DOI: https://doi.org/10.21203/rs.3.rs-2847736/v1
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron is a major coronavirus variant, which was prevalent in China at the end of 2022 and caused widespread infection. As a low-immune group, renal transplant recipients with SARS-CoV-2 infection are prone to developing serious pneumonia or an adverse outcome event if the infection is not treated in time. Here, we analyze the possible risk factors of infection severity.
Methods: Ninety-two cases of moderate and severe SARS-CoV-2 infection after renal transplantation were collected. Statistical methods, including Fisher’s tests, F test, Spearman relative values, and multi-parameter logistic regression models, were used to analyze the risk factors for severe SARS-CoV-2 infection in renal transplant recipients.
Results: Forty-four cases complicated with hypertension wereobserved in the study cohort, among whom 30 were severe (OR: 4.63, P < 0.001). Meanwhile, 30 male patients presented with severe SARS-CoV-2 (OR: 2.45, P = 0.039) out of 51 male patients infected with Omicron. In renal transplant patients, hypertension comorbidity was closely correlated with clinical presentation (R = 0.369, P < 0.001). Interestingly, we found an increased risk of death in renal transplant patients with diabetes (OR: 5.53, P = 0.052), albeit with no significance. Blood routine test, chemistries, and additional indices showed increased neutrophils and C-reactive protein in patients with severe disease compared with themoderate group according to one-way analysis of variance (P = 0.004), while CD3 (P = 0.02) and CD4 (P = 0.04) showed lower expressional levels.Moreover, there was an evident correlation between clinical presentation and outcomes (R = 0.315, P = 0.002), which indicated that a severe status triggers worse outcomes or death events. We also observed meaningful correlations between neutrophil levels and hypertension comorbidity (R = 0.222, P = 0.034) and between interleukin-6 (IL-6) levels and diabetes comorbidity (R = 0.315, P = 0.011), with IL-6 considered a key factor in the context of coronavirus disease. Finally, urea nitrogen (P = 0.03) levels were significantly higher in patients with severe disease than in those with moderate disease, while serum creatinine (P = 0.06) levels showed no significant differences between patients with severe and moderate disease.
Conclusions: Renal transplant recipients were generally susceptible to infection with the Omicron variant, with a more pronounced incidence of severe illness observed in men than in women. Hypertension in renal transplant recipients may increase the rate of severe disease, and diabetes mellitus may further increase mortality.
Since the outbreak of coronavirus disease (COVID-19) in 2019, the virus has spread widely worldwide, with the emergence of several variants, among which Omicron was the main variant circulating in China at the end of 2022 and caused widespread infection. Omicron has the characteristics of rapid transmission, short incubation period, immune escape, general susceptibility of the population, and virulence reduction (1, 2). Most people infected with Omicron have moderate or asymptomatic disease and only require symptomatic treatment. However, in the elderly, people with chronic underlying diseases, and the immunocompromised population, pneumonia or other serious conditions may develop, requiring hospitalization and effective health measures to be taken.
Studies have shown that kidney transplant recipients have a higher mortality rate and are 10 to 15 times more likely to be hospitalized due to Omicron infection than the general population, despite often receiving double or triple doses of the vaccine. Omicron infection in kidney transplant recipients is not necessarily moderate, and hospitalization rates remain high at approximately 56% (3). Most renal transplant recipients only show symptoms of upper respiratory tract infection, such as fever and cough, which can be cured by reducing immunosuppressants and symptomatic treatment. However, in some recipients, immunosuppressants are not reduced in time after infection, or the recipients also have hypertension, diabetes, or chronic kidney disease (CKD), which can result in pneumonia and further hospitalization.
As we do not have statistics on all kidney transplant recipients at our center, the incidence of pneumonia-related hospital admissions is approximately 5–8% based on outpatient follow-up and hospital admission. Here, we describe the clinical presentation, treatment options, risk factors, and outcomes of Omicron variant infections in hospitalized kidney transplant recipients.
Kidney transplant recipients with Omicron pneumonia who were hospitalized in the Department of Organ Transplantation at Renmin Hospital of Wuhan University from December 20, 2022, to January 31, 2023, were followed-up. The hospitalized patients were renal transplant recipients whose home or outpatient treatment was ineffective, and whose pneumonia had progressed to the point of hospitalization. The clinical diagnosis mainly depended on throat swab nucleic acid and lung CT for classification into moderate and severe types (including critical type). The main clinical symptoms, underlying diseases, respiratory support, test results, therapeutic schemes, immunotherapy, and clinical outcomes were collected. Ninety-two cases were hospitalized, comprising 51 men and 41 women, with an average age of 47.5 years. Forty-seven cases were moderate, 45 were severe, and eight died.
Blood counts (neutrophil (NEU), hemoglobin (HGB), lymphocyte (LYM), and platelet (PLT) counts); blood chemistry (serum creatine (CRE), urea nitrogen (UREA), albumin (ALB), creatine kinase (CK), and lactate dehydrogenase (LDH)); B-type natriuretic peptide (BNP); levels of procalcitonin (PCT), cardiac troponin-1 (CTN), C-reactive protein (CRP), interleukin-6 (IL-6), D-dimer, and immune cell subsets (CD3, CD4, and CD8); lung computed tomography (CT) results; and electrocardiogram (ECG) results were used to evaluate the general condition of the patients. Arterial blood gas analysis was conducted if considered necessary.
Oxygen support was given according to the patient’s subjective symptoms, pulse oxygen saturation, and degree of pulmonary infection. Critical patients were transferred to the intensive care unit (ICU) for intubation support. The patients were not strictly grouped according to the treatment plan after admission. First, mycophenolate mofetil (MMF) was stopped, and the dose of calcineurin inhibitor (CNI) was reduced by 1/3 to 1/2. Most patients stopped MMF and CNI and were treated with corticosteroids only. The patients without fever were treated with methylprednisolone 40 mg QD intravenously, while those with fever were treated with methylprednisolone 40 mg BID or Dexamethasone 5 mg BID for anti-inflammation, as well as human immunoglobulin 5 g QD * 5–10 D intravenously. Patients with severe disease were treated with Paxlovid 150/100 mg or 150/200 mg * 5 D, oral Azevudine 5 mg QD * 7–14 D, or oral Barretini 4 mg QD * 7 D. The IL-6 receptor antagonist Tocilizumab 162 mg * 2 was given subcutaneously to patients with recurrent fever or rapid progression of pneumonia.
Independent Fisher’s test was used to analyze the demographics, clinical presentation, and hemodynamic outcomes. Independent one-way analysis of variance (F test) was used to analyze initial hemodynamic and laboratory values, and hemodynamic outcomes of laboratory values. Spearman relative values for renal transplant cohort with COVID-19. The association between hypertension and clinical symptoms was investigated using multi-parameter logistic regression models with added covariables including sex, age, transplant time, fever, cough, diarrhea, and olfactory and taste changes.
Omicron is more likely to progress to severe disease in renal transplant recipients with hypertension, with greater risk observed in men than in women
The results of demographic analysis and statistical Fisher’s test showed that 30 cases of 45 male renal transplant recipients presented severe disease as Omicron infection (OR: 2.45, P = 0.039), demonstrating that men infected with Omicron had a higher risk of severe disease than women. Meanwhile, among all patients, 44 cases were complicated with hypertension, among whom 30 had severe disease following infection with Omicron (OR: 4.63, P < 0.001), demonstrating that hypertension is associated with an increased risk of severe disease. Additionally, clinical presentations such as fever, cough, expectoration, olfactory changes, and taste changes were more commonly observed in the patients with severe disease, indicating that patients infected with Omicron with severe disease showed increased severity of clinical features.
| All | Moderate disease | Severe disease | OR (95%CI) | P-value | |||
|---|---|---|---|---|---|---|---|
| Sex | Male | 51 | 21 | 30 | 2.45 (0.98–6.3) | 0.039* | |
| Female | 41 | 26 | 15 | – | – | ||
| Age (years) | ≥ 60 | 9 | 4 | 5 | 1.34 (0.27–7.25) | 0.737 | |
| < 60 | 83 | 43 | 40 | – | – | ||
| Vaccination | Vaccinated | 11 | 2 | 9 | 4.27 (0.79–43.92) | 0.096 | |
| Unvaccinated | 59 | 29 | 30 | – | – | ||
| Smoking | Smoker | 1 | 0 | 1 | 0 (0–37.34) | 0.489 | |
| Non-Smoker | 91 | 47 | 44 | – | – | ||
| Years from transplant to diagnosis | Within 1 year | 17 | 9 | 8 | – | 0.909 | |
| 1 ~ 3 years | 2 | 1 | 1 | – | – | ||
| 3–5 years | 33 | 17 | 16 | – | – | ||
| 5–10 years | 19 | 8 | 11 | – | – | ||
| > 10 years | 19 | 11 | 8 | – | – | ||
| Comorbidities (Disease–free) | HTN | 44 (48) | 14 (33) | 30 (15) | 4.63 (1.8–12.52) | 0.001** | |
| DM | 11 (81) | 4 (43) | 7 (38) | 1.97 (0.46–9.89) | 0.349 | ||
| Presenting Symptoms (Symptoms–free) | Fever | 82 (10) | 38 (9) | 44 (1) | 10.21 (1.31–465.83) | 0.015* | |
| Cough | 74 (16) | 34 (13) | 40 (3) | 5.01 (1.23–29.7) | 0.013* | ||
| Expectoration | 64 (25) | 28 (19) | 36 (6) | 4.01 (1.32–13.96) | 0.009** | ||
| Diarrhea | 17 (69) | 8 (39) | 9 (30) | 1.46 (0.44–4.92) | 0.589 | ||
| Olfactory changes | 13 (73) | 3 (44) | 10 (29) | 4.96 (1.15–30.45) | 0.017* | ||
| Taste changes | 12 (74) | 1 (46) | 11 (28) | 17.55 (2.33–791.02) | 0.001** | ||
| * P-value < 0.05; **P-value < 0.01. HTN: Hypertension; DM: Diabetes mellitus | |||||||
Neutrophil count, Urea, and D-dimer were significantly higher in severe patients than in moderate patients, but lower levels of CD3 and CD8 were found in severe patients
The results of blood routine test, chemistries, and additional indices showed significant increases in neutrophils and CRP in patients with severe disease compared with those with moderate disease (one-way analysis of variance, P = 0.004) but lower expression of CD3 (P = 0.02) and CD4 (P = 0.04). Next, CRE and UREA indicators were monitored to establish the influence of renal function after Omicron infection. UREA (P = 0.03) was found at significantly higher levels in severe patients than in moderate patients, while CRE (P = 0.06) showed no significant differences. D-dimer (P < 0.01), as a critical indicator for health state, has also been used to evaluate the severity of Omicron infection, which contributes to subsequent clinical statuses and outcomes.
| All | Moderate disease | Severe disease | P-value | |
|---|---|---|---|---|
| Blood count, median (IQR) | ||||
| WBC × 1000/µL | 4.42 (4.33–4.51) | 4.07 (3.115–6.055) | 4.59 (3.05–6.25) | 0.63 |
| Neutrophil count/µL | 3.725 (3.19–4.26) | 3.42 (2.105–4.5) | 4.2 (2.71–9.18) | 0.004** |
| Platelets × 1000/µL | 162.5 (161.02–163.98) | 163 (126.5–211.5) | 154 (124–206) | 0.763 |
| Lymphocyte count/mL | 0.5 (0.49–0.51) | 0.57 (0.375–0.745) | 0.43 (0.25–0.73) | 0.091 |
| Hgb, g/dL | 119 (116.7–121.3) | 119 (110.2–126.8) | 118 (99–131) | 0.36 |
| Chemistries median (IQR) | ||||
| CRE, µmol/L | 120 (117.45–122.55) | 109 (85–145.5) | 141 (103–202) | 0.064 |
| UREA, mmol/L | 10.465 (10.33–10.6) | 8.3 (6.09–13.48) | 11.1 (8.615–19.08) | 0.033** |
| CK, U/L | 33 (30.87–35.13) | 32 (0.51–59.5) | 36 (0.72–57.25) | 0.605 |
| CTN, ng/mL | 0.022 (–0.152–0.196) | 0.013 (0.006–0.026) | 0.070 (0.012–0.140) | 0.289 |
| ALB, g/L | 36 (35.89–36.11) | 36.35 (34.7–39.15) | 36 (33.9–37.8) | 0.168 |
| LDH, U/L | 245 (240.33–249.67) | 220 (201.5–279.5) | 267 (210.2–308.2) | 0.251 |
| Additional labs, median (IQR) | ||||
| CD3, n/µL | 278 (271.54–284.46) | 307 (220–453) | 185.5 (99.5–289.2) | 0.020* |
| CD4, n/µL | 105 (100.62–109.38) | 117.5 (74–225.2) | 59.5 (36.01–127) | 0.030* |
| CD8, n/µL | 131 (127.91–134.09) | 165 (110–214.5) | 97 (44.25–160.5) | 0.061 |
| CRP, mg/L | 23.48 (22.61–24.35) | 20.925 (4.73–33.33) | 25.84 (19.41–49.88) | 0.009 |
| PCT, ng/mL | 0.108 (0.04–0.18) | 0.074 (0.056–0.1383) | 0.171 (0.09–0.42) | 0.129 |
| D-dimer, mg/L | 1.59 (1.394–1.786) | 1.04 (0.76–1.74) | 4.05 (1.46–7.89) | 0.001** |
| IL-6, pg/mL | 7.01 (5.77–8.25) | 5.785 (4.593–14.905) | 12.39 (6.665–17.975) | 0.773 |
| BNPs, pg/mL | 422.5 (241.06–603.94) | 394 (172–728.5) | 517 (170–1422) | 0.779 |
| *P-value < 0.05; **P-value < 0.01. PCT: Procalcitonin, CRP: C-reactive protein, and CTN: Cardiac troponin-1 | ||||
Demographic analysis and statistical Fisher’s test were employed to further investigate the key factors affecting the outcome of Omicron infection in renal transplant recipients. As a result, drug use was considered a major factor for the outcome of Omicron infection. Patients infected with Omicron with severe disease had adverse outcomes after therapeutic interventions with Paxlovid, Tocilizumab, and Baricitinib. However, the selective use of drugs according to the patient’s current health status leads to evaluations of the influence ofdrugs on outcomes in renal transplant recipients being meaningless. Interestingly, we found that there were high risks of death or severe infection in patients with diabetes (OR: 5.53, P = 0.052) with a renal transplant, although these results are not significant; this is because one patient in our study died from abnormal hyperglycemia and because a correlation value of 0.222 (P < 0.05) was shown between diabetes comorbidity and outcome, although the significance level was not constant. Notably, severe infection status had a higher risk of inducing adverse outcomes.
| All | Better | Worse or death | OR (95%CI) | P-value | ||
|---|---|---|---|---|---|---|
| Sex | Male | 51 | 46 | 5 | 1.37 (0.25–9.4) | 0.728 |
| Female | 41 | 38 | 3 | – | – | |
| Age | ≥ 60 | 9 | 8 | 1 | 1.35 (0.03–13.08) | 0.576 |
| < 60 | 83 | 76 | 7 | – | – | |
| Vaccination | Vaccinated | 11 | 10 | 1 | 0.75 (0.02–6.96) | 1.000 |
| Unvaccinated | 59 | 52 | 7 | – | – | |
| Smoking | Smoker | 1 | 1 | 0 | – | 1.000 |
| Non-smoker | 91 | 83 | 8 | |||
| Years from transplant to diagnosis | Within 1 year | 17 | 15 | 2 | – | 0.506 |
| 1–3 years | 2 | 2 | 0 | |||
| 3–5 years | 33 | 32 | 1 | |||
| 5–10 years | 19 | 16 | 3 | |||
| > 10 years | 19 | 17 | 2 | |||
| Comorbidities (disease–free number) | HTN | 44 (48) | 40 (44) | 4 (4) | 1.1 (0.19–6.32) | 1.000 |
| DM | 11 (81) | 8 (76) | 3 (5) | 5.53 (0.73–35.34) | 0.052 # | |
| Presenting symptoms (symptom–free number) | Fever | 82 (10) | 75 (9) | 7 (1) | 0.84 (0.09–42.01) | 1.000 |
| Cough | 74 (16) | 67 (15) | 7 (1) | 1.56 (0.18–75.25) | 1.000 | |
| Expectoration | 64 (25) | 57 (24) | 7 (1) | 2.92 (0.34–138.2) | 0.433 | |
| Diarrhea | 17 (69) | 15 (65) | 2 (4) | 2.14 (0.18–16.64) | 0.339 | |
| Olfactory changes | 13 (73) | 11 (69) | 2 (4) | 3.08 (0.25–24.67) | 0.223 | |
| Taste changes | 12 (74) | 12 (68) | 0 (6) | 0 (0–5.49) | 0.589 | |
| Respiratory support | ECMO | 1 | 0 | 1 | – | < 0.001 *** |
| Nasal tube | 19 | 19 | 0 | – | – | |
| Low-flow intake | 35 | 35 | 0 | – | – | |
| High-flow uptake | 4 | 3 | 1 | – | – | |
| High-flow + mask | 2 | 1 | 1 | – | – | |
| Mask | 10 | 9 | 1 | – | – | |
| Tracheal intubation | 4 | 0 | 4 | – | – | |
| No use equipment | 17 | 17 | 0 | – | – | |
| Drug use | Methylprednisolone/Dexamethasone | 88 (4) | 80 (4) | 8 (0) | – | 1.000 |
| Paxlovid | 13 (79) | 7 (77) | 6 (2) | 30.37 (4.45–359.63) | < 0.001* | |
| Azvudine | 65 (27) | 59 (25) | 6 (2) | 1.27 (0.21–13.69) | 1.000 | |
| Tocilizumab | 15 (77) | 10 (74) | 5 (3) | 11.77 (1.96–87.66) | 0.003** | |
| Baricitinib | 28 (64) | 22 (62) | 6 (2) | 8.22 (1.35–89.3) | 0.009** | |
| Clinical presentation | Severe disease | 45 (47) | 37 (47) | 8 (8) | – | 0.002** |
*P-value < 0.05; **P-value < 0.01; and #P-value close to significance.
Similarly, the relationship between outcomes and markers of immune inflammation or renal function can be calculated to determine novel factors accounting for valid medical intervention. As expected, the results of the blood routine test and additional laboratory analysis demonstrated that healthy state indicators such as CRE, CRP, PCT, and D-dimer were predictably higher in patients with worse or death outcomes. However, the UREA level showed no significant difference between patients with better and worse outcomes, while no other key factors were found to be related to the outcomes of Omicron infection.
| All | Better | Worse or death | P-value | |
|---|---|---|---|---|
| Blood count, median (IQR) | ||||
| WBC × 1000/µL | 4.42 (4.33–4.51) | 4.47 (3.132–6.175) | 4.24 (2.925–5.503) | 0.491 |
| Neutrophil count/µL | 3.725 (3.19–4.26) | 3.75 (2.14–7.735) | 3.05 (2.342–4.492) | 0.269 |
| Platelets × 1000/µL | 162.5 (161.02–163.98) | 164 (126.8–212) | 148.5 (122.2–163.5) | 0.385 |
| Lymphocyte count/mL | 0.5 (0.49–0.51) | 0.51 (0.3325–0.75) | 0.41 (0.365–0.5725) | 0.557 |
| Hgb, g/dL | 119 (116.7–121.3) | 119 (105–128.5) | 110 (88.75–134.25) | 0.689 |
| Chemistry median (IQR) | ||||
| CRE, µmol/L | 120 (117.45–122.55) | 119 (88–159.2) | 244.5 (114.5–396.8) | 0.019* |
| UREA, mmol/L | 10.465 (10.33–10.6) | 10.06 (7.02–13.76) | 15.6 (10.99–19.34) | 0.123 |
| CK, U/L | 33 (30.87–35.13) | 34 (0.475–61.75) | 0.96 (0.77–42.00) | 0.28 |
| CTN, ng/L | 0.022 (− 0.152–0.196) | 0.017 (0.006–0.063) | 0.1825 (0.1197–0.6515) | 0.897 |
| ALB, g/L | 36 (35.89–36.11) | 36 (34.25–38.85) | 37.45 (36.08–39.35) | 0.361 |
| LDH, U/L | 245 (240.33–249.67) | 253 (207–301) | 175.5 (155.8–195.2) | 0.146 |
| Additional labs, median (IQR) | ||||
| CD3, n/µL | 278 (271.54–284.46) | 286 (179–418) | 121.5 (103.8–149) | 0.073 |
| CD4, n/µL | 105 (100.62–109.38) | 109.5 (43.25–219) | 57 (54.25–58.75) | 0.164 |
| CD8, n/µL | 131 (127.91–134.09) | 146.5 (79–213.8) | 66.5 (45.75–93.75) | 0.090 |
| CRP, mg/L | 23.48 (22.61–24.35) | 22.75 (13.35–35.71) | 35.52 (22.9–61.59) | 0.016* |
| PCT, ng/mL | 0.108 (0.04–0.18) | 0.102 (0.064–0.2605) | 0.346 (0.1087–1.6233) | 0.031* |
| D-dimer, mg/L | 1.59 (1.394–1.786) | 1.46 (0.945–2.438) | 10.75 (6.6–15.62) | < 0.001** |
| IL-6, pg/mL | 7.01 (5.77–8.25) | 6.945 (4.812–17.582) | 17.89 (7.12–40.31) | 0.127 |
| BNPs, pg/mL | 422.5 (241.06–603.94) | 386 (167.8–941.4) | 714 (488.5–959) | 0.994 |
*P-value < 0.05; **P-value < 0.01.
Spearman correlation analysis demonstrated that hypertension comorbidity is associated with the occurrence of severe disease, while diabetes mellitus comorbidity is related to the outcomes of Omicron infection
To further demonstrate the correlation between key factors, Spearman correlation was used to distinguish the relationships among clinical presentation, outcomes, hypertension comorbidity, and diabetes comorbidity. The results were consistent with the above hypothesis that in renal transplant patients, hypertension comorbidity is closely correlated with clinical presentation (R = 0.369, P < 0.001). Meanwhile, diabetes mellitus presented a significant correlation with outcomes (R = 0.243, P = 0.020), suggesting its importance in renal transplant patients after Omicron infection. Moreover, immune makers such as CRP, IL-6, CD4, CD8, and NEU showed an obvious correlation with clinical presentation or outcome, as did indicators such as D-dimer, PCT, and CTN in healthy state or renal function. Interestingly, we observed meaningful correlations between NEU and hypertension comorbidity (R = 0.222, P = 0.034) and between IL-6 and diabetes comorbidity (R = 0.315, P = 0.011), which is particularly relevant given that IL-6 is a key factor in COVID-19. In addition, the evident correlation between clinical presentation and outcomes (R = 0.315, P = 0.002) indicated that severe disease is associated with worse outcomes or death events. Moreover, D-dimer and CTN showed a significant correlation with outcomes, except for diabetes comorbidity.
| Clinical presentation | Outcome | Hypertension comorbidity | Diabetes comorbidity | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Factor | R | P-value | Factor | R | P-value | Factor | R | P-value | Factor | R | P-value |
| D-dimer | 0.533 | < 0.001 | D-dimer | 0.514 | < 0.001 | CP | 0.369 | < 0.001 | IL-6 | 0.315 | 0.011 |
| PCT | 0.347 | 0.002 | CTN | 0.441 | 0.004 | NEU | 0.222 | 0.034 | CD4 | 0.272 | 0.042 |
| CTN | 0.342 | 0.029 | CP | 0.315 | 0.002 | UREA | 0.161 | 0.129 | O | 0.243 | 0.020 |
| O | 0.315 | 0.002 | PCT | 0.192 | 0.090 | WBC | 0.138 | 0.189 | PLT | 0.226 | 0.030 |
| CRP | 0.289 | 0.019 | CRP | 0.180 | 0.148 | CTN | 0.137 | 0.392 | CD3 | 0.185 | 0.168 |
| CRE | 0.274 | 0.008 | IL-6 | 0.177 | 0.158 | CK | 0.135 | 0.413 | CRP | 0.170 | 0.171 |
| IL-6 | 0.271 | 0.029 | CRE | 0.173 | 0.099 | DM | 0.117 | 0.268 | CTN | 0.165 | 0.303 |
| NEU | 0.222 | 0.033 | UREA | 0.171 | 0.108 | D-dimer | 0.115 | 0.411 | LYM | 0.138 | 0.191 |
| UREA | 0.222 | 0.035 | BNP | 0.149 | 0.234 | PLT | 0.106 | 0.316 | ALB | 0.121 | 0.252 |
| LDH | 0.183 | 0.293 | ALB | 0.113 | 0.286 | IL-6 | 0.068 | 0.588 | HTN | 0.117 | 0.268 |
| BNP | 0.120 | 0.336 | HGB | –0.037 | 0.728 | CRE | 0.062 | 0.558 | CD8 | 0.114 | 0.405 |
| WBC | 0.047 | 0.656 | LYM | –0.049 | 0.640 | BNP | 0.050 | 0.689 | CP | 0.109 | 0.303 |
| CK | 0.034 | 0.836 | WBC | –0.051 | 0.630 | HGB | 0.046 | 0.662 | PCT | 0.058 | 0.609 |
| PLT | 0.016 | 0.880 | NEU | –0.082 | 0.437 | LDH | 0.037 | 0.832 | CRE | 0.035 | 0.738 |
| HGB | 0.004 | 0.972 | PLT | –0.082 | 0.437 | O | 0.013 | 0.899 | BNP | –0.007 | 0.956 |
| ALB | –0.135 | 0.202 | CK | –0.085 | 0.605 | PCT | –0.011 | 0.922 | CK | –0.010 | 0.954 |
| LYM | –0.169 | 0.108 | CD4 | –0.187 | 0.169 | ALB | –0.059 | 0.576 | D-dimer | –0.011 | 0.938 |
| CD8 | –0.289 | 0.031 | CD8 | –0.227 | 0.092 | LYM | –0.063 | 0.553 | WBC | –0.085 | 0.423 |
| CD4 | –0.330 | 0.013 | CD3 | –0.259 | 0.052 | CD4 | –0.068 | 0.618 | HGB | –0.099 | 0.348 |
| CD3 | –0.356 | 0.007 | LDH | –0.287 | 0.095 | CD3 | –0.073 | 0.587 | UREA | –0.140 | 0.190 |
| CD8 | –0.106 | 0.437 | NEU | –0.160 | 0.127 | ||||||
| CRP | –0.163 | 0.192 | LDH | –0.235 | 0.175 | ||||||
Results were calculated using the Spearman method. CP: Clinical presentation; O: Outcome.
Logit model further confirmed that hypertension is a risk factor for progression to severe infection with Omicron in renal transplant recipients with the inclusion of covariables
To exclude random events, the logistic regression model was executed to verify the relationship between hypertension comorbidity of renal transplant patients and clinical presentation after Omicron infection. Related important indicators were included in the model to acquire OR values and re-estimate the risk of severe disease after Omicron infection. The results demonstrated that the renal transplant cohort with hypertension comorbidities showed a greater risk of severe disease after Omicron infection.
| Classes | OR (95%CI) | P-value |
|---|---|---|
| Sex male | 2.41 (1.09–5.33) | 0.27 |
| Age ≥ 60 | 2.19 (0.46–10.39) | 0.62 |
| Vaccine | 6.58 (1.69–25.53) | 0.16 |
| Hypertension | 7.73 (3.45–17.32) | 0.01* |
| Diabetes | 4.19 (1.27–13.85) | 0.23 |
| Transplant time ≥ 10 years | 1.59 (0.56–4.53) | 0.66 |
| Transplant time 3–5 years | 1.64 (0.58–4.65) | 0.64 |
| Transplant time 1–3 years | 1.14 (0.42–3.07) | 0.90 |
| Fever | 3.47 (0.73–16.44) | 0.42 |
| Cough | 4.55 (1.8–11.49) | 0.10 |
| Diarrhea | 0.21 (0.07–0.64) | 0.16 |
| Olfactory Changes | 0.6 (0.13–2.78) | 0.74 |
| Taste Changes | 109.46 (7.82–1532.37) | 0.08 |
*P-value < 0.05.
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.
During the epidemic of the novel Omicron coronavirus variant, renal transplant recipients were found to be generally susceptible, with no significant sex difference. However, there was a more pronounced incidence of severe illness observed in men than in women, and diabetes mellitus may further increase mortality. Importantly, inflammatory factors such as cellular immune subpopulation, D-dimer, PCT, and IL-6 can be used as important references for the judgment of disease progress and prognosis. The early treatment of new coronary infections in renal transplant recipients is critical, especially the timely downregulation of immunosuppressants and the use of antiviral drugs.
Acknowledgments
We would like to thank Chen Yinglian for his assistance. We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.
Author contributions
ZC designed this study; ZC and TW collected all patient data; and ZC analyzed the data and wrote the manuscript. All of the authors read and approved the final version of the manuscript.
Funding
None.
Availability of data and materials
The raw data that support the findings of this report are available from Renmin Hospital of Wuhan University.
Ethics approval and consent to participate
This study was approved by the ethics committee of Renmin Hospital of Wuhan University (WDRY2022-K181). We confirmed that all methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects and/or their legal guardian(s) along with ethics approval statement.
All procedures were performed according to the guidelines of the Chinese transplant ethics.
Consent for publication
Written informed consent was obtained from the patient and patients for publication of this article and any accompanying images.
Competing interests
The authors declare that they have no competing interest to report regarding the present study.