Key words : Blood type, Flu vaccine, Renal transplantation, SARS-CoV-2

Introduction

Coronavirus disease 2019 (SARS-CoV-2 or COVID-19) is a public health emergency and a pandemic with concerns of international proportions. This illness has been spreading rapidly throughout the world, with nearly every country thus far documenting this infection. According to the World Health Organization, on March 11, 2020, COVID-19 was declared as a global pandemic. The disease is primarily transmitted person-to-person in hospitals and family settings, with the droplet route being the principal mode of spread, consequently causing pneumonia and acute respiratory distress syndrome. Although clinicians have observed many extrapulmonary manifestations of COVID-19,¹ preliminary evidence has suggested that the respiratory system is the first target organ for the virus, causing mild to severe disease and, in some cases, even death.^2-4 Furthermore, transmission can still occur during the incubation period and even from asymptomatic infected individuals.⁵

Presently, everyone in the community is at risk for COVID-19 and may become infected; however, the mortality rate is significantly higher for older people and those with underlying medical problems, such as cardiovascular diseases, diabetes, chronic respiratory diseases, hypertension, and cancer.^6,7 In addition to the respiratory system, COVID-19 disease can also affect the kidneys, with severe kidney damage occurring in 15% to 20% of patients. Therefore, patients with chronic kidney disease are vulnerable to infection and kidney damage. In studies from China, 44% and 26.9% of people who were infected with COVID-19 had proteinuria and hematuria, respectively, showing that kidney transplant recipients are also at a high risk.^8-10

Akdur and colleagues showed that kidney transplant can be performed with high success rates during the COVID-19 pandemic.¹¹ Clinical mani-festations of COVID-19 in transplant recipients are almost the same as fever, dry coughs, chest pains, chills, shortness of breath or difficulty breathing, and increased serum C-reactive protein levels. Patients can also have nonspecific symptoms of COVID-19, such as gastrointestinal symptoms (nausea, diarrhea), loss of taste or smell, and even skin symptoms.^3,12 A definitive diagnosis of COVID-19 is made by analyzing samples from airway aspirations or from sputum inductions. Laboratory tests to detect the virus involve the use of real-time polymerase chain reaction (RT-PCR) tests and partial or total sequencing of the viral genome.¹³

Kidney transplant recipients use immunosup-pressive drugs to prevent transplant rejection. As a result, they have weaker immune systems to fight off the virus. According to studies, people with diabetes mellitus, high blood pressure, and obesity (body mass index ?40 kg/m2) are at a higher risk of mortality.^14-16 Different drug protocols have been proposed for the treatment of these patients, and drug interactions can be a concern in their treatment. Likewise, another important concern is the risk of transplant rejection by the reduction in the dose of the immunosuppressive agents.

A general strategy for treatment of transplant recipients is to reduce the dose of immunosup-pressive agents and even discontinue some for a short time. However, this procedure can lead to kidney transplant rejection or increased creatinine levels and kidney failure.

In this study, our aim was to evaluate the risk factors for increased mortality in kidney transplant patients with COVID-19.

Materials and Methods

This single-center retrospective study was approved by the ethics committees of the Sina Organ Procurement Unit, Tehran University of Medical Sciences, Tehran, Iran (IR.TUMS.IKHC.REC.1399.359). The requirement to obtain informed consent for this retrospective study was waived. The study sample size included all kidney transplant patients who received kidneys from deceased donors and who had COVID-19. The researchers reviewed all 1079 kidney transplants from deceased donors at the Sina Organ Procurement Unit. All patients were asked to refer to this center if they observed symptoms such as shortness of breath, fever, cough, gastrointestinal symptoms, and other suspected symptoms associated with COVID-19 infection. We found that 153 kidney transplant recipients were referred to our center with suspicious symptoms of COVID-19. Chest computed tomography scans and RT-PCR tests were conducted for a definitive diagnosis of COVID-19 in patients with suspicious symptoms. In total, 138 kidney transplant recipients were COVID-19 positive.

Patient demographics, clinical and laboratory data, clinical course, and therapeutic and medical history information were obtained from a review of the medical records and patient interviews, which had been used to inquire on their situation. Clinical severity and assessment parameters were divided into 3 categories according to the severity of the disease: mild, moderate, and severe.¹⁷

In patients categorized as mild, symptoms included fever less than 38 °C, cough, without shortness of breath or hypoxia, headache, loss of taste and smell, nausea, vomiting and uncomplicated upper respiratory tract infections. In patients categorized as having moderate disease, patients demonstrated clinical features of pneumonia, including fever equal to or more than 38 ºC, cough, dyspnea, hypoxia with oxygen saturation <94% (range, 90%-94%) on room air, gastrointestinal and neurological symptoms (severe headache), and respiratory rates of 24 to 30 breaths/min. In patients categorized as having severe disease, patients had advanced signs of clinical pneumonia plus 1 of the following clinical criteria: respiratory rate >30 breaths/min, severe respiratory distress, tachypnea and shortness of breath, oxygen saturation <90%, and arterial partial pressure/fraction of inspired oxygen ?300.

Most patients referred to the hospital with suspicious symptoms of COVID-19 had one of the following symptoms: lymphopenia (lymphocyte count ? 1100 ?L), shortness of breath, oxygen saturation <93%, respiratory rate >30 breaths/min, and radiologic findings compatible with COVID-19.

Clinical management protocol
The clinical protocol at our center for kidney transplant recipients included lopinavir, ritonavir, and atazanavir (ritonavir was not used in the Sina Hospital transplant recipients because of inhibition of the cytochrome P450 enzyme). Regardless of age, mycophenolate and azathioprine were discontinued in patients. Prednisolone dose was increased, and calcineurin inhibitors were continued as before. Tacrolimus was continued at a trough level of 3 to
5 ng/mL and cyclosporine was continued at a level of 50 to 100 ng/mL. Other drugs used in their treatment include calcitriol, adult cotrimoxazole, atorvastatin, pantoprazole, and losartan.

For critically ill patients, all immunosuppressive drugs were discontinued and only steroids were continued. If less than 3 months had passed since the patient’s transplant, valganciclovir and cotrimoxazole were continued and, correspondingly, discontinued if white blood cell count decreased to 4000/mm³. If valganciclovir was discontinued, the PCR results for cytomegalovirus were checked weekly. At least 2 weeks after the onset of symptoms and with a negative swab test, patients could resume immunosup-pressive drugs (azathioprine and mycophenolate) as before. Patients would receive hydroxychloroquine at therapeutic doses. If the patient had severe illness, they would be given 2 medications (hydroxychloroquine and antibiotics).

Statistical analyses
We used SPSS software version 16 for the statistical analysis. Continuous variables are reported as means (±SD), and categorical variables are expressed as frequency (%). Variables were compared across outcome groups (death vs recovered). Normality assumptions were tested using the Shapiro-Wilk test. We used t test for comparison of continuous data. Logistic regression analysis was used to identify patient loss and the associated risk in terms of odds ratio and 95% confidence intervals. P < .05 was considered statistically significant.

Results

In this study, 138 deceased donor kidney transplant recipients who had transplant procedures at the Sina Hospital, Tehran, Iran, before the pandemic of COVID-19 and who had developed COVID-19 were included in this study.

Overall, the patients were predominantly male
(n = 83, 60.1%) with a median age of 47.09 ± 13.75 years and a median time since transplant of 51 months (IQR, 1-276 months). The mean time between transplant and COVID-19 diagnosis was 627 days. Among these patients, 84 (60.8%) had hypertension and 43 (31.2%) had diabetes mellitus.

Of 138 patients with COVID-19 diagnosis, 21 (15.2%) died from COVID-19. The mean age of the deceased patients was 55.33 ± 12.41 years, and the mean age of the recovered patients was 27.16 ± 4.9 years.

During the COVID-19 pandemic, diagnosis of disease was complicated by a diversity of symptoms and imaging findings, with variable severity of disease at the time of presentation. The most frequent initial clinical manifestation was fever (n = 94, 68.1%), followed by cough (n = 69, 50.0%), dyspnea (n = 50, 36.2%), myalgia (n = 42, 30.4%), and diarrhea (n = 32, 23.2%).

The most common cause of kidney failure in both the recovered and deceased patient groups was hypertension. In addition, the most common blood groups in the recovered and deceased patient groups were O and B, respectively. As shown in Table 1, age was significantly related to mortality from COVID-19 (P = .003). We also found significant differences between mortality and blood group type, presence of diabetes and hypertension, disease severity, and flu vaccination (Table 1).

Severe illness occurred in 34 of 138 patients (24.6%) after admission to the hospital, and 28 of 138 patients (20.3%) needed ventilation. The 64 patients who had received the flu vaccine within the past year had fully recovered from COVID-19 (P = .05).

After risk adjustment for age, we found that presence of diabetes and hypertension and blood group type were factors for significantly higher risk of death (Table 2).

Discussion

This retrospective study consisted of 138 deceased donor kidney transplant recipients seen at the Sina Hospital (Tehran, Iran) who had confirmed COVID-19. All patients who exhibited COVID-19-like symptoms were referred to our hospital for further examination of possibility of infection with COVID-19. After confirmation of the disease, patients were treated accordingly in our hospital.

In a study from Coates and colleagues on 7 patients infected with COVID-19, the authors suggested that home management of infected patients in the community could be successful without hospitalization.18 However, the treatment and progression of the disease in transplant recipients may be different from nontransplant patients in the community.¹⁸

People with heart disease, especially those with comorbidities (diabetes, hypertension), have a higher risk of mortality from COVID-19.^19-21 In patients with established diabetes, there is a high risk for patients to experience severe disease or increased in-hospital mortality associated with COVID-19.²² In their study, Wang and colleagues reported that, of the 138 patients with COVID-19, 46.4% had 1 or more coexisting medical conditions, including 31.2% with hypertension and 10.1% with diabetes.²⁰ Hypertension has been shown to be associated with a nearly 2.5-fold significant increase in the risk of severe COVID-19 infections.^23,24

We observed a relationship between COVID-19 susceptibility and ABO blood group type. In their recent study, Gerard and colleagues stated that people with the blood group A are more susceptible than others for infection with COVID-19. The reason for this was attributed to the presence of the anti-A antibody in the bloodstream, which probably prevents virus cell binding, thus generating a protective effect in the blood groups that have this antibody.²⁵ Li and colleagues reported that patients with anti-A antibody in their serum were significantly less represented in those with COVID-19 compared with those groups lacking anti-A antibody.²⁶

Cardiac complications are common in patients with infection, including COVID-19. It is estimated that approximately 3% of deaths from infection are due to cardiac arrest. Other risk factors for cardiac arrest include age, history of heart disease, and severity of infection.²⁷

One solution for transplant recipients is vaccination; our study revealed that the flu vaccine prevented or reduced the severity of the disease. In our study, 51.4% of our patients had been vaccinated against the flu in the past year, and there were no mortalities in these patients. Salem and colleagues²⁸ and Li and colleagues²⁹ also recommended the use of the flu vaccine, at least in part as a bystander adjuvant to minimize the severity of COVID-19 disease.

Because of the novel nature of this subject and the lack of research, there is still no comprehensive protocol developed for COVID-19-positive transplant recipients. The protocol for immunosuppressive drugs in transplant patients with COVID-19 should be changed depending on the age, duration since transplant, severity of COVID-19 disease, and presence of underlying disease.

In our study, 14 patients had received transplants less than 6 months before diagnosis of COVID-19; we found that the mortality rate was higher for patients with COVID-19 infections in the first 6 months posttransplant. Compared with the overall mortality rate in the United States of 1% to 5%30 and a mortality rate of 24% among COVID-19-positive patients,³¹ our mortality rate was 15.2% in kidney transplant recipients.

With regard to immunosuppressive agents, 17 patients with severe infections who were admitted to our hospital discontinued all immunosuppressive drugs and were given only 20 mg of prednisolone daily along with intravenous immunoglobulin (10-20 g daily). In a study by Banerjee and colleagues,¹² the group recommended that antiproliferative agents (mycophenolate mofetil and azathioprine) be discontinued during hospitalization, whereas prednisolone dose should be unchanged or increased and tacrolimus dose should be decreased.

Conclusions

COVID-19 has been shown to cause moderate or severe disease in kidney transplant recipients, possibly due to immunosuppressive therapy. At our institution, kidney transplant recipients with confirmed COVID-19 experienced less fever as an initial symptom. Moreover, COVID-19 patients with underlying disease were associated with higher mortality, severity of infection, and progression of disease. Overall, the appropriate management of renal complications in kidney transplant recipients and flu vaccinations may help lead to more favorable outcomes.

Of note, our sample size of kidney transplant patients who received the COVID-19 vaccine was small, and thus we could not assess the effect of vaccine in this group.

References:

1. Centers for Disease Control and Prevention. Prevent Getting Sick. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/
   CrossRef - PubMed
   
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5
   CrossRef - PubMed
   
3. Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA. 2020;323(14):1406-1407. doi:10.1001/jama.2020.2565
   CrossRef - PubMed
   
4. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513. doi:10.1016/S0140-6736(20)30211-7
   CrossRef - PubMed
   
5. Lipsitch M, Donnelly CA, Fraser C, et al. Potential biases in estimating absolute and relative case-fatality risks during outbreaks. PLoS Negl Trop Dis. 2015;9(7):e0003846. doi:10.1371/journal.pntd.0003846
   CrossRef - PubMed
   
6. Wang T, Du Z, Zhu F, et al. Comorbidities and multi-organ injuries in the treatment of COVID-19. Lancet. 2020;395(10228):e52. doi:10.1016/S0140-6736(20)30558-4
   CrossRef - PubMed
   
7. Haberal M. Covid-19 Update. Exp Clin Transplant. 2020;18(2):139-140. doi:10.6002/ect.2020.000e
   CrossRef - PubMed
   
8. Athari SZ, Mohajeri D, Nourazar MA, Doustar Y. Updates on coronavirus (COVID-19) and kidney. J Nephropathol. 2020;9(4):e34. doi:10.34172/jnp.2020.34
   CrossRef - PubMed
   
9. Li Z, Wu M, Yao J, et al. Caution on kidney dysfunctions of COVID-19 patients. medRxiv. 2020. doi:10.1101/2020.02.08.20021212
   CrossRef - PubMed
   
10. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829-838. doi:10.1016/j.kint.2020.03.005
    CrossRef - PubMed
    
11. Akdur A, Karakaya E, Ayvazoglu Soy EH, et al. Liver and kidney transplant during a 6-month period in the COVID-19 pandemic: a single-center experience. Exp Clin Transplant. 2020;18(5):564-571. doi:10.6002/ect.2020.0388
    CrossRef - PubMed
    
12. Banerjee D, Popoola J, Shah S, Ster IC, Quan V, Phanish M. COVID-19 infection in kidney transplant recipients. Kidney Int. 2020;97(6):1076-1082. doi:10.1016/j.kint.2020.03.018
    CrossRef - PubMed
    
13. Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal. 2020;10(2):102-108. doi:10.1016/j.jpha.2020.03.001
    CrossRef - PubMed
    
14. Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA. 2020;323(18):1775-1776. doi:10.1001/jama.2020.4683
    CrossRef - PubMed
    
15. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Centers for Disease Control and Prevention, US Department of Health and Human Services; 2020.
    CrossRef - PubMed
    
16. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3
    CrossRef - PubMed
    
17. Clinical Management Protocol. COVID-19. Accessed September 30, 2020. https://www.mohfw.gov.in/pdf/ClinicalManagementProtocolforCOVID19.pdf
    CrossRef - PubMed
    
18. Coates PT, Wong G, Drueke T, Rovin B, Ronco P; Associate Editors, for the Entire Editorial Team. Early experience with COVID-19 in kidney transplantation. Kidney Int. 2020;97(6):1074-1075. doi:10.1016/j.kint.2020.04.001
    CrossRef - PubMed
    
19. Dai X. ABO blood group predisposes to COVID-19 severity and cardiovascular diseases. Eur J Prev Cardiol. 2020;27(13):1436-1437. doi:10.1177/2047487320922370
    CrossRef - PubMed
    
20. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069. doi:10.1001/jama.2020.1585
    CrossRef - PubMed
    
21. Centers for Disease Control and Prevention. Estimates of diabetes and its burden in the United States. National Diabetes Statistics Report. Atlanta, GA: US Department of Health and Human Services; 2014.
    CrossRef - PubMed
    
22. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). Chin Med J (Engl). 2020;133(9):1087-1095. doi:10.1097/CM9.0000000000000819
    CrossRef - PubMed
    
23. Lippi G, Wong J, Henry BM. Hypertension and its severity or mortality in Coronavirus Disease 2019 (COVID-19): a pooled analysis. Pol Arch Intern Med. 2020;130(4):304-309. doi:10.20452/pamw.15272
    CrossRef - PubMed
    
24. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382(13):1199-1207. doi:10.1056/NEJMoa2001316
    CrossRef - PubMed
    
25. Gerard C, Maggipinto G, Minon JM. COVID-19 and ABO blood group: another viewpoint. Br J Haematol. 2020;190(2):e93-e94. doi:10.1111/bjh.16884
    CrossRef - PubMed
    
26. Li J, Wang X, Chen J, Cai Y, Deng A, Yang M. Association between ABO blood groups and risk of SARS-CoV-2 pneumonia. Br J Haematol. 2020;190(1):24-27. doi:10.1111/bjh.16797
    CrossRef - PubMed
    
27. Marrie TJ, Shariatzadeh MR. Community-acquired pneumonia requiring admission to an intensive care unit: a descriptive study. Medicine (Baltimore). 2007;86(2):103-111. doi:10.1097/MD.0b013e3180421c16
    CrossRef - PubMed
    
28. Salem ML, El-Hennawy D. The possible beneficial adjuvant effect of influenza vaccine to minimize the severity of COVID-19. Med Hypotheses. 2020;140:109752. doi:10.1016/j.mehy.2020.109752
    CrossRef - PubMed
    
29. Li Q, Tang B, Bragazzi NL, Xiao Y, Wu J. Modeling the impact of mass influenza vaccination and public health interventions on COVID-19 epidemics with limited detection capability. Math Biosci. 2020;325:108378. doi:10.1016/j.mbs.2020.108378
    CrossRef - PubMed
    
30. Akalin E, Azzi Y, Bartash R, et al. Covid-19 and kidney transplantation. N Engl J Med. 2020;382(25):2475-2477. doi:10.1056/NEJMc2011117
    CrossRef - PubMed
    
31. Elias M, Pievani D, Randoux C, et al. COVID-19 infection in kidney transplant recipients: disease incidence and clinical outcomes. J Am Soc Nephrol. 2020;31(10):2413-2423. doi:10.1681/ASN.2020050639
    CrossRef - PubMed