COVID-19 is caused by a novel coronavirus (SARS-CoV-2) that induces respiratory and systemic diseases. The new coronavirus pneumonia epidemic is still spreading, causing great harm to the health and lives of people worldwide, and posing great challenges to global public health. Omicron, as the main epidemic variant, is very difficult to prevent and control because of its faster transmission speed, short incubation period, potential for immune escape, and general susceptibility. Simultaneously, the toxicity of Omicron is notably reduced compared to that of previous strain types, and the severe disease and fatality rates were correspondingly reduced. Currently, most people infected with Omicron show moderate or asymptomatic disease and do not need special treatment before recovering in approximately 7–14 days. However, the elderly, patients with chronic underlying diseases (e.g., hypertension, diabetes, CKD, cancer chemotherapy, and autoimmune diseases), patients who have undergone organ transplantation, and patients who take immunosuppressants have a higher rate of severe disease and mortality, representing a considerable challenge for the effective treatment of patients.
From December 20, 2022, to January 31, 2023, 92 patients with pneumonia caused by Omicron infection after renal transplantation were treated at our organ transplantation center. The patients included 51 men and 41 women, including 30 men and 15 women with severe disease and eight deaths (three women and five men). The rates of severe cases and mortality were higher in men than in women. Epidemiological studies have shown that the rate of severe illness and mortality in men with COVID-19 infection is significantly higher than that in women, indicating that sex is an important factor affecting the prognosis of SARS-CoV-2 infection (4). Yuan et al.(5) showed that male hamsters exhibit more severe physiological features and pathological changes in the lungs after infection than female hamsters. Later, the same group demonstrated that progesterone had an important protective effect against severe COVID-19 infection in female hamsters and could effectively reduce the pathogenicity of SARS-CoV-2 in male hamsters (5).
In the current study, among the 44 cases of renal transplantation with hypertension, 30 cases were severe, accounting for 68.2%, indicating that hypertension is closely related to the rate of severe disease (Table 1). Studies have shown that SARS-CoV-2 infects human cells via binding a “spike” protein on its surface to angiotensin-converting enzyme 2 (ACE2) within the host (6). ACE2 is a key regulator of the renin–angiotensin–aldosterone system (RAAS). SARS-CoV-2 disrupts the ACE/ACE2 balance and RAAS activation, which ultimately leads to COVID-19 progression, especially in patients with comorbidities, such as hypertension, diabetes mellitus, and cardiovascular disease (7).
To further demonstrate the correlation between key factors, the Spearman method was used to detect the correlation with clinical presentation, outcomes, hypertension comorbidity, and diabetes comorbidity. The result demonstrated that in renal transplant patients, hypertension comorbidity was highly correlated with clinical presentation (R = 0.369, P < 0.001) (Tables 1 and 5). This correlation between hypertension and clinical symptoms was verified using logistic regression models with added covariables (Table 6). Male sex and hypertension comorbidity are pivotal factors to estimate the severe risk of Omicron infection in renal transplant recipients. Furthermore, clinical features such as fever, cough, expectoration, olfactory changes, and taste changes contribute to the evaluation of the risk of severe disease of Omicron infection in renal transplant recipients (Table 1).
Among the 11 cases of renal transplantation complicated with diabetes mellitus, seven cases were severe (63.6%) (Tables 1 and 3). Regarding the outcomes, diabetes comorbidity also represented a weak correlation with outcomes (R = 0.243, P = 0.020), highlighting the importance of diabetes comorbidity in renal transplant patients with COVID-19 (Table 5). In addition, the evident correlation between clinical presentation and outcomes (R = 0.315, P = 0.002) demonstrated that severe status triggers worse outcomes or death events. Increasing evidence points to a potential interaction between diabetes and COVID-19. Diabetes has been described as a risk factor for severe COVID-19 infection, with an increased risk of death. It is plausible that COVID-19 creates a perturbation in the glycometabolic complex system, with resulting hyperglycemia and insulin resistance, which not only complicates the pathophysiology of pre-existing diabetes but may also lead to new-onset diabetes (8). Because of the difficulty in controlling blood glucose, patients with diabetes have obvious insulin resistance after using hormone therapy, with effective blood sugar control often being difficult with insulin doses that are two to three times higher than usual. Additionally, hyperglycemia further increases the difficulty in controlling lung infection. The most recent molecular evidence suggests that insulin resistance, rather than SARS-CoV-2-provoked beta-cell impairment, plays a major role in the observed rapid metabolic deterioration in diabetes or new-onset hyperglycemia during the COVID-19 clinical course (9). In renal transplant recipients infected with Omicron, the outcome is critical, and the statistical analysis of outcomes demonstrated that diabetic comorbidity was a major factor associated with Omicron infection in renal transplant recipients.
The levels of neutrophil, CPR, PCT, and IL-6 were significantly higher in severe patients than mild patients, while the expression of CD3 and CD8 in severe patients was lower (Tables 2 and 4). Importantly, patients with chronic oral immunosuppression, low immunity, and the depletion of T lymphocytes caused by COVID-19 exhibit further decreases in immune cells; the former increases the susceptibility and severity of renal transplant recipients, while the latter leads to higher severity and mortality in renal transplant recipients. Moreover, studies have shown that SARS-CoV-2 can activate and mature proinflammatory cytokines in the body. Cytokine markers are a group of polypeptide signaling molecules that can induce and regulate many cellular biological processes by stimulating surface cell receptors. SARS-CoV-2 is associated with the activation of innate immunity, increasing neutrophils, mononuclear phagocytes, and natural killer cells, as well as decreasing CD4+ and CD8+ T cells (10). Coronaviruses are capable of eliciting the release of larger quantities of IL-6 from human epithelial cells. IL-6 inhibits Th1 cell-dependent antiviral responses and impairs the functions of CD8+ cytotoxic and natural killer T cells. Indeed, IL-6 overexpression seems to be associated with low numbers of CD4+ and CD8+ T lymphocytes (11). Renal transplant recipients have lower immune competence to protect against foreign viruses because of their long-term use of immunosuppressant drugs. Therefore, indicators relating to host immunity and renal function were detected to better understand the severe disease observed after Omicron infection in renal transplant recipients. Severe disease cases have a weak immune response and weak renal function because of lower levels of CD3 and CD4 and higher UREA levels, although increasing numbers of neutrophils and CRP levels were found in patients with severe disease following Omicron infection.
In the cohort study, the D-dimer level was significantly elevated in severe patients and those with a deteriorating outcome (Table 2), suggesting that it can be used as an important prognostic indicator. The D-dimer mean values increased significantly in deceased COVID-19 and hospitalized ICU patients, indicating a potential predictive and prognostic severity marker, particularly among COVID-19 patients in the ICU (12). D-dimer reflects the activation of coagulation and fibrinolysis in patients infected with COVID-19. Patients with COVID-19 have a hypercoagulable state and are prone to cardiovascular and cerebrovascular complications. Indeed, we highlight the case of a patient with severe infection who presented with myocardial damage and massive cerebral infarction during the perioperative period, which resulted in hemiplegia, and ultimately, death by respiratory failure (Fig. 1). The D-dimer level is higher in critically ill patients, which is closely related to prognosis. In the clinic, the hypercoagulable state can be improved by anticoagulant therapy with low molecular weight heparin.
It seems that none of the critical novel indices detected by us were involved in the Omicron outcome, while the UREA level was not significantly different between the two disease groups, although increased CRE had been demonstrated and is expected in adverse outcome patients. Therefore, renal function may have a weak association with Omicron outcome, although further data are needed to support this theory. CKD of different degrees is common in renal transplantation patients, and acute kidney injury (AKI) is common in renal transplantation patients after infection. Moreover, COVID-19-induced AKI may lead to tubular, endothelial, and glomerular injury (13). It is closely related to the severe rate and prognosis of renal transplant patients with new coronary infections. In this general vs. severe comparative study cohort, the serum creatinine level was 109 (85–145.5) µmol/L for the general type, 8.3 (6.09–13.48) mmol/L for urea nitrogen, and 141(103–202) µmol/L,11.1 (8.615–19.08) mmol/L for the severe type. Both the levels of serum creatinine and urea nitrogen were higher in the severe group than in the common group, but only UREA showed a significant difference (Table 2). In the cohort analysis of renal function and prognosis, the elevation of serum creatinine and blood urea nitrogen predicted a poor prognosis. Patients with CKD have an increased risk of critical SARS-CoV-2 infection and AKI development. CKD is associated with more adverse clinical outcomes, more severe disease, higher mortality, and poorer prognosis among patients with COVID-19 (14).
Early treatment of Omicron infection in renal transplant recipients is essential, particularly the timely downregulation of immunosuppressants after infection, early antiviral treatment, prevention of inflammatory factor storm, correction of the hypercoagulable state, and the control of blood glucose. Because of long-term oral administration of immunosuppressants such as CNI, MMF, and Pred, the immunity of renal transplant recipients is relatively low, and the early symptoms may be delayed. Simultaneously, infection with Omicron further damages lymphocytes, leading to the release of a large number of cytokines. Importantly, the virus may have invaded the lungs by the time fever, cough, and other symptoms are obvious. We conclude that early use of antiviral drugs and substantial reduction in immunosuppressants are critical to reducing hospitalization in renal transplant recipients (Table 3). After the patient missed the best opportunity for outpatient treatment leading to pulmonary infection, our protocol was to decisively stop the use of immunosuppressants, treat with corticosteroids alone, and simultaneously give human blood gamma globulin to modulate the immune therapy, treatment such as oral antiviral drug and anticoagulation, whereas the choice of antiviral drug regimen itself is not superior or inferior. Treatment with receptor antagonists, such as IL-6, is important to dampen inflammatory storms in patients with recurrent fever and progressive lung infections, with experience suggesting that early use further reduces the critical illness rate. Eight patients in this study died of respiratory failure, all of whom were treated with IL-6 during the receptor antagonist phase of the disease but ultimately failed to change the outcome, presumably missing the best opportunity.