|Year : 2020 | Volume
| Issue : 4 | Page : 275-282
The impact of comorbidities on clinical course and outcome, in kidney transplant recipients with COVID-19: A systematic review and analysis
Amit Bansal1, Anant Kumar1, Richa Mittal Bansal2, Ruchir Maheshwari1, Samit Chaturvedi1
1 Department of Urology, Renal Transplant and Robotics, Max Super Specialty Hospital, New Delhi, India
2 Department of Pediatrics, Safdarjung Hospital, New Delhi, India
|Date of Submission||12-Jul-2020|
|Date of Acceptance||22-Aug-2020|
|Date of Web Publication||30-Dec-2020|
Dr. Amit Bansal
Department of Urology, Renal Transplant and Robotics, Max Super Specialty Hospital, 1, 2, Press Enclave Marg, Saket Institutional Area, Saket, New Delhi - 110 017
Source of Support: None, Conflict of Interest: None
Background: The literature on the impact of comorbidities on the severity and outcome of COVID-19 in kidney transplant patients is limited. We aimed to review the same. Methods: We conducted this review as per Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. PUBMED, Embase, Scopus, and Science Direct were searched for studies, available online till May 31, 2020. Studies reporting comorbidities, clinical course, and outcome of each kidney transplant patient with COVID-19 were included. Studies on any other organ transplant, recommendations, or review articles were excluded. The impact of comorbidities on severity and outcome was assessed. The study appraisal was done using Joanna Briggs Institute Critical Appraisal Checklist. Continuous variables were compared using Mann–Whitney U-test. Categorical variables were compared using Fisher's exact test. A univariate and multivariate logistic regression for predictors of severity and outcome, was done. P < 0.05 was considered statistically significant. The study protocol was registered with PROSPERO (CRD42020190114). Results: We analyzed 19 studies (56 patients) out of the 355 identified. The most common comorbidity was hypertension (83.92%). Nearly 30.35% of the patients had severe clinical course. The mortality rate was 19.64%. Advanced age was statistically significantly associated with severe course (P = 0.0173) and death (P = 0.0005). Men were more likely to have nonsevere course (P < 0.0001). No comorbidity had any impact on the severity or outcome. Patients with severe disease had higher odds of dying (P = 0.002). Conclusions: Comorbidities were not found to have any significant impact, hence the contribution of immunosuppression toward the severity of COVID-19 needs to be studied. Ours is the first review to assess the impact of comorbidities in kidney transplant patients with COVID-19 but limited by the number of patients.
Keywords: Comorbidity, COVID-19, kidney transplant
|How to cite this article:|
Bansal A, Kumar A, Bansal RM, Maheshwari R, Chaturvedi S. The impact of comorbidities on clinical course and outcome, in kidney transplant recipients with COVID-19: A systematic review and analysis. Indian J Transplant 2020;14:275-82
|How to cite this URL:|
Bansal A, Kumar A, Bansal RM, Maheshwari R, Chaturvedi S. The impact of comorbidities on clinical course and outcome, in kidney transplant recipients with COVID-19: A systematic review and analysis. Indian J Transplant [serial online] 2020 [cited 2021 Mar 4];14:275-82. Available from: https://www.ijtonline.in/text.asp?2020/14/4/275/305437
| Introduction|| |
COVID-19 was first reported in Wuhan, Hubei province, China, in December 2019. Since then, it has spread worldwide and has become a pandemic. We have reams of literature describing various facets of this virulent virus in the general population.,, Mortality in general population is reported around 9.7%, and 29.5% patients need intensive care. Preexisting hypertension (HT) and pulmonary and cardiovascular comorbidities have been associated with a severe clinical course.
Kidney transplant recipients usually have multiple comorbidities, in addition to immunosuppression. This might influence the severity and outcome of a COVID-19 infection. Hence, the question next arises, whether we can extrapolate the results of the general population, to this particular subgroup. In the absence of a large-scale study or a systematic review, we cannot do so. The available reviews only discuss the management of immunosuppression, or the impact of immunosuppression, in these patients. Hence this study was carried out.
The objective of this review was to study the impact of comorbidities on clinical course and outcome, in kidney transplant recipients with COVID-19 infection.
| Methods|| |
A systematic review of the literature on COVID-19 and kidney transplantation was carried out. The following databases were searched for published studies available from their inception, till May 31, 2020: PubMed, Embase, Science Direct, and Scopus. We used the following keywords and MESH terms: COVID-19 and kidney transplant.
(((((((”covid 19”[All Fields] OR “covid 2019”[All Fields]) OR “severe acute respiratory syndrome coronavirus 2”[Supplementary Concept]) OR “severe acute respiratory syndrome coronavirus 2”[All Fields]) OR “2019 ncov”[All Fields]) OR “sars cov 2”[All Fields]) OR “2019ncov”[All Fields]) OR ((”wuhan”[All Fields] AND (”coronavirus”[MeSH Terms] OR “coronavirus”[All Fields])) AND (2019/12/1:2019/12/31[Date-Publication] OR 2020/1/1:2020/12/31[Date-Publication]))) AND ((((”kidney transplantation”[MeSH Terms] OR (”kidney”[All Fields] AND “transplantation”[All Fields])) OR “kidney transplantation”[All Fields]) OR (”kidney”[All Fields] AND “transplant”[All Fields])) OR “kidney transplant”[All Fields])
This systematic review was registered in the international database of prospectively registered systematic reviews (PROSPERO, registration number = CRD42020190114). The review protocol can be accessed online via the PROSPERO website (https://www.crd.york.ac.uk/prospero/#myprospero). The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist was adhered to when preparing this manuscript.,, The review methodology followed the recommendations published by PRISMA.,,
- Good-quality studies in any language, reporting the clinical course, comorbidities, and outcome of each kidney transplant patient with COVID-19.
- Studies giving general recommendations
- Review articles (to avoid overlap of patient population)
- Studies reporting the clinical course and outcomes of the patients as a group
- Studies reporting outcomes of COVID-19 in any transplant patient, other than kidney transplant.
Study data extraction
Three authors (AB, RMB, and SC) independently performed full-text review to extract relevant data using a predefined template from the studies included in final review. Data were then cross-checked for consistency and in case of discrepancy, data were rechecked, and help of another author (AK) was sought when required. Data pertaining to the following variables were extracted: age, time since transplantation, symptoms at the time of presentation, comorbidities, severity of clinical course during admission, and clinical outcome (recovered/discharged, dead or still admitted). Patients were then classified based on severity (nonsevere vs. severe) and based on outcome (dead vs. not dead [recovered/discharged/still admitted]). Severe clinical course was defined as need for intensive care unit (ICU) stay and/or mechanical ventilation. It may be noted that values such as hemoglobin level, serum creatinine, glomerular filtration rate, serum albumin, and other lab parameters, of each patient, were not uniformly available in the included studies. These were often represented as summary statistics of the group, and hence could not be analyzed in this review. In the absence of a standardized treatment protocol, authors in the included studies have followed varied indigenous treatment protocols. There was extensive heterogeneity noted in the treatment regimens and myriad number of drugs were used in a nonstandardized manner. Thus, the impact of these treatment protocols could not be studied in the current small sample size, and hence not included in this review.
Two authors (AB and RM) independently assessed the studies for possible bias using the Joanna Briggs Institute Critical Appraisal Checklist for case reports and case series (last amended in 2017). In case of any discrepancy, help of another author (AK) was sought. All included studies were found to be of good quality. However, it is pertinent to remember that all included studies are of Level IV evidence.
Cases from the eligible literature were aggregated and compiled in MS Excel 365 under specified data points. Analysis of the same was done using the Graphpad Prism 8 (GraphPad software, San Diego CA 92108) and SPSS version 23.0 (IBM® SPSS® Statitics). Continuous variables were presented as mean and standard deviation and were compared using Mann–Whitney's U-test. Categorical variables were presented as percentages/proportions and were compared using Fisher's exact test. A univariate logistic regression was done for predictors of severity and outcome of the disease in such patients. Multivariable controlled regression was not done due to small sample size. P < 0.05 was considered for statistical significance.
Declaration of patient consent
No patients were involved. The publicly available data was used.
Patients confidential data was not used and only publicly accessible documents were used and institutional ethics approval was deemed not necessary. Study complies with principles of Declaration of Helsinkini.
| Results|| |
The literature search revealed 355 articles, of which 19 articles were selected and analyzed in this review [Table 1] and [Table 2]. ,,,,,,,,,,,,,,,,,, We screened and excluded 153 articles (152 were not relevant and one article was not available as full text). [Figure 1] depicts the flow diagram of the systematic literature search, adhering to the PRISMA statement. Most articles were case reports, letters to the editor, and editorials. Data extraction and synthesis were performed using articles on kidney transplant with COVID-19 infection.
|Table 2: Classification of patients based on the severity of clinical course and outcome|
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|Figure 1: Study selection (Preferred Reporting Items for Systematic Reviews and Meta.Analysis flow diagram)|
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The total number of patients analyzed was 56, with a median age of 55 years and 71.42% of these were male [Table 3]. Almost a third of the population was ≥60 years of age. The most common presenting symptom was fever (51.79%), and the most common comorbidity was HT (83.92%). Preexisting respiratory system disease (Res.) was noted in two patients and both had nonsevere course. ICU stay and/or mechanical ventilation was needed in 30.35% of the total patients. Nearly 19.64% of the patients died. We found a higher likelihood of severe clinical course (P = 0.017), with advanced age [Table 4]. For patients ≥60 years of age, the odds of severe clinical course were 2.2 times, although this value did not attain statistical significance (P = 0.175). Males were statistically significantly more likely to have nonsevere clinical course than females (P < 0.0001) [Figure 2]. None of the comorbidities had any significant impact on the severity of clinical course. Even if a patient had ≥3 comorbidities, no significant impact on severity was noted.
An analysis based on the outcome [Table 5] revealed that, advancing age was a statistically significant predictor of mortality (P = 0.0005). Patients ≥60 years of age had 4.812 times the risk of dying (P = 0.027) [Figure 3]. Gender difference, time since transplantation, and comorbidities did not have any significant impact on the outcome. However, it is quite interesting to note that the risk of dying increased to 4.4 times, if the patient had preexisting respiratory diseases, although this does not reach statistical significance (P = 0.309). The severity of COVID-19 was statistically significantly associated with mortality (P = 0.0016) [Figure 4]. It was almost ten times that of nonsevere course (odds ratio [OR] 10.667, P = 0.002). Even if a patient had ≥3 comorbidities, no significant impact on outcome was noted.
| Discussion|| |
We had a heterogeneous study population. These patients belonged to different centers around the globe, with varied treatment protocols. Approximately 95% of them had one or more comorbidities (HT – 83.92%, diabetes mellitus [DM] – 32.51%, cardiovascular system (CVS) disease – 14.29%, and Res. – 3.58%).
Recently, Richardson et al. reported the findings of COVID-19 in the general population of New York. They reported similar prevalence of DM (33.8%) and CVS (18%). However, the prevalence of HT (56.6%) and Res. (17.3%), was different. Similarly, varying prevalence of comorbidities among the general population afflicted with COVID-19, was reported from China (HT – 21.1%, DM – 9.7%, CVS disease – 8.4%, and Res. – 1.5%). This difference in prevalence of comorbidities can be explained by difference in geographical locations and ethnicity.
In our study population, 30.35% of the patients needed intensive care (severe group). This contrasts with 22.47%, reported in the general population from New York and 26.1% reported from China. This difference may be explained by assuming difference in the ICU admission protocol, among different centers. ICU admission criteria have not been clearly defined in any of the included studies.
We noted that patients with severe disease were statistically significantly older (P = 0.0173). One study (in nontransplant patients) reported direct association of age more than 60 years with the severity of COVID-19 and higher fatality rate.
Similarly, we noted that the chances of death in kidney transplant patients increased significantly, with the advanced age (P = 0.0005). Nacif et al. reported fatality rate in kidney transplant patients to be 17.39%, with significantly higher rate in those ≥60 years of age (44.44%, P = 0.039). Even among the general population, Verity et al. demonstrated an age gradient in the risk of death in a COVID-19-infected population. Another study from New York reported that age was an independent predictor of mortality.
Our review found that the chances of death in patients with severe clinical course was statistically significantly higher than those with nonsevere disease (P = 0.0016). Patients with severe clinical course had ten times higher risk of dying than those with nonsevere course (OR 10.667, P = 0.002).
It is interesting to note that the odds of dying from COVID-19 were 4.4 times, if the patient had any preexisting Res. (P = 0.309). We believe, these odds may become statistically significant with a larger sample size.
Females are known to develop enhanced innate and adaptive immune responses than males. Moreover, recently, there have been studies suggesting that the pathogenesis of COVID-19 may involve exaggerated host inflammatory response., Putting these results into context, females might have a significantly severe course due to enhanced immune response to COVID-19. This may explain why males were found to have significantly lower odds of having severe clinical course as compared to females.
The case fatality rate in our review was 19.64% versus 9.70% (in the general population). We have also noted that none of the comorbidities had any statistically significant impact on the severity or outcome. Hence, can we assume that the increased mortality rate could be due to immunosuppression? It would be premature to say so because the number of patients in this review is small. Another limitation of this study is that the patients belong to different centers across the globe. Varied protocols of management of immunosuppression have been mentioned. In addition to this, some centers have tried new drugs, such as tocilizumab. This can potentially affect the clinical course and the outcome of the patients. More studies/data are required to get meaningful conclusions.
Limitations and strengths
This study is limited by a small sample size, available from isolated case reports. Due to this, a meta-analysis could not be done. The results of statistical analysis of such a small number of patients provide conclusions, neither definitive, nor strong enough to extrapolate over a larger population. This may explain why no impact of comorbidities was found in this study. Whereas, in the general population, patients with HT, DM, chronic obstructive pulmonary disease, or CVSs have been noted to have significantly higher odds of having severe clinical course. We are confident that a study similar to ours, over a larger population, may significantly alter the odds of the impact of comorbidities. Another limitation is the different immunosuppression protocols followed at different centres.
The strength of the study lies in it being the first systematic review to analyze the impact of comorbidities on clinical severity and outcome of COVID-19, in kidney transplant patients.
| Conclusions|| |
Kidney transplant recipients are a vulnerable subgroup of COVID-19 patients, with elderly patients at higher risk. With available data, contribution of comorbidity appears to be insignificant, which may change as more data become available. Compared to the general population, mortality in kidney transplant recipients is higher, probably secondary to immunosuppressed status. The impact of immunosuppression needs to be studied further. Further research should help in risk stratification among these patients. Standardized treatment protocols should evolve with individualization of treatment as per requirement as more experience is gained. A multicentric collaboration is the need of the hour for the benefit of kidney transplant recipients in the COVID era.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al
. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-33.
Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al
. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA 2020;323 (20):2052-2059.
Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al
. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis. Int J Infect Dis 2020;94:91-5.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al
. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323 (11):1061-1069.
Johnson KM, Belfer JJ, Peterson GR, Boelkins MR, Dumkow LE. Managing COVID-19 in renal transplant recipients: A review of recent literature and case supporting corticosteroid-sparing immunosuppression. Pharmacotherapy 2020;40:517-24.
Minotti C, Tirelli F, Barbieri E, Giaquinto C, Donà D. How is immunosuppressive status affecting children and adults in SARS-CoV-2 infection? A systematic review. J Infect 2020;81:e61-6.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al
. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and claboration. PLOS Med 2009;6:e1000100.
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLOS Med 2009;6:e1000097.
Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, et al
. PRISMA harms checklist: Improving harms reporting in systematic reviews. BMJ 2016;352:i157.
Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, et al
. Chapter 7: Systematic reviews of etiology and risk. J Briggs Inst Rev Man J Briggs Inst 2017.
Alberici F, Delbarba E, Manenti C, Econimo L, Valerio F, Pola A, et al
. A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia. Kidney Int 2020;97:1083-8.
Banerjee D, Popoola J, Shah S, Ster IC, Quan V, Phanish M. COVID-19 infection in kidney transplant recipients. Kidney Int 2020;97:1076-82.
Bush R, Johns F, Acharya R, Upadhyay K. Mild COVID-19 in a pediatric renal transplant recipient. Am J Transplant 2020;20:2942-2945.
Bussalino E, De Maria A, Russo R, Paoletti E. Immunosuppressive therapy maintenance in a kidney transplant recipient with SARS-CoV-2 pneumonia: A case report. Am J Transplant 2020;20:1922-4.
Chen S, Yin Q, Shi H, Du D, Chang S, Ni L, et al
. A familial cluster, including a kidney transplant recipient, of Coronavirus Disease 2019 (COVID-19) in Wuhan, China. Am J Transplant 2020;20:1869-74.
Fontana F, Alfano G, Mori G, Amurri A, Tei L, Ballestri M, et al
. COVID-19 pneumonia in a kidney transplant recipient successfully treated with tocilizumab and hydroxychloroquine. Am J Transplant 2020;20:1902-6.
Gandolfini I, Delsante M, Fiaccadori E, Zaza G, Manenti L, Degli Antoni A, et al
. COVID-19 in kidney transplant recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2020;20 (7):1941-1943.
Guillen E, Pineiro GJ, Revuelta I, Rodriguez D, Bodro M, Moreno A, et al
. Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2020;20 (7):1875-1878.
Kates OS, Fisher CE, Stankiewicz-Karita HC, Shepherd AK, Church EC, Kapnadak SG, et al
. Earliest cases of coronavirus disease 2019 (COVID-19) identified in solid organ transplant recipients in the United States. Am J Transplant 2020;20:1885-90.
Kim Y, Kwon O, Paek JH, Park WY, Jin K, Hyun M, et al
. Two distinct cases with COVID-19 in kidney transplant recipients. Am J Transplant 2020;20:2269-75.
Kocak B, Arpali E, Akyollu B, Yelken B, Tekin S, Kanbay M, et al
. A case report of oligosymptomatic kidney transplant patients with COVID-19: Do they pose a risk to other recipients? Transplant Proc 2020;52 (9):2663-2666.
Lauterio A, Valsecchi M, Santambrogio S, De Carlis R, Merli M, Calini A, et al
. Successful recovery from severe COVID-19 pneumonia after kidney transplantation: The interplay between immunosuppression and novel therapy including tocilizumab. Transpl Infect Dis 2020;e13334.
Marx D, Moulin B, Fafi-Kremer S, Benotmane I, Gautier G, Perrin P, et al
. First case of COVID-19 in a kidney transplant recipient treated with belatacept. Am J Transplant 2020;20:1944-6.
Nair V, Jandovitz N, Hirsch JS, Nair G, Abate M, Bhaskaran M, et al
. COVID-19 in kidney transplant recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2020;20 (7):1819-1825.
Namazee N, Mahmoudi H, Afzal P, Ghaffari S. Novel Corona Virus 2019 pneumonia in a kidney transplant recipient. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2020;20 (9):2599-2601.
Ning L, Liu L, Li W, Liu H, Wang J, Yao Z, et al
. Novel coronavirus (SARS-CoV-2) infection in a renal transplant recipient: Case report. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2020;20 (7):1864-1868.
Kumar RN, Tanna SD, Shetty AA, Stosor V. COVID-19 in an HIV-positive kidney transplant recipient. Transpl Infect Dis 2020;e13338.
Seminari E, Colaneri M, Sambo M, Gallazzi I, Di Matteo A, Roda S, et al
. SARS Cov-2 infection in a renal-transplanted patient: A case report. Am J Transplant 2020;20:1882-4.
Wang J, Li X, Cao G, Wu X, Wang Z, Yan T. COVID-19 in a kidney transplant patient. Eur Urol 2020;77:769-70.
Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al
. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant 2020;20 (7):1849-1858.
Glynn JR. Protecting workers aged 60-69 years from COVID-19. Lancet Infect Dis 2020;20 (10):1123.
Nacif LS, Zanini LY, Waisberg DR, Pinheiro RS, Galvão F, Andraus W, et al
. COVID-19 in solid organ transplantation patients: A systematic review. Clinics (Sao Paulo) 2020;75:e1983.
Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al
. Estimates of the severity of coronavirus disease 2019: A model-based analysis. Lancet Infect Dis 2020;20:669-77.
Cummings MJ, Baldwin MR, Abrams D, Jacobson SD, Meyer BJ, Balough EM, et al
. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: A prospective cohort study. Lancet 2020;395:1763-70.
Jaillon S, Berthenet K, Garlanda C. Sexual dimorphism in innate immunity. Clin Rev Allergy Immunol 2019;56:308-21.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al
. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.
Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al
. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-inflammatory strategies. J Biol Regul Homeost Agents 2020;34:327-31.
Wang B, Li R, Lu Z, Huang Y. Does comorbidity increase the risk of patients with COVID-19: Evidence from meta-analysis. Aging (Albany NY) 2020;12:6049-57.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]