key: cord-349838-p6vfzbla
authors: Algwaiz, Ghada; Aljurf, Mahmoud; Koh, Mickey; Horowitz, Mary M.; Ljungman, Per; Weisdorf, Daniel; Saber, Wael; Kodera, Yoshihisa; Szer, Jeff; Jawdat, Dunia; Wood, William A.; Brazauskas, Ruta; Lehmann, Leslie; Pasquini, Marcelo C.; Seber, Adriana; Lu, Pei Hua; Atsuta, Yoshiko; Riches, Marcie; Perales, Miguel-Angel; Worel, Nina; Okamoto, Shinichiro; Srivastava, Alok; Chemaly, Roy F.; Cordonnier, Catherine; Dandoy, Christopher E.; Wingard, John R.; Kharfan-Dabaja, Mohamed A.; Hamadani, Mehdi; Majhail, Navneet S.; Waghmare, Alpana A.; Chao, Nelson; Kröger, Nicolaus; Shaw, Bronwen; Mohty, Mohamad; Niederwieser, Dietger; Greinix, Hildegard; Hashmi, Shahrukh K.
title: Real-world issues and potential solutions in HCT during the COVID-19 pandemic: Perspectives from the WBMT and the CIBMTR's Health Services and International Studies Committee
date: 2020-07-24
journal: Biol Blood Marrow Transplant
DOI: 10.1016/j.bbmt.2020.07.021
sha: 
doc_id: 349838
cord_uid: p6vfzbla

The current COVID-19 pandemic, caused by SARS-CoV-2, has impacted many facets of hematopoietic cell transplantation (HCT) in both developed and developing countries. Realizing the challenges as a result of this pandemic affecting the daily practice of the HCT centers, and the recognition of the variability in practice worldwide, the Worldwide Network for Blood & Marrow Transplantation (WBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) Health Services and International Studies Committee have jointly produced an expert opinion statement as a general guide to deal with certain aspects of HCT including diagnostics for SARS-CoV-2 in HCT patients, pre-and-post-HCT management, donor issues, medical tourism and facilities management. During these crucial times, which may last for months or years, the HCT community must reorganize to proceed with transplant activity in those patients who urgently require it, albeit with extreme caution.This shared knowledge may be of value to the HCT community in the absence of highquality evidence-based medicine.

In recent history, several epidemics have affected the care of hematopoietic cell transplantation (HCT) recipients/donors including SARS coronavirus (SARS-CoV-1), influenza A virus subtype H1N1, Zika, and the Ebola virus. The issues arising from these epidemics were relatively geographically limited compared to the current COVID-19 pandemic, caused by SARS-CoV-2. By July 19, 2020, over 13 millioncases of COVID-19 have been reported worldwide. (1) Numerous aspects of the virus remain unknown, such as the immune response and natural course of the disease, the exact incubation period, and the rate of spread among asymptomatic people, among other factors. These uncertainties make it particularly challenging to study the pattern of possible spread and create efficient management and prevention strategies. It is also difficult to predict the disease severity of COVID-19 in HCT recipients. Thus far, limited data are published on disease severity, clinical course, and duration of infectivity of COVID-19 in HCT patients. (2, 3) Importantly, HCT remains the standard of care and the only potential cure for many hematological malignancies, genetic diseases, hemoglobinopathies, autoimmune diseases, and immunodeficiencies. (4, 5) The transplant community is facing many challenges concerning the day-to-day practice in HCT, and the entire process of referrals to evaluations, scheduling, admission, chemotherapy/radiation administration, donor procurement, and discharge planning, among others, is disrupted. SARS-CoV-2 is a highly communicable virus that incites a variable immune response resulting in uncertainties about protective as well as deleterious immune responses to the virus. While the majority of the infected individuals clear the virus without major complications, in a minority of the patients, the infection leads to a life-threatening clinical situation involving any organ (especially the lungs), diffuse intravascular thrombosis, and ultimately leads to acute respiratory distress syndrome (ARDS) and multiorgan failure, which has complex pathology and mechanism. While acknowledging all aforementioned challenges and taking into account current recommendations or guidelines issued by the American Society for Transplantation and Cellular Therapy (ASTCT) and the European Society for Blood and Marrow Transplantation (EBMT) (which are WBMT members), herein, we aim at providing a consensus among the authors from WBMT and CIBMTR's HSIS committee and other HCT experts who represent multiple continents and allude to the current worldwide threat to HCT patient from the COVID-19 pandemic (7, 8) . For recommendations on the management of patients being treated with CAR-T cells, the reader is referred to a recent publication on this topic. (9) Organizational issues:

Creating hospital-wide multidisciplinary COVID-19 teams (including specialists in infectious diseases, critical care medicine, pulmonary medicine, etc.) is essential to facilitate the manage-6 ment of patients and make adjustments based on new information as it becomes available. Enabling telephone or video communication for attendance of multidisciplinary team meetings is important for the coordinated care of the patients. To facilitate reporting, some registries, including the CIBMTR and EBMT, are actively collecting information on HCT and other cellular therapy patients infected with COVID-19. HCT programs require adequate HCT staff prior to resuming transplant during the Covid-19 pandemic.

Continuing availability of blood products is a prerequisite to plan HCT since supply has been a major issue during the pandemic. Possibility to reduce the threshold for blood product transfusion should be discussed from the beginning. Additionally, blood loss prevention strategies should be maximized e.g. minimizing blood draws or treatment with tranexamic acid if clinically 

Persons infected with the SARS-CoV-2 can present with a variety of symptoms which include fever, rhinorrhea, cough, chest pain, shortness of breath, diarrhea, and skin rash.

Two kinds of tests are available for COVID-19. A viral test using PCR to detect the virus and an antibody-based test showing the occurrence of previous infection (it can take 1-3 weeks after infection to become positive). Notably, PCR based testing does not distinguish between live and dead SARS-CoV-2. For diagnosis of COVID-19 infection in HCT recipients, testing with realtime reverse transcription-polymerase chain reaction (RT-PCR) should occur from the nasopharyngeal swab, however, sputum sample or nasal swabs can also be used. (12) Each center needs to understand the sensitivity, specificity, and predictive values of the specific test being used which may be affected by the regional prevalence of the infection. Pitfalls in SARS-CoV-2 PCR diagnostics have been published recently. (13) At present, there is no known role for antibodybased (serologic) testing for SARS-CoV-2 for diagnostic purposes. Exposure (especially to contacts with COVID-19 patients) and symptom history, physical examination, and chest imaging are helpful to evaluate HCT patients.

In cases where the diagnosis is not clear, bronchoscopy with bronchoalveolar lavage may be pursued in selected cases, albeit with extreme caution as the pulmonologists doing the procedures can also be at risk of acquiring the SARS-CoV-2 infection.. Specific symptoms/findings described to be associated with SARS-CoV-2 infection are fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting or diarrhea. Symptoms may range from asymptomatic (e.g. no fever) to mild or to severe symptoms. (14) Laboratory test like CRP, D-Dimer and LDH may help assess the severity of the infection and should optimally be done in each patient with confirmed COVID-19. (15, 16) . Suspected patients with classic COVID-19 symptoms in an appropriate medical setting, may be cohorted or isolated as soon as possible in special wards or units (temporary or permanent depending on the institutional policies and/or resources). Once the RT-PCR test comes back negative, then only should these patients be considered as standard risk HCT patients and managed accordingly." In the absence of 8 appropriate diagnostic tools (i.e. RT-PCR), physicians may have to rely on history, physical exam, and chest imaging, in which case a chest CT scan may be more helpful as it is more sensitive than a chest radiograph. The CDC has removed both chloroquine and hydroxychloroquine from its guidelines. Table 1 reviews several of these agents, including their current uses in HCT patients and GVHD.

It is important to take into consideration the possible increased risk of complications in HCT patients with COVID-19 due to the status of immune reconstitution (delayed in allogeneic HCT recipients for up to a year), concurrent medications including immunosuppression, the general state of the patient (performance status and psychosocial condition), existing comorbidities (especially cardiovascular or pulmonary), presence or absence of GVHD, disease status (COVID-19 severity), mucositis (mucosal barrier injury predisposes to infections), and malnutrition (which can itself lead to a decreased immunologic response to infections). (19) (20) (21) Also, superimposed bacterial infection, fungal and other common viral reactivation, such as cytomegalovirus or Epstein-Barr virus may occur, should be closely monitored and treated if indicated. There are no data to support the discontinuation of immunosuppressive drugs in HCT recipients infected with COVID-19 infection. Currently, data for the effectiveness of certain drugs/immunomodulators are available for COVID-19 treatment; however, many randomized clinical trials are currently being performed using a variety of agents for COVID-19 management. We, therefore, recom-9 mend that unapproved drug use in HCT patients should be considered in a clinical trial or approved for exceptional use after hospital ethics approval.

Successful coordination of the HCT program with the overall strategy of the hospital or health system to cope with the current pandemic is needed. It is important to ensure that the staff is protected so that the center does not experience loss of expert personnel to exposure (requiring quarantine) or infection. Strict adherence to infection control measures is imperative to minimize the transmission of the virus in HCT inpatient and outpatient units.

All patients, including those without symptoms, should be thoroughly evaluated for both clinical symptoms that might suggest incipient COVID-19 and both symptomatic and asymptomatic patients tested for SARS-CoV-2 with RT-PCR 1 or 2 days before entering the transplant ward for conditioning. If the suspicion of acquiring SARS-CoV-2 is high, i.e. in those exposed to persons with active upper respiratory tract infection symptoms, then a second test with RT-PCR is advisable despite even if the initial RT-PCR was negative, due to the possibility of false-negative results. Additionally, a CT scan of the chest can be very helpful in these cases as it has shown to be more sensitive than a chest radiograph. 

It is recommended that urgent transplants (e.g. acute leukemias, high-risk myelodysplastic syndrome, certain refractory bone marrow failure (BMF) syndromes, and autologous HCTs [if being performed for curative intent] for high-risk myelomas, Hodgkin's, large cell lymphomas, and germ cell tumors) are not delayed in patients at substantial risk from loss of disease control.

In general, non-urgent transplants should be deferred as clinically permissible, especially for stable non-rapidly progressive non-malignant disorders, particularly for hemoglobinopathies, selected immunodeficiencies, and selected genetic conditions.

In general, the use of peripheral blood stem cells (PBSC) with cryopreservation and testing for quality of thawed product before starting the conditioning is strongly encouraged. The use of post-transplant cyclophosphamide (PTCy) has increased significantly for both haploidentical and HLA-matched HCTs globally, and a recent study showed no detrimental effect of a cryopreserved product on the survival when using PTCy for GVHD prophylaxis in HCT for hematologic malignancies. (10) Therefore, we consider this to be a reasonable strategy for HCTs for hematologic malignancies; however, for bone marrow failure (especially for severe aplastic anemia) fresh bone marrow products remain the standard of care as indicated by a recent study. Table 1 ). d) In all other scenarios, the patient should be evaluated by a multidisciplinary team for an individualized decision.

Special infection control measures including strict proper personal protective equipment should be followed as recommended by international, national, and local guidelines. A team/unit dedicated to the care of COVID-19 patients should be separated and isolated from staff caring for transplant patients. Ideally, there should be a specific site/unit for cohorting these patients. Some hospitals in developing countries may have little capacity for private rooms however, the HCT patients, given their immunocompromised state, should not be cohorted in shared rooms.

Regarding the selection of the appropriate industrial climate control system for HCT patients, we recommend the following:

1-HCT patients with suspected COVID-19 should not stay in positive pressure rooms. They should be tested in neutral pressure (or negative pressure) rooms (in private rooms, if available). If no PCR test is available and/or suspicious is high, patients should be kept in private rooms (neutral or negative pressure), if possible, or cohorted. It may be advisable to perform these tests immediately before admissions and wait for results if possible.

rooms and must be transferred to negative pressure (or neutral pressure) rooms immediately. 13 3-HCT patients with a negative test for SARS-CoV-2 and having no symptoms should continue management in high-efficiency particulate air (HEPA) filtered positive pressure rooms as per the institutional policy for immunocompromised patients.

Staff should be screened for symptoms before entering the HCT unit, and face surgical masks and eye protection should be worn at all times during the rounds (refer to the guidance document by the EBMT). Prophylactic G-CSF for early neutrophil engraftment may be considered for HCT patients unless contraindicated. There is no published evidence whether this practice can improve outcomes; however, there could be an advantage of early discharge from the hospital for risk reduction of infections. Theoretically, the inflammatory cascade in ARDS (28) (mediated in part by IL-6) may be enhanced by cytokines, however, currently, there are no data to support the administration of G-CSF . The cytokine may accelerate the risk of ARDS in COVID-19 confirmed cases. (29) The transfusions thresholds should be minimized in the light of the actual or anticipated shortage of blood products. As general guidance, a hemoglobin threshold of < 70 g/L should be considered as an indication for blood transfusion in both autologous and allogeneic HCT patients. (30) For platelet transfusion, a threshold of less than 10x10 9 /μL is reasonable in most cases.

Transplant patients may be at increased risk of both secondary infections and organ damage with COVID-19. The usual recommendations for infection prevention, including strict hand hygiene, wearing surgical or procedural masks at all times, and social/physical distancing, should be strongly encouraged.

Outpatient visits should be postponed or carried out using tele-and/or televideo conference where indicated. During the early post-HCT period, especially for allogeneic HCTs, a face-to- 14 face visit may be required to detect early acute GVHD of the skin and mucosa. Ambulatory transplants should be encouraged to minimize exposure to hospital visits, if the necessary infrastructure is available.

Prolonged viral shedding will likely be seen in HCT patients as this is a common occurrence with other respiratory viruses. Separate areas in the outpatient settings for potential infectious and noninfectious individuals should be available with checkpoints at the entrance. Patients with confirmed COVID-19 infections should be regularly tested (depending on the institutional policies and/or the governmental regulations) until the PCR turns negative. Until then, they should still be regarded as potentially infectious. Other important issues to address include social distancing in the waiting area, wearing masks until in waiting rooms, direct rooming (i.e., no waiting), no visitors in the outpatient area, and avoidance of common areas (including cafeteria). 

Transplant candidate requiring an HCT in a country which has facilities for HCT should ideally stay within the home country. Provided that the clinical condition allows delaying the procedure.

This may be different for international travel within driving distances. For example, patients with severe aplastic anemia will have particular difficulty if no transplant center in their home country performs allogeneic HCTs for BMF syndromes; and in pediatrics, timely HCT may be required in pediatric patients diagnosed with certain inherited conditions e.g. Hurlers Syndrome.

Patients who received HCT in a foreign country should avoid travel back to their respective countries in the immediate post-HCT period, especially if they are currently residing in a coun-15 try/state/province/city which has an extremely high prevalence of SARS-CoV-2. If a transplant recipient will require frequent visits in the initial months following HCT, he should remain at the original transplant center until the clinical condition is stable (e.g. 3-4 months after allogeneic HCT).

The rise of the COVID-19 pandemic has impacted all aspects of HCT. We believe our shared knowledge will be of value to the HCT community in the absence of high-quality evidence-based medicine at present. The current emergency may continue for months or years until herd immunity is achieved (due to the availability of an effective vaccine or as a result of natural infection).

Thus, during these crucial times, the HCT community must reorganize to proceed with transplants in those who urgently need them, and concurrently, deal with nuances that come with a pandemic e.g. nosocomial transmission prevention, protection of HCT staff, and treatment of COVID-19 in HCT patients. The extreme variability of the worldwide geopolitical situation due to COVID-19 requires HCT programs to practice differently. We hope that this article provides general guidance to clinicians and the institutional leadership to deal with the real-world scenarios. ARDS is usually associated with IL-6 increase thereby providing the rationale for anti-IL6 or anti-IL6 receptor antibody therapy (28, 37) Tocilizumab also increases the risk of secondary infections.

Used for the treatment of acute GVHD. Also used for the treatment of cytokine release syndrome after CAR-T cell therapy. 

Azithromycin Tested in a French trial and found to reinforce the positive effect of hydroxychloroquine on the COVID-19 viral load.

Used as a treatment for the lung GVHD.

(BOS) A significant number of GVHD patients will also be on "azoles" for antifungal prophylaxis so the risk of QTc prolongation could be further enhanced if concurrently used with full dose azithromycin, chloroquine or both. Chloroquine and hydroxychloroquine

Best evidence thus far has failed to demonstrate benefit in hard clinical outcomes, but some trial results have been encouraging with a suggestion of reduction of viral load or a reduction in PCR positivity of COVID-19. (42) One US retrospective analysis showed no benefit and association with higher mortality in patients receiving hydroxychloroquine. (43) Other studies have shown no benefit, with potential harm such as arrhythmias. (44) (45) (46) (47) Used occasionally in chronic GVHD.

Metabolized by cytochrome P450. Significant QTc prolongation. Concerns of increased toxicity with cyclosporine and imatinib (used in chronic GVHD) such as myopathies

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 [4] Cell Therapy Facility, Blood Services Group, Health Sciences Authority, Singapore [5] 

Antiviral Lopinavir/Ritonavir Recently published trials showed no significant effect on mortality. (Very low evidence due to risk of bias such as lack of blinding) (48) No definite role specifically in HCT.Severe GI symptoms, QTc prolongation and multiple drug interactions due to CYP3A inhibition especially with salmeterol-fluticasone which is used frequently in the treatment of BOS as 'FAM" protocol FavipiravirPreliminary results of a Japanese clinical trial showed that, in COVID-19, favipiravir, compared to arbidol, did not significantly improve the clinical recovery rate at day 7. (49) No definite role specifically in HCT.There is associated raised serum uric acid with the use of favipiravir. 

No known role in COVID- 19 Commonly used in GVHD.Azithromycin interaction with the CYP3A4 inducers. CAR-T cells (cryopreserved vs. fresh products)

Approved for posttransplant relapse of ALL and NHL.Post CAR-T cell infusion, any drug treatment should strictly be in the context of clinical trials. CAR-T cell therapy may be affected due to the restricted availability of tocilizumab, thereby consider CAR-T cell therapy on those who have an urgent need. General guidance from the CAR T-cell consortium should be considered.