We are now over 6 months into the coronavirus 2019 (COVID-19) pandemic. On a global level, the pandemic has resulted in profound disruptions in transplant programs and has drastically reduced the number of transplants performed, especially in the early months, creating both medical and ethical dilemmas.1-4 Reports of high mortality from COVID-19 infection in solid organ transplant (SOT) recipients, as well as uncertainties about optimal therapies, have added to clinicians’ concerns.5-17 SOT recipients frequently have comorbidities that have been associated with the severity of COVID-19 disease in the general population, including hypertension, diabetes, cardiovascular disease, and obesity.5-18 However, we know far less about the efficacy and safety of targeted therapies for COVID-19 in the SOT population. Some clinical trials have excluded immunocompromised patients or those with renal or liver dysfunction at the time of hospital admission. Thus, there is yet to be a robust evidence base for effective therapeutics for COVID in SOT recipients,19 but much can be learned through existing case series5-17 and, more recently, larger multicenter registries.20-22 This overview, while not a systematic review, will attempt to delineate the larger picture of therapeutic trends over time, both in SOT recipients and in the general population with COVID-19, with an eye to evidence gaps to be addressed in the future.
The Biphasic Pattern of COVID-19 Infection
As a background for a discussion of therapeutics, it is important to recall the biphasic pattern of COVID-19 infection. Initial symptoms may include fever, dry cough, myalgias, malaise, headache, nausea, diarrhea, and loss of taste or smell. Subsequently, some patients progress to an inflammatory phase involving worsening hypoxemia, respiratory failure, and multiorgan dysfunction. Lipworth et al described this as “a cytokine-mediated hyperinflammatory response and coagulopathy, which in many respects simulates a viral-induced multiorgan autoimmune response.”23 The magnitude and trajectory of elevated inflammatory markers, such as C-reactive protein (CRP), interleukin-6 (IL-6), and ferritin, are predictive of clinical deterioration and the need for mechanical ventilation, with IL-6 playing a particularly important role.24 Mortality is highest in patients who require mechanical ventilation, and therefore, therapeutic interventions are often aimed at preventing the progression of hypoxemia.
In accordance with the biphasic clinical pattern, therapies for COVID-19 are typically grouped into 2 categories: antivirals and immunomodulatory agents. Antivirals promote control of the virus itself; for example, remdesivir inhibits viral replication via the viral RNA-dependent RNA-polymerase.25 Immunomodulatory therapies, on the other hand, are intended to mitigate the host inflammatory response to SARS-CoV-2.26 The third category of nonpharmacologic interventions, such as proning and ventilator management, is outside the scope of this overview.
The 2 Eras of Therapeutics
Looking back over the months since the start of the pandemic, we can divide them roughly into 2 eras: (1) the early era, from February to May 2020, in which the available evidence was largely in the form of case series and preprints, and was dominated by the use of drugs such as hydroxychloroquine, azithromycin, and lopinavir–ritonavir, with tocilizumab used for the inflammatory phase; and (2) the later era, from approximately June 2020 on, after the publication of larger studies including some randomized trials, with now widespread use of remdesivir, dexamethasone, convalescent plasma, and therapies in clinical trials. Evaluating the quality of the large volume of evidence is a complex matter, and most studies have not been randomized controlled trials, but we can safely say that treatment protocols have evolved considerably over time. So far, the strongest evidence of benefit in the general population appears to be for remdesivir and dexamethasone. Remdesivir shortened recovery time in a large randomized placebo-controlled trial, ACTT127; there may have been a survival benefit although this did not reach statistical significance.27 Dexamethasone was associated with lower mortality in patients requiring mechanical ventilation or supplemental oxygen, compared with a usual care arm, in a large, randomized, open-label trial (the RECOVERY trial).28 Convalescent plasma was administered on an expanded-access protocol to >35 000 patients; as there was no control group in this protocol, the investigators reported a mortality benefit in their analysis of higher antibody-titered plasma units, particularly for patients transfused within 3 days of diagnosis.29
Overview of Therapeutics in SOT: The Early Era
Laracy et al25 have recently comprehensively reviewed the evidence for antiviral therapies for COVID-19 in SOT recipients, and Fernandez-Ruiz and Aguado have reviewed the landscape of immunomodulatory therapies.26 Much of the evidence originally was from single-center or smaller case series, which made it difficult to make firm recommendations,19 but recently, larger multicenter registries20-22 have created a broader foundation, in the absence of randomized trials targeted to SOT recipients. Even so, most published observational studies in SOT recipients to date have reported mainly the therapies that predominated in the early months, given the time required for follow-up and publication of these studies; therefore, at this time, there is relatively less information on outcomes in SOT recipients treated with more recent therapies such as remdesivir, dexamethasone, and convalescent plasma.
Examples of early therapeutic patterns in SOT recipients include the Swiss Transplant Cohort Study, which published their early experience in May 2020 of 21 patients, of whom 1/3 received targeted therapies (primarily hydroxychloroquine and lopinavir/ritonavir).10 In the case series by Fernandez-Ruiz et al, lopinavir–ritonavir was used in 50%, hydroxychloroquine in 27.8%, and interferon-beta in 16.7%; case fatality rate was 27.8%.11 Higher CRP levels were associated with higher mortality, and tocilizumab was added for progressive respiratory failure. A case series from Saudi Arabia described 67 SOT recipients; 83% received hydroxychloroquine, 89% azithromycin, and 23% tocilizumab, with low mortality of 3%, but may have had a less severely ill population.12 In a case-control study of 41 SOT recipients compared with 121 nontransplant controls from the University of Michigan, treatment with hydroxychloroquine was associated with a 10-fold higher hazard of death in SOT recipients, although that may also have reflected treatment criteria.13 Pereira and colleagues reported on 90 patients from Columbia-Presbyterian in New York City at the height of the pandemic, in the early era: 91% received hydroxychloroquine, 66% azithromycin, 21% tocilizumab, 24% bolus steroids, and 3% received remdesivir. Mortality was 18% overall, 24% of hospitalized, and 52% of ICU patients.9
Three larger national multicenter registries have recently published data. The French SOT COVID Registry included 279 kidney transplant recipients (243 inpatients) diagnosed up through April 21, 2020, with severe COVID-19 disease in 46%, and a 30-day mortality of 22.8%.20 Targeted therapies included hydroxychloroquine (24.7%), azithromycin (29.2%), antiviral drugs (7.8%), and tocilizumab (5.3%); antivirals included oseltamivir, lopinavir–ritonavir, and remdesivir (only in 2 patients with severe disease).20 A large Spanish kidney transplant registry of 414 patients, in whom the predominant treatments were hydroxychloroquine (89%), azithromycin (50%), steroids (49%), lopinavir–ritonavir (34%), and tocilizumab (19%), reported an overall mortality of 26.3%, which rose to 36.3% in patients who had pneumonia without gastrointestinal symptoms.21 In the largest multicenter registry of SOT recipients to date, Kates et al from the University of Washington reported on 482 SOT recipients from >50 centers. Of these, 61% received hydroxychloroquine, 10% received steroids, 13% tocilizumab or sarilumab, and 3% remdesivir, with an overall mortality of 20.5%.22
In the more recent era, the use of hydroxychloroquine has declined, as its efficacy has been questioned in larger studies,30 and heightened concerns about safety have emerged, including the risk of QTc prolongation (especially when co-administered with drugs such as azithromycin). A randomized placebo-controlled trial of 800 healthcare workers did not show a benefit of hydroxychloroquine in preventing acquisition of COVID-19.31 Many centers now do not recommend the use of hydroxychloroquine except in the context of a clinical trial. Similarly, the use of lopinavir/ritonavir has waned after the publication of the study by Cao et al, which did not show benefit,32 in addition, the drug-drug interactions are problematic for SOT recipients.33
Immunomodulatory Agents Inhibiting IL-6, and Others
The agents that inhibit IL-6 or the IL-6 receptor deserve mention and extend through both eras of therapeutics, hence are discussed in their own section. In particular, tocilizumab has been widely used in patients progressing into the inflammatory phase, on analogy with its use in the treatment of chimeric antigen-receptor T-cell-associated cytokine release syndrome.34-40 In case series in both the general population and SOT recipients, tocilizumab was associated with rapid responses in some patients, both with respect to clinical symptoms and inflammatory markers.20,36,37,40 However, such therapy often has been reserved for those with greater severity of illness9,11 making effects more difficult to assess. Perez-Saez reported on 80 kidney transplant recipients with severe COVID-19 treated with tocilizumab; despite an overall mortality rate of 32.5%, those in whom CRP decreased had better survival.35 Somers et al reported on 154 mechanically ventilated patients with COVID (including 7 SOT recipients), of whom half received tocilizumab in nonrandomized fashion.40 In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR 0.55, 99% CI 0.33, 0.90).40 There were more secondary infections in patients who received tocilizumab (54% versus 26%) but this did not translate into increased mortality.40 In this study, tocilizumab was most commonly given early after intubation, which might be the key to the benefit observed. Although a recent news release indicating that a Phase 3 randomized trial of tocilizumab did not meet its endpoint in the general population, it is premature to conclude that this drug is not effective.41 Results summarized above still leave open the possibility that a subset of patients might benefit, and timing might be important.
Regarding other immunomodulatory therapies currently in clinical trials, a case report from Cedars-Sinai described a heart transplant recipient with hypoxemia and high inflammatory markers, who rapidly improved after receiving clazakizumab (a humanized IgG1 monoclonal antibody against IL-6) on compassionate use under investigational new drug (from the US FDA).42 Bruton tyrosine kinase inhibitors are inhibitors of the NLRP3 inflammasome and might mitigate the course of the inflammatory phase, as was observed in patients who were already taking this drug for Waldenstrom’s macroglobulinemia43 or received it in a pilot study for worsening COVID-19 pneumonia.44 Janus kinase inhibitors are also in clinical trials, and one was the subject of the ACTT2 trial (remdesivir versus remdesivir plus baracitinib, NCT04401579) for which results are awaited.
Overview of Therapeutics in SOT: The Later Era
In the later era, the antiviral agent remdesivir has played a major role, after the publication of studies including the randomized placebo-controlled ACTT1 trial which showed a statistically significantly shorter time to recovery.27 In the United States, remdesivir has been available either in clinical trials (including subsequent iterations of ACTT), or under an emergency use authorization (EUA) from the US Food and Drug Administration with a distribution system designed by the US government. The original EUA included criteria for remdesivir use: for treatment of patients hospitalized for COVID-19 who had severe disease, but as of August 28, 2020, the EUA has been expanded to include patients who do not have severe disease.45
To date, there have been relatively few published data on the safety and efficacy of remdesivir in SOT recipients. In terms of safety, transaminase elevation associated with remdesivir has been reported; it should not be used in patients with ALT >5 times the upper limit of normal, and should be discontinued if liver function abnormalities occur or worsen. Early on, there was a concern about the use of remdesivir in patients with altered renal function, which may have led to some transplant recipients not receiving it, as well as potentially excluding them from remdesivir clinical trials.46 This restriction based on renal function has now been questioned, in that remdesivir does not appear to have adverse effects on renal function in published trials.46 In addition, the cyclodextrin vehicle of this intravenous preparation is similar to that used in intravenous voriconazole, is present in low concentration, and would be unlikely to accumulate significantly in a 5-day to 10-day standard course of remdesivir.46 Therefore, although more information is needed, some centers have lifted estimated glomerular filtration rate restrictions on remdesivir. Considering its potential benefits, transplant clinicians are encouraged to confer with pharmacy specialists at their center, and to consider the possible use of remdesivir in patients with altered renal function, especially those with acute onset of kidney injury that is expected to resolve.46
Use of dexamethasone has not been widely reported in SOT recipients as yet, although some patients in observational studies did receive steroids at varying doses.9 The dose used in the RECOVERY trial,28 6 mg/d (typically for 10 d), is equivalent to 40 mg/d of prednisone and thus is substantially higher than maintenance prednisone in transplant recipients. Regardless of the treatments given, there is a risk of secondary bacterial and fungal infections after severe COVID.20,22,47 Nonetheless, dexamethasone is the only agent to have shown a clear mortality benefit in a large, well-designed, randomized trial in the general population, and therefore should be at least considered as a therapy for SOT recipients in the groups shown to benefit in the RECOVERY trial, namely those requiring supplemental oxygen or mechanical ventilation.28 To be sure, vigilance for secondary infections in the aftermath of dexamethasone will be important. Although not yet studied, it may be helpful to monitor tests such as the cytomegalovirus PCR and fungal biomarkers after dexamethasone in SOT recipients, to minimize the risk of later infectious complications.
Convalescent plasma has been administered in the US either through an expanded-access protocol,29 or in clinical trials. There are ongoing discussions about the interpretation and implications of the report of >35 000 patients who received convalescent plasma via expanded access, in terms of the reported association of benefit with higher antibody-titered plasma.29 Ongoing randomized trials in both inpatients and outpatients, as well as individuals exposed to COVID-19, are in progress. The use of convalescent plasma has been reported in retrospective studies of SOT recipients, including a case series of 13 patients from Mt Sinai in New York, 8 of whom had improved oxygenation by day 7 after treatment,48 and another case series of 3 patients, in whom there were no major safety concerns.49 Questions had arisen early on regarding whether or not some units of convalescent plasma might contain high titers of anti-HLA antibodies and whether that might have an adverse effect on alloimmunity in some SOT recipients,50 but the case series so far have not reported immunologic side effects.48,49
There are multiple other agents in development and in trials for the treatment of COVID-19, including monoclonal antibodies to major viral proteins, direct-acting antiviral agents, and novel or repurposed immunomodulatory agents, but since data are currently lacking in SOT recipients, these are beyond the scope of this review.
Management of Immunosuppression
Immunosuppression management is also a topic of interest. In the French SOT COVID Registry, certain immunosuppressive agents were frequently withdrawn: antimetabolites (70.8%), mammalian target of rapamycin (mTOR) inhibitors (62.1%), and less frequently calcineurin inhibitors (28.7% overall, and 52% in patients with severe disease).20 In a study from Barcelona comparing SOT recipients to nontransplant controls with COVID-19, mycophenolate mofetil (MMF) and mTOR inhibitors were generally held, while tacrolimus doses were decreased.33 In the University of Washington registry, the antimetabolite was held in 56% and reduced in 10%; <1% of patients had all immunosuppression held.22 Interestingly, the University of Washington registry did not find any association between the intensity of baseline immunosuppression and COVID-19 outcomes.22 The rationale for discontinuing or reducing the dose of MMF, which appears to be the most common immunosuppression modification across multiple studies, includes the utility of this intervention in controlling other viral infections (BK virus, cytomegalovirus) and also the association of a low absolute lymphocyte count with adverse outcomes of COVID-19.51 However, although there is as yet no consensus on the exact details, it is widely agreed that maintaining some degree of immunosuppression may provide protection vis-à-vis progression into the inflammatory phase and respiratory failure. Many transplant centers continue calcineurin inhibitors (although they may alter the target trough level) and maintain prednisone, although more recently after publication of the RECOVERY trial,28 substituting dexamethasone for prednisone has become an option in hypoxemic patients.
In our single-center experience (unpublished data), we have observed a 2.5% mortality in SOT recipients hospitalized with COVID-19 at Johns Hopkins, lower than in most published studies. While this may reflect a less severely ill group of patients, several interventions were implemented across both eras: MMF was held in nearly all patients; the majority also received vitamin D supplementation,51 and most received empiric antibiotics (usually a cephalosporin and doxycycline) for prevention or treatment of bacterial coinfections. Vitamin D supplementation has recently generated renewed interest, with emerging evidence that vitamin D deficiency is associated with worse outcomes in the general population with COVID-19.52 Although more data in SOT recipients would be welcome, vitamin D supplementation is a reasonable intervention to consider, after diagnosis of COVID-19 in SOT recipients, whether hospitalized.
The use of antimicrobials for prevention or treatment of secondary infections, as mentioned above, is another element of management that would benefit from more rigorous study. Empiric antibacterial therapy could lead to antimicrobial resistance, C. difficile – associated diarrhea, or other adverse effects. On the other hand, bacterial secondary infections are relatively common. The French SOT COVID registry identified bacterial coinfections in 23.5%,20 and the University of Washington registry by Kates et al identified types of pneumonia in 8% and bloodstream infections in 6% of hospitalized SOT recipients with COVID-19.22 Since some pulmonary infections in the ICU may not be microbiologically defined, the actual incidence is likely higher. Roberts et al found coinfections in 45% of ICU-admitted versus 5% of ICU nonadmitted SOT recipients with COVID.17 These risks may be affected by the administration of different targeted therapies. Whether outcomes could be improved by empiric antibacterial therapy before or concurrent with the onset of respiratory failure, cannot be determined from the available data, but it has been the practice at many centers to do so; better evidence is needed for how to balance benefits and risks of empiric antibacterial therapy.47
Longer-term follow-up of SOT recipients will be important. Much of the literature in the general population has focused on outcomes such as survival, hospital days, ICU days, and need for mechanical ventilation. Beyond those outcomes, in the SOT population, we will want to know more about: (1) allograft outcomes and immunologic parameters, including the incidence of acute cellular rejection, antibody-mediated rejection, and de novo donor-specific antibody in the aftermath of COVID, especially in patients who have had their immunosuppression reduced during the acute illness; (2) the incidence of late secondary infections, bacterial or fungal or viral, especially in patients who have received dexamethasone or immunomodulatory therapies; and (3) the incidence of long-term sequelae of COVID-19 in SOT recipients, including persistent gastrointestinal symptoms, undernutrition, fatigue, weakness, neurologic syndromes, heart failure, and others which could add to the already considerable burden of frailty in some patients.53
In summary, our knowledge regarding the treatment of COVID-19 in SOT recipients has expanded considerably since the early months of the pandemic; many single-center studies and some larger multicenter registries have added valuable information, yet there is still much to be learned. We need to know more about which SOT recipients benefit from particular therapies, the optimal timing of these therapies, and the balance of benefits and risks of particular therapies, such as late secondary infections. We would encourage clinical trials in the future to include SOT recipients. In parallel to trends in COVID-19 treatment in the general population, we have visualized the preceding months as 2 separate eras. We await longer-term follow-up of SOT recipients’ outcomes, especially those managed with therapeutic strategies of the more recent era.
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