**4. Discussion**

In this retrospective case study of 59 LTRs with symptomatic SARS-CoV-2 infections, we noted a high overall mortality rate of 13%, an inpatient mortality of 24%, and a 75% mortality rate in those mechanically ventilated.

A higher FEV1 at baseline was found to be protective against hospitalization with an OR = 0.91 (95% CI 0.87–0.98, *p* = 0.02). The risk for severe COVID-19 and a high mortality rate in LTRs have been demonstrated in previous reports [25–28]. A study across 68 ICUs in different regions of the United States found a 28-day ICU mortality of 40% in severe COVID-19 cases in 98 SOTRs (including four LTRs) [26]. In a registry from the University of Washington of 1900 SOT cases, including over 150 LTRs with at least 28-days follow-up after SOT, the mortality rate was 15% regardless of the season (these data were collected from the spring to fall of 2020). Over a third of hospitalized patients required an ICU level of care [10]. In the largest single-center study to date that included 32 LTR patients with severe COVID-19, the reported overall mortality rate was 47% (with a 100% mortality rate in those requiring invasive mechanical ventilation) [1]. In a study of 11 LTRs hospitalized for COVID-19, the ICU admission rate was 45%, and the mortality rate was 71% in those requiring mechanical ventilation [5].

All deaths in our study occurred in hospitalized LTRs with severe or critical COVID-19. Of the eight patients that died, COVID-19 was the cause of death in seven of the patients, and one patient died from antibody-mediated rejection two months following the COVID-19 infection. Six of the eight patients on invasive mechanical ventilation died. No deaths were identified in non-hospitalized LTRs with mild or moderate COVID-19 symptoms. Although the immunosuppression in LTRs may play a role, the key determinants of severity and mortality in SARS-CoV-2-infected LTRs are advanced age and underlying comorbidities. The comorbidities frequently seen in LTRs are arterial hypertension, renal failure, and cardiovascular diseases, which are also risk factors for adverse outcomes in COVID-19 in the general population.

Although our mortality rate was consistent with previous reports, our cohort had a larger proportion of African Americans (27%) compared with that in other studies. Previous reports suggested that the African American population is more severely affected by COVID-19, which was attributed to a higher prevalence of underlying comorbidities, as well as social inequalities resulting in less access to the health care system, especially at the beginning of the pandemic [29]. Most COVID-19 cases and deaths occurred during the

period of Delta variant activity, and generally paralleled the patterns of COVID-19 reported in the state of Michigan.

Furthermore, our report highlighted the risk of vaccine-breakthrough infections (30/64, 46.8% of the described cases) and the risk of COVID-19-related hospitalization and death, even in LTRs with a series of two doses of a COVID-19 vaccine. The hospitalization and mortality rates in our 30 LTRs with vaccine-breakthrough infections were 40% (12/30) and 13% (4/30), respectively. In comparison, a recent study of breakthrough COVID-19 infections in 14 LTRs that received two doses of an mRNA vaccine reported an 85.7% hospitalization and a 0% mortality rate at 4 weeks [28]. The favorable outcomes reported in that study may be a consequence of a younger cohort of patients (median age: 54 years) and milder disease at the time of hospitalization, as only 50% of the patients had clinical features of lower respiratory tract infection. Moreover, breakthrough COVID-19 infections in our cohort occurred at a median of 123 days post-vaccination when the vaccine-induced immunity is expected to wane. COVID-19 vaccination is an important strategy in preventing severe disease, hospitalization, and death; however, immune responses to vaccination are impaired in LTRs [20]. Less than a quarter of LTRs developed protective levels of antibodies after two or three doses of mRNA vaccines in studies that measured IgG antibody titers against domains of the SARS-CoV-2 spike protein to assess the serological response [30–33]. Similarly, cell-mediated immune responses are suboptimal in LTRs [34]. Factors that affect poor immune responses in LTRs include the use of cell-cycle inhibitors, such as mycophenolic acid; old age; induction therapy; and a regimen combination of tacrolimus plus mycophenolic acid with/without steroids [35]. The type of vaccine and optimal number of COVID-19 mRNA vaccine doses still need to be determined [20]. Most guidelines currently recommend four doses of an mRNA vaccine for transplant recipients, as well as the vaccination of close contacts [36,37].

The limitations of this study included its retrospective design, single-center data, absence of the genotyping of variants, and lack of autopsies to support cause of death. However, the study had several strengths including the large number of LTRs with COVID-19 diagnosed during the early and late periods of the pandemic when more modalities of therapy became available. In addition, the study described one of the largest cohorts of LTRs with vaccine-breakthrough infections.
