVID-19: a single center experience, Luo [/bib_ref] [bib_ref] Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble..., Nishimoto [/bib_ref].
Baricitinib: Janus kinas inhibitor, approved for rheumatoid arthritis [bib_ref] Baricitinib therapy in COVID-19: a pilot study on safety and clinical impact, Cantini [/bib_ref] Interference with viral endocytosis.Concerns for impairment of IFN-mediated antiviral response
In a pilot study of 12 patients with moderate COVID-19 disease, the baricitinib group showed improved respiratory function parameters and CRP values compared with the standard of care.
No adverse events were noted. and no cancer patients were included [bib_ref] Baricitinib in patients with refractory rheumatoid arthritis, Genovese [/bib_ref].
Anakinra A recombinant human IL-1 receptor antagonist. Approved for rheumatoid arthritis. Off label use for familial Mediterranean fever and hemophagocytic lymphohistiocytosis syndrome [bib_ref] Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress..., Cavalli [/bib_ref] [bib_ref] Anakinra for severe forms of COVID-19: a cohort study, Huet [/bib_ref] Counteract SARS-CoV-2Ainduced severe inflammatory response with macrophage activation syndro-meAlike picture or cytokine release syndrome [bib_ref] Anakinra for colchicine-resistant familial Mediterranean fever: a randomized, double-blind, placebo-controlled trial, Ben-Zvi [/bib_ref].
Clinical trials are currently conducted outside the United States.
A small Italian retrospective study of 29 patients showed a better mortality rates in patients with acute respiratory distress syndrome who received high-dose i.v. anakinra. Patient also received hydroxychloroquine and lopinavir/ritonavir [bib_ref] Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome..., Bruck [/bib_ref].
A French study compared outcomes of 52 patients with COVID-19 with 44 historical patients. The anakinra group had lower rates of mechanical ventilation or death (25% versus 73%; P < .0001) with similar results for death only (P = .0063).
[fig] Figure 1: Evaluation of HCT and cellular therapy candidates. [/fig]
[fig] Figure 2: Suggested infection prevention practices for bone marrow transplant units. [/fig]
[table] Table 1: Extrapulmonary Manifestations of COVID-19 Described in Mostly Nonimmunocompromised Hosts [/table]
[table] Table 3: Immunomodulatory and Anti-Inflammatory Agents Under Investigation for COVID-19 Drug/Mechanism Proposed Concept Published Reports/Clinical Observations Tocilizumab: A recombinant humanized monoclonal antibody against both soluble and membrane-bound IL-6 receptor Inhibits IL-6Amediated proinflammatory responses. No established IL-6 cutoff values to predict disease severity or clinical outcomes. [/table]