PDF
Citation
Print
INTRODUCTION
Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone significant evolution, leading to the emergence of variants such as Alpha, Beta, Gamma, Delta, and Omicron. The Omicron variant was first identified in South Africa in November 2021 [1] and has since triggered renewed global outbreaks. This variant's genetic mutations have enabled it to evade immune responses more effectively and to spread more rapidly than previous strains [2]. Although the Omicron variant generally causes milder infections with lower rates of hospitalization, severe disease, and mortality than its predecessors [3], kidney transplant recipients (KTRs) remain particularly at risk. Due to their immunocompromised status and comorbidities, KTRs are more susceptible to COVID-19 progression, complications, and mortality compared to the general population [4,5].
In a meta-analysis conducted by Ho et al. [6] during the pre-Omicron era, the pooled rate of critical COVID-19 among KTRs was 27.7%, while the pooled mortality rate was 21.2%. Although the incidence of moderate to critical COVID-19 cases among KTRs seems to be lower in the Omicron era, it remains substantial. Among vaccinated KTRs during this period, the rates of pneumonia range from 6% to 16.2%, intensive care unit (ICU) admissions from 1.7% to 6.5%, and mortality from 0.9% to 3.3% [7–9]. From a broader perspective, healthcare costs increase with the severity of COVID-19. A health-economic evaluation by Uno et al. [10] in Japan demonstrated that patients with moderate COVID-19 incurred higher healthcare costs than those with mild disease, and costs increased further with severe or critical illness.
At our center, we have implemented a proactive approach to COVID-19 vaccination and treatment for our KTRs [11]. Our objective was to assess and document the incidence of moderate, severe, and/or critical COVID-19 infections during a period when the Omicron variant predominated in a well-vaccinated group of KTRs managed with this strategy. Additionally, we aimed to identify the factors associated with moderate to critical disease, in order to address modifiable risk factors and concentrate resources on the surveillance and management of individuals at higher risk.
METHODS
The study received approval from the SingHealth Centralized Institutional Review Board (CRIB 2019/2969). As this was an audit of clinical practices during the COVID-19 outbreak, and study participants were not subject to additional risks, the requirement for informed consent was waived.
Definitions
Definitions for mild, moderate, severe, and critical COVID-19 infection were standardized according to the consensus definitions published in the National Institutes of Health COVID-19 treatment guidelines [12]. A mild infection was characterized by symptomatic illness without dyspnea, or clinical or radiological signs of pneumonia or lower respiratory tract infection (LRTI). Moderate infection involved clinical or radiological evidence of pneumonia or LRTI, but without hypoxia. Severe illness was defined by an oxygen saturation of less than 94% on room air. Critical illness was identified as an infection complicated by respiratory failure, septic shock, or multiple organ dysfunction [12].
Study Design
This retrospective review analyzed the outcomes of COVID-19-infected KTRs at Singapore General Hospital, a tertiary hospital with an established transplant service, from January 1, 2022, to December 31, 2023.
COVID-19 Infection Triage and Management Workflow
At our center, KTRs diagnosed with COVID-19 through either Antigen Rapid Testing or polymerase chain reaction were instructed to notify their transplant coordinators. A specialized multidisciplinary team led by a renal transplant physician then evaluated and triaged the patient using teleconsultation and laboratory tests [11]. KTRs who had high-risk features for severe disease—such as being unvaccinated, less than 6 months posttransplant, or having recently undergone increased immunosuppression for rejection treatment within the past 3 months—or those exhibiting symptoms like clinical instability, hypoxia, breathlessness, or significant laboratory abnormalities, were recommended for hospitalization for further care [11]. Conversely, patients without high-risk features and who were clinically stable were managed on an outpatient basis. Factors such as the day of illness, vaccination status, serological response to COVID-19 vaccination, severity of illness, and the predominant circulating COVID-19 subvariant, guided the use of antivirals (remdesivir or molnupiravir) and/or monoclonal antibodies (tixagevimab/cilgavimab, casirivimab/imdevimab, or sotrovimab, if available and appropriate), with or without anti-inflammatory agents (dexamethasone, tocilizumab, or baricitinib). Treatment decisions were made at the physician's discretion and in line with prevailing national guidelines [13]. Stable KTRs without high-risk features who exhibited asymptomatic or mild disease received oral antiviral therapy, primarily molnupiravir, while those with high-risk features or moderate to critical disease were administered remdesivir [13].
At our center, we strongly recommend that all KTRs complete their primary vaccination against SARS-CoV-2, which includes receiving at least three doses of the vaccine. Additionally, they are encouraged to receive the updated vaccine booster within 1 year of their last dose, following national recommendations [14].
Study Population
All adult KTRs (≥18 years old) under follow-up at our center who were diagnosed with SARS-CoV-2 infection between January 1, 2022, and December 31, 2023, were included in the analysis. Since genetic sequencing was not routinely performed, it was not possible to precisely determine the exact SARS-CoV-2 subvariant. In Singapore, the first cases of the SARS-CoV-2 Omicron variant were detected on December 2, 2021. However, it was not until January 2022 that local community cases of Omicron infection began to surpass the number of imported cases [15]. Consequently, COVID-19 infections from January 2022 onwards were classified as occurring during the Omicron era.
Data Collection and Outcomes
Patient demographics, comorbidities, renal transplantation details, immunosuppression status, vaccination history, laboratory results, and outcomes of COVID-19 were extracted from electronic medical records. We analyzed the incidence and characteristics of KTRs with asymptomatic or mild COVID-19 and compared these to KTRs who developed moderate to critical disease. The primary objective was to identify factors associated with moderate to critical COVID-19 disease.
Statistical Analysis
Categorical variables were presented as frequencies or percentages. Continuous variables were assessed for normal distribution using the Shapiro-Wilk test and described with mean±standard deviation if normally distributed, or median (interquartile range [IQR]) if not. Categorical variables were compared using Pearson chi-square test or Fisher exact test. Continuous variables were compared using the Mann-Whitney U-test for nonnormally distributed data and the independent samples t-test for normally distributed data. Univariate logistic regression analysis was conducted to determine if the following factors were associated with increased odds of COVID-19 illness of at least moderate severity: age, sex, body mass index, presence of diabetes, presence of hypertension, white blood cell count, glomerular filtration rate (GFR), recently augmented immunosuppression for treatment of rejection within 3 months of the current COVID-19 infection, duration of symptoms prior to seeking care, and receipt of the last vaccine dose within 1 year prior to the current COVID-19 infection. Factors that showed statistical significance in the univariate logistic regression were subsequently included in a multivariate logistic regression model. Statistical significance was defined as a two-tailed P-value <0.05.
RESULTS
During the study period, 603 episodes of COVID-19 infections were diagnosed in 582 patients at our center. Of these, 554 cases (91.9%) were classified as asymptomatic or mild, while 49 cases (8.1%) were classified as moderate to critical infections. There were 44 cases (7.3%) of pneumonia, 20 patients (3.3%) required oxygen supplementation, and 4 patients (0.7%) needed ventilatory support. Overall, 331 KTRs (54.9%) were hospitalized, with a median hospitalization duration of 4 days (range, 3–6 days). Additionally, 54 KTRs (9.0%) experienced acute kidney injury, 2 (0.3%) required renal replacement therapy, 2 (0.3%) experienced graft loss, and there were 5 (0.8%) COVID-19-related deaths.
Baseline Characteristics
The baseline characteristics of the study population are shown in Table 1, analyzed per unique episode. The average age of the KTRs was 55.8±11.3 years, with 302 (50.1%) being male. The median GFR was 52 mL/min/1.73 m2 (IQR, 36–69 mL/min/1.73 m2), with patients exhibiting asymptomatic or mild COVID-19 showing significantly higher GFRs than those with moderate to critical illness (50 vs. 38 mL/min/1.73 m2, P<0.001). Hypertension was the most prevalent comorbidity (n=449, 74.5%), followed by diabetes mellitus (n=163, 27.0%), as shown in Supplementary Table 1. The median International Severe Acute Respiratory Infection Consortium 4C (ISARIC 4C) score was 5 (IQR, 3–7). Patients with asymptomatic or mild infections had a lower median ISARIC 4C score compared to those with at least moderate severity (5 [IQR, 3–6] vs. 7 [IQR, 4–10]; P<0.001). KTRs typically presented within a median of 2 days (IQR, 2–3 days) from the onset of symptoms, with no significant differences noted between the two groups. Additionally, there were no significant differences in immunosuppression regimens or in the presence of recent augmented immunosuppression for rejection treatment within the 3 months preceding COVID-19 infection.
Our study population was predominantly vaccinated, with 94.4% of KTRs having completed their primary vaccination series (Table 1). A greater percentage of KTRs with asymptomatic or mild infection had completed their primary vaccination series compared to those with at least moderate disease (94.9% vs. 87.8%, P=0.049). The average time between the last vaccine dose and the onset of COVID-19 was 226.8±191.4 days; this interval was significantly shorter for those with asymptomatic or mild infection compared to those with at least moderate disease (221.0±185.7 vs. 293.6±240.0 days, P=0.046). Additionally, 476 (78.9%) of KTRs had received their last vaccine dose within the year preceding their current infection, with a higher proportion observed in the asymptomatic or mild infection group compared to those with moderate to critical disease (80.9% vs. 65.3%, P=0.010). Among the 471 KTRs (78.1%) with measured levels of SARS-CoV-2 spike receptor binding domain (RBD), median RBD levels were significantly higher in the group with asymptomatic or mild COVID-19 compared to those with moderate to critical disease (808 vs. 84 AU/mL, P=0.003).
Furthermore, 73.6% of KTRs received COVID-19 therapeutics (Table 1). A smaller percentage of the group with asymptomatic or mild infections received therapeutics compared to those with at least moderate disease (71.5% and 98.0%, respectively, P<0.001). Supplementary analysis comparing characteristics between KTRs who received therapeutics and those who did not revealed that the former group had a lower median RBD level (158 vs. 3,135 AU/ml, P<0.001), a higher median ISARIC 4C score (5 [IQR, 3–7] vs. 4 [IQR, 2–6], P<0.001), and a smaller proportion who had received their last vaccine dose within 1 year prior to the current infection (73.9% vs. 95.0%, P<0.001) (Supplementary Table 2). The differences in therapeutic use between groups reflected our center’s treatment practices: 19.3% of asymptomatic/mild cases received molnupiravir compared to 2.0% of moderate to critical cases (P=0.003). Additionally, 40.6% of asymptomatic/mild cases received remdesivir versus 93.9% of moderate to critical cases (P<0.001). Given the low incidence of severe or critical COVID-19, the use of dexamethasone was minimal (2.8%), and very few patients required baricitinib and tocilizumab (0.7% and 0.0%, respectively).
Factors Associated with Moderate to Critical COVID-19 Illness
The results of univariate and multivariate logistic regression analyses examining factors associated with moderate to critical COVID-19 infection are presented in Table 2. Univariate analysis indicated that increased age and a longer duration of symptoms before seeking medical care were linked to higher odds of developing moderate to critical disease. Conversely, a higher GFR and having received a vaccine booster within the past year were protective factors. Multivariate analysis confirmed that these factors continued to be significantly associated with increased odds of moderate to critical COVID-19 infection. Specifically, increased age was associated with higher odds of moderate to critical disease (adjusted odds ratio [aOR], 1.037; 95% confidence interval [CI], 1.006–1.069), as was a longer duration of symptoms before seeking care (aOR, 1.288; 95% CI, 1.155–1.436). Conversely, a higher GFR (aOR, 0.971; 95% CI, 0.956–0.986) and receipt of a vaccine booster within the past year (aOR, 0.414; 95% CI, 0.212–0.809) were associated with decreased odds of developing moderate to critical COVID-19 disease.
DISCUSSION
In this study, we present real-life data on the incidence and factors associated with moderate, severe, and critical COVID-19 illness among a well-vaccinated cohort of KTRs during the period dominated by the Omicron variant of SARS-CoV-2. Our findings indicate that increased age, reduced GFR, prolonged symptom duration before seeking medical attention, and having received the last vaccine dose more than a year prior to the current infection significantly correlate with COVID-19 illness of at least moderate severity. To our knowledge, this study is among the largest real-world analyses of COVID-19 outcomes and risk factors for moderate to critical disease in well-vaccinated KTRs during the Omicron era. [7–9,16,17].
Our findings indicate that advanced age and lower GFR are associated with moderate to critical COVID-19 infection in KTRs, aligning with results from other studies. An observational study by Li et al. [16] at a Beijing center found that increased age and higher creatinine levels were linked to pneumonia in KTRs infected with COVID-19 during the Omicron wave. Similarly, Zahradka et al. [18] reported that advanced age and lower GFR were associated with 30-day mortality among a cohort of KTRs at a Czech center. Recognizing these nonmodifiable risk factors can help in better prioritizing resources for the close monitoring and treatment of higher-risk individuals, such as older KTRs or those with reduced GFR.
It is well-established that vaccination against COVID-19 provides protection against moderate to critical infections [19], particularly as the number of vaccine doses received increases [20]. In our cohort with a high baseline vaccination rate—94.4% of KTRs had completed their primary three-dose series—we observed that those who received their most recent vaccine dose within the past year had lower odds of experiencing moderate to critical COVID-19. This finding highlights the importance of keeping vaccinations current, including booster doses.
Prior vaccination may not provide adequate neutralization against Omicron variants, as evidenced by Moal et al. [21], who observed that sera from vaccinated KTRs exhibited poor neutralizing activity against Omicron BA.1, BA.2, BA.4, and BA.5 variants in live-virus assays. Waning immunity following the completion of the primary vaccination series is also well-documented among the general population [22], and this effect is likely more pronounced in immunocompromised individuals such as KTRs, who generally have weaker vaccine responses than healthy adults [23]. These findings collectively underscore the importance of booster doses, although the optimal frequency for KTRs remains uncertain. Figueroa et al. [24] demonstrated that a fourth dose of the mRNA-1273 vaccine, administered at least 4 months after the primary three-dose series, enhanced neutralizing antibody responses in solid organ transplant recipients (SOTRs) [24]. A matched cohort study by Naylor et al. [25] in Canada, which compared 3,120 SOTRs who received a third vaccine dose with 3,120 matched SOTRs who received a fourth dose, found that the fourth dose was associated with a lower incidence of COVID-19-related hospitalization and mortality during the Omicron era. In this study, the median time between the third and fourth doses was 125 days (IQR, 111–136 days) [25]. While these studies support a 4-month interval between COVID-19 booster doses and the previous dose, such a frequent schedule may not be practical or acceptable for all recipients. In Singapore, the current national recommendation advises that immunocompromised individuals receive their boosters no later than 1 year from their last dose [14]. Our data, which show that a vaccine dose received within the past year reduces the risk of moderate to severe COVID-19 in KTRs, reinforce our national recommendation and suggest its potential applicability to other institutions.
Lastly, we found that a longer symptom duration before seeking care was significantly associated with increased odds of moderate to critical COVID-19 infection. This observation aligns with a study by Zahradka et al. [18], which analyzed 955 COVID-19 cases among KTRs at a Czech transplant center. The study found that delayed referral to the transplant center was independently associated with a 2.08-fold increase in the odds of 30-day mortality (aOR, 2.08; 95% CI, 1.08–3.98). We hypothesized that earlier access to medical care could lead to prompt treatment and improved outcomes. Supporting this, research by Sakaguchi et al. [26] and Alonso-Navarro et al. [27] demonstrated that a shorter time to the initiation of antiviral therapy was associated with lower rates of severe disease [26] and reduced ICU admissions [27]. Furthermore, earlier medical intervention may also decrease mortality rates. A study by Alaa et al. [28], which examined 6,068 patients from the COVID-19 Hospitalization in England Surveillance System registry, found that a longer interval between the onset of symptoms and hospitalization was significantly associated with increased all-cause mortality. The authors suggested that this could be due to the delayed correction of physiological derangements and hypoxia [28].
Our results have important implications. The COVID-19 response has transitioned from a pandemic to an endemic phase both globally and in Singapore [14]. This shift has led to the relaxation of stringent COVID-19 control measures at a national level, including the lifting of mandatory universal masking and isolation precautions, and a reduction in government subsidies for COVID-19 testing and treatment [14]. Additionally, vaccine fatigue has reportedly become widespread [29], and Singapore is no exception to this trend [30]. Our study's findings urge caution against a nonchalant attitude toward COVID-19, particularly among immunocompromised individuals such as KTRs, even during this period of endemicity with the Omicron variant predominating. Our results emphasize the importance for KTRs to stay current with their annual COVID-19 booster doses, even after completing their initial vaccination series. They should also seek prompt assessment and treatment if they contract COVID-19.
A significant strength of this study is its real-world setting with a large, highly vaccinated KTR cohort. However, the study has several limitations. Our cohort was drawn from a single center, and practices were influenced by local institutional protocols and national policies, which may not be generalizable. We acknowledge the possibility of selection bias, as patients who were asymptomatic or mildly symptomatic may not have sought medical care and would not be included in our data. Another limitation is the absence of data on human leukocyte antigen mismatch among the KTRs. Additionally, we lacked data on the timing of previous COVID-19 infections in KTRs, if any, and it is possible that some KTRs did not receive vaccination boosters but had developed natural immunity from prior infections. Lastly, our study’s retrospective observational design prevented us from establishing causal relationships. Further prospective studies in KTRs are needed to evaluate interventions that may help reduce the risk of moderate to critical COVID-19 disease, such as determining the optimal frequency of booster vaccines.
In a cohort of KTRs with high baseline vaccination rates who contracted the Omicron variant of SARS-CoV-2, several factors were identified as significant in the progression to moderate or critical COVID-19. These factors include increased age, reduced GFR, prolonged symptom duration before seeking medical attention, and having received the last vaccine dose more than a year prior. It is advisable for KTRs to seek medical care promptly for assessment and treatment if they contract COVID-19. Additionally, they should ensure that their COVID-19 vaccine boosters are current, ideally within one year of their last dose. While our findings and recommendations are specific to KTRs, these principles may also be relevant to other immunocompromised groups, such as solid organ and bone marrow transplant recipients. Further research in these cohorts may be warranted.
XML Download