key: cord-0773106-hz3frwmt authors: nan title: C4 article: Implications of COVID‐19 in transplantation date: 2020-11-06 journal: Am J Transplant DOI: 10.1111/ajt.16346 sha: ce498ab9f7bf41c05eca7f4ef846865778717f98 doc_id: 773106 cord_uid: hz3frwmt A novel coronavirus has had global impact on individual health and health care delivery. In this C4 article, contributors discuss various aspects of transplantation including donor and recipient screening, management of infected patients, and prevention of coronavirus disease (COVID). Donor screening with SARS‐CoV‐2 nucleic acid testing (NAT) close to the time of procurement is recommended. Many programs are also screening all potential recipients at the time of admission. The management of COVID has evolved with remdesivir emerging as a new potential option for transplant recipients. Dexamethasone has also shown promise and convalescent plasma is under study. Prevention strategies for transplant candidates and recipients are paramount. Pediatric‐specific issues are also discussed. Strategies for the psychological well‐being of patients and providers are also imperative, in addition to future research priorities for transplantation. SARS-CoV-2, a novel coronavirus, originated in China in late 2019 and has since caused an unprecedented pandemic with COVID- 19 impacting almost all regions globally. Mortality is estimated to be 1%-3% and the predominant risk factor for mortality is age >60 years along with comorbid illnesses such as hypertension. Interestingly, children are less impacted although there are recent reports of a Kawasaki-like inflammatory syndrome that may be linked to COVID-19. Although the majority of severe disease involves the respiratory tract, other complications such as neurologic disease (confusion, cognitive difficulties, early strokes) as well as a hypercoagulable state can occur. Organ donation and transplantation have been greatly impacted by the pandemic. Donation rates significantly fell during the pandemic peaks although there was some geographic variability in this. Living donor transplantation was halted in many areas due to anticipated lack of hospital capacity and the concern for nosocomial transmission of virus. Significant concern was generated that high rates of severe COVID-19 disease would be seen in immunosuppressed transplant recipients. Indeed, transplant recipients appear to have a greater risk of mortality than the general population, although the exact increase in risk is difficult to ascertain as this has varied among studies and with time. Several case reports and case series of transplant recipients with COVID-19 have now been published and mortality ranges 18%-30%, although these studies are primarily reflective of a hospitalized population. [1] [2] [3] The potential bias in a more severely affected population needs to be taken into account during the interpretation of morbidity and mortality data. Serosurveys may shed more light in terms of how many transplant patients may have had milder disease courses. Notably, this is a rapidly changing situation, thus we are focusing on the current state of the disease. This is the third in a series of C4 (defined as current, controversial, collaborative, and crowdsourced) articles that was first pub- Real-time polymerase chain reaction (RT-PCR), using a laboratory developed test (LDT) or a commercial assay, is the main diagnostic approach at most centers. Assays utilize different viral targets (RdRp, E gene, spike, Open Reading Frame [ORF] 1a, and nucleocapsid [N]). 4 The underlying kinetics of viral infections are key to understanding PCR test performance. Viral replication begins 24-48 hours prior to symptom onset and peaks at days 3-5 after symptom onset. 5, 6 Patients with more severe infections typically have higher viral loads in all locations and shed virus longer (21 vs. 14 days). 7, 8 Higher viral loads are noted with increasing age. While viral shedding is prolonged for many patients, for those with mild disease, culturable virus is generally no longer detected when the viral load drops below 10 6 copies or Ct (cycle threshold) value >34 which generally occurs around day 8 after symptom onset. 9, 10 Virus has been detected outside the respiratory tract, including the blood and stool, but these sites are not typically sampled for diagnostic purposes. 11 False-negative PCR testing from upper airway samples is more common very early and late after infection. Likewise, patients with pneumonia who may have detection of virus from lower but not upper respiratory tract samples have been described. False-negative PCR testing may occur with worsening clinical status later in the disease course. 12 As discussed below, serologic testing for SARS-CoV-2, may be useful in this setting. Across studies, samples from the lower respiratory tract have consistently had both higher viral loads and a higher percent positivity rate versus nasal samples (93% vs. 63%). 13, 14 Several studies have demonstrated saliva to yield excellent sensitivity and slightly higher viral loads than nasal swab with significant ease in collection. 7, 15 Several studies have demonstrated the ability to detect virus from asymptomatic and presymptomatic patients. Virus in these patients can frequently be cultured suggesting presence of transmissible virus. 16, 17 In the United States, all current SARS-CoV-2 assays are being used under Emergency Use Authorization (EUA, https://www. fda.gov/medic al-devic es/emerg ency-situa tions -medic al-devic es/ emerg ency-use-autho rizat ions). Without a gold standard of diagnosis, it is difficult to define these test characteristics and the performance of the assays approved under the EUA has not been widely studied. The few studies that have been completed suggested excellent sensitivity and specificity with agreement across most assays; most have noted slightly lower sensitivity with the Abbott ID Now system. [18] [19] [20] [21] Several studies have suggested that CT scans of chest are more sensitive than upper respiratory PCR testing early in the disease course. 22, 23 Findings are typically nonspecific and testing poses risk of exposure to radiology staff, so current guidelines generally do not recommend imaging for the diagnosis of COVID-19 (https:// www.acr.org/Advoc acy-and-Econo mics/ACR-Posit ion-State ments/ Recom menda tions -for-Chest -Radio graph y-and-CT-for-Suspe cted-COVID 19-Infec tion). However, in cases of high suspicion for COVID-19 lower respiratory tract disease and repeated PCR negativity, a CT chest can be done although radiologic findings of COVID-19 are not specific. Measuring antibody responses to SARS-CoV-2 may be useful for clinical, epidemiologic, therapeutic, and prevention efforts. In particular, serologic testing may have a role in (1) detection of PCRnegative cases, especially for patients who present late with viral loads below the detection limit of RT-PCR assays; (2) identification of convalescent plasma donors if quantitative assays are used; (3) contact tracing after a suspected exposure; (4) epidemiologic studies of disease prevalence in the community; and (5) verification of vaccine efficacy. However, serologic testing is also fraught with pitfalls due to technical and analytical heterogeneity, especially when tests are not rigorously validated (leading to false positives and false negatives) and when testing is applied to a mass scale in low prevalence settings (leading to false positives). The benefits and approaches of serology have been reviewed extensively elsewhere. 4 IgM antibodies begin to develop 3-7 days after symptom onset with IgG developing on symptom days 11-14; most are positive by 3 weeks after symptom onset. 24 Titers typically decline after 2 months, as they do with many infections, but the duration of protection is not well studied to date. Furthermore, assays are just beginning to be validated and current tests have a wide range of sensitivity and specificity. Few of the available tests confirm the detection of neutralizing antibodies. Patients infected with SARS-CoV-2 can have dramatically different courses of illness. Risk factors for severe disease include comorbidities such as obesity, diabetes, hypertension, renal disease, cardiovascular disease, chronic respiratory disease, and cancer. Risk factors for mortality include older age, higher Sequential Organ Failure Assessment score, and d-dimer >1 mcg/ml on admission. 25 Some reports suggest that transplant recipients are at greater risk of complications of COVID-19 owing to immunosuppression whereas others infer that the immunosuppression has a limited impact and it is the comorbidities that drive the risk. 26 29 and management varies by severity of illness (Table 1) . Asymptomatic and mild infections can be managed at home. Priorities include close monitoring for clinical deterioration as well as isolation in order to prevent transmission to others. Acetaminophen can help manage fever and myalgia. Nonsteroidal anti-inflammatory drugs are not known to be problematic in patients with COVID- 19, 30 although they are often avoided to prevent nephrotoxicity in transplant recipients taking concomitant calcineurin inhibitors. Despite initial reports, renin-angiotensin-aldosterone system inhibitors should be continued in patients in stable condition. 31, 32 Moderate and severe disease requires hospital admission for supportive care. At a minimum, routine monitoring should assess for fever, myalgia, GI symptoms, respiratory status, renal dysfunction, myelosuppression, thrombosis, and psychiatric assessment. Hospitalized adults should receive venous thromboembolism prophylaxis. Empiric broad spectrum antibiotics should be given if bacterial pneumonia or sepsis is suspected, with daily reevaluation and de-escalation or discontinuation as soon as able. As per the RECOVERY trial, patients who require supplemental oxygen or mechanical ventilation may derive a mortality benefit from dexamethasone. 33 Therapies used in the treatment of COVID-19 are the same in transplant recipients as in non-transplant patients ( Table 2) . Several potential antiviral therapies used early in the pandemic including hydroxychloroquine [35] [36] [37] and lopinavir/ritonavir have been found ineffective and should not be used to prevent or treat infection in transplant patients. 38 The most promising antiviral at this time is remdesivir, which has been fully or conditionally approved by health authorities around the world based on clinical trials. 39 Transplant activity during the COVID-19 pandemic has been significantly curtailed. 73 The decision of when and how to transition from a state of low transplant activity toward a return to "normal" activity is challenging. Patients with suspected or confirmed COVID-19 should be placed in a single-patient room with the door closed and a dedicated bathroom. Airborne infection isolation rooms (single-patient, negative-pressure room) should be reserved for patients who will undergo an AGP. To limit HCP exposure, facilities could designate a unit within their facility to care for patients with known or suspected COVID-19. With the same goal, HCP should be designated to work specifically in these units whenever possible. 79 In a study of 56 patients from Wuhan, China the median time between onset of symptoms to NP RT-PCR negative was 24 days. 80 SARS-CoV-2 has not been cultured more than 9 days after the onset of symptoms in patients with mild disease; albeit the sample size of these studies was small. 9 83 Collectively, these data prompted an update to the CDC guidelines regarding the duration of isolation and precautions for adults with COVID-19 ( Table 4 ). The revision favors a symptom-based strategy although a test-based strategy could be considered in consultation with infectious diseases experts for severely immunocompromised patients. 84 Regardless of the strategy used retesting after discontinuation of isolation is discouraged. There are little data to guide the decision to discontinue isolation in SOT recipients. There is concern, based on data with influenza, of prolonged infectivity with SARS-CoV-2 but this has not been confirmed. 85 The optimal strategy (time or test based) and timing of discontinuation of isolation for SOT recip- To minimize the spread of SARS-CoV-2 from one HCP to another, most centers have adopted the following measures. 79 after the onset of symptoms. 86 Furthermore, it noted that even expanded symptom-based screening fails to identify all infected HCP. For this reason, universal masking of HCP within the health care facility is strongly recommended. The HCP of organ procurement organizations (OPOs) are also at risk of acquiring SARS-CoV-2. The first line of protection is the screening that is recommended for all patients before entering a health care facility. 79 There is ample evidence that the COVID-19 pandemic has adversely impacted the psychological health of patients and providers alike. Harm-reduction strategies implemented to attenuate viral transmis- The pandemic creates unique challenges for the population of im- The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. There are no data to be shared. 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