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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2021  |  Volume : 32  |  Issue : 6  |  Page : 1689-1699
Clinical Characteristics, Biochemical Markers, and Outcomes of Postrenal Transplant Patients with Coronavirus Diseases 2019: A Single-Center Experience


Renal Transplant Unit, National Institute of Solid Organ and Tissue Transplantation, Dow University Hospital, Ojha Campus, Karachi, Pakistan

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Date of Web Publication27-Jul-2022
 

   Abstract 

The transplant recipient stays in an immunocompromised state for a definite period of time to reduce the risk of rejection and hence has more susceptibility to acquiring infections given the current coronavirus disease 2019 (COVID-19) pandemic. This study is aimed to document the clinical features of COVID-19 and biochemical markers in postrenal transplant population. This study was conducted at the renal transplant department of Dow University Hospital, Karachi, for a duration of one month and was designed as a retrospective observational study. It included all postrenal transplant patients who were assessed for COVID-19 through either nasopharyngeal or oropharyngeal swab for polymerase chain reaction. A total of 159 individuals were assessed and 28.30% were found COVID-19 positive. The mortality rate was 8.88% out of the 45 infected patients. The mean age of COVID-19-infected patients was 34.75 ± 11.50 years with 60% of males and 40% of females. The most frequent comorbidities were hypertension and diabetes mellitus. The current use of immunosuppressants either tacrolimus or cyclosporine was independently associated with acquiring COVID-19 (P <0.001) with an adjusted odds ratio [aOR] [95% confidence interval (CI)] of 1.703 (0.842-2.683) while diabetes was not associated with acquiring COVID-19 (P = 0.001) with an aOR (95% CI) of 0.513 (0.240-1.095). The frequent symptoms were fever, dry cough, sore throat, dyspnea, and arthralgia/myalgia. Diabetes mellitus was associated with early onset (P = 0.031), while the use of mycophenolate mofetil (P = 0.008) and corticosteroids (P = 0.002) was associated with delayed onset of bilateral pulmonary infiltrates. Our study brings the most recent data on postrenal transplant COVID-19 infection.

How to cite this article:
Asghar MS, Khan MT, Hamid Rb, Lal N, Ahmed I, Hameed B, Yasmin F. Clinical Characteristics, Biochemical Markers, and Outcomes of Postrenal Transplant Patients with Coronavirus Diseases 2019: A Single-Center Experience. Saudi J Kidney Dis Transpl 2021;32:1689-99

How to cite this URL:
Asghar MS, Khan MT, Hamid Rb, Lal N, Ahmed I, Hameed B, Yasmin F. Clinical Characteristics, Biochemical Markers, and Outcomes of Postrenal Transplant Patients with Coronavirus Diseases 2019: A Single-Center Experience. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Aug 14];32:1689-99. Available from: https://www.sjkdt.org/text.asp?2021/32/6/1689/352430



   Introduction Top


Solid organ transplantation has increased worldwide since the first successful human kidney transplantation was performed in 1954.[1] The transplant recipient stays in an immunocompromised state for a definite period of time to reduce the risk of rejection and hence has more susceptibility to acquiring infections given the current coronavirus disease 2019 (COVID-19) pandemic. The patient can acquire infection from any possible source. Different patients have different variations of signs and symptoms which may impact the respiratory system or gastrointestinal system or both, and the patient may also be experiencing systemic manifestations of the disease simultaneously. Transplant patients suffer from leukopenia and lymphopenia throughout the process which also increases the risk of acquiring infections by manifolds. Inflammatory markers may often be elevated in infected transplant recipients but may be altered due to immunosuppressive medication. Serial measurements may, therefore, have a greater prognostic value than single measurements.[2],[3]

Such patients may present with dyspnea and may have documented COVID-19 but have clear chest radiographs, while their computed tomography would show bilateral patchy infiltrates and/or ground-glass opacities. Coinfections with COVID-19 caused by bacterial pathogens and the likes of other respiratory viruses like cytomegalovirus were also seen but were not common. There is a high possibility of transmission between organ donor and recipient; therefore, both should be thoroughly screened before the procedure takes place.[4],[5]

Renal transplant patients with COVID-19 need individualized and special tailoring of an immunosuppressive regimen. In the case of coinfection, refraining from antiviral therapy may cause uncontrolled and life-threatening infection.[6] However, a tailored regimen may increase the risk of rejection and some recipients recovered from COVID-19 without any changes to their immunosuppressive Treatment[7].

The management of acute COVID-19 in renal transplant recipients is similar to that for nontransplant patients. Management is usually tailored in moderate-to-severe cases in which there is an increased need for hospitalization. As a first step, antimetabolite (e.g., mycophenolate mofetil/sodium) particularly is often reduced or held for patients with lymphopenia (e.g., absolute lymphocyte count <700 cells/mL).[8],[9],[10] Usually, the calcineurin inhibitor (CNI) is continued because CNIs inhibit interleukin (IL)-6 and IL-1 pathways; these cytokines may contribute to the development of the severe, dysregulated immune response seen in some patients with severe COVID-19. The need for glucocorticoids differs in each case. Glucocorticoid use usually causes prolonged viral shedding and poor outcomes in other epidemic coronaviruses, but data suggest a better outcome in patients with severe COVID-19. While adjusting the level of immunosuppression, due importance should be given to the risk of acute rejection.[11],[12],[13] Although many posttransplants are already on prolonged course systemic steroids, they might be showing suppressed viral activity or distinct clinical features from the general infected population.

COVID-19 may itself increase the risk of acute rejection, and an increased inflammatory immune response may add to the severity of the disease. Therefore, mediating the immune response by giving a low dose of immunosuppressives may prove to be helpful for the patient. Experimental data suggest that immunosuppressives such as mTOR inhibitors may help patients recover from COVID-19.[14] Further, trials are being run to prove the same. This study was conducted to document the clinical features of COVID-19 and biochemical markers in postrenal transplant population. The secondary objective was to link certain comorbidities and biomarkers with not only severity of the disease but also with harboring the infection and development of pulmonary infiltrates.


   Materials and Methods Top


This study was conducted at the renal transplant department of a tertiary care hospital, Karachi, for a duration of one month and was designed as a retrospective observational study. It included all postrenal transplant patients who were assessed for COVID-19 through either nasopharyngeal or oropharyngeal swab for polymerase chain reaction (PCR). The diagnostic kit used exploits the principle of real-time fluorescence (real-time PCR), USA-WA1/2020 stock concentration 2.8E+05 TCID50/mL, with a lower detection limit of 0.003 TCID50/mL. A pro forma was prepared to have two sections: the first section covered demographic details including name (as optional), age (in years), gender, and comorbidities including diabetes, hypertension, and others, while the second section includes the clinical and biochemical data of postrenal transplant patients suffering from COVID-19. The duration of transplant, duration of diagnosis of chronic kidney disease (CKD), provision of hemodialysis, and current use of immunosuppressants were also documented. The patients were followed through their clinical course until an outcome is achieved. A total of 159 patients were assessed for COVID-19 PCR and were included for initial descriptive analysis, while 45 of them were positive for COVID-19 and hence were applied with inferential statistics, as shown in [Figure 1] (methodology flowchart).
Figure 1. Flow diagram of patient selection criteria.

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After collection of data, the analyses will be conducted by using IBM SPSS Statistics software version 25.0 (IBM Corp, Armonk, NY, USA). All descriptive variables will be described as mean and standard deviation. The means will then be compared using an independent sample t-test. The comparison of categorical data was done either using the Chi-square test or Fisher’s exact test accordingly. P<0.05 was considered statistically significant (two-tailed). Inferential statistics will be applied to know the linear relationship of factors linking with COVID-19. Univariate linear regression obtaining odds ratio (OR) and its 95% confidence interval [95% confidence interval (CI)] were followed by multivariate analysis obtaining adjusted odds ratio (aOR) for associated factors. A Kaplan–Meier survival curve was generated among those patients who developed bilateral pulmonary infiltrates and survival logs were associated with variables to obtain log-rank (MantelCox) significance.


   Results Top


Out of the total 159 included patients, 28.30% were found COVID-19 positive. Among them, 28.88% were managed on an outpatient basis, 44.44% were admitted in an isolation ward, while the rest 26.67% were admitted to intensive care facilities either high-dependency unit (HDU) (n = 3) or intensive care unit (ICU) (n = 9). The mortality rate was 8.88% out of the 45 infected patients. The mean age of COVID-19-infected patients was significantly less than noninfected transplant recipients (P <0.001) with equal gender predisposition (P = 0.790). Body mass index and baseline creatinine levels were insignificant, while duration of CKD diagnosis (P = 0.03) and duration of transplant (P = 0.045) were significantly less in COVID-19-infected patients. The most frequent comorbidities in COVID-positive patients were hypertension (35.55%) and diabetes mellitus (31.11%). The current use of immunosuppressants included corticosteroids (97.77%), mycophenolate mofetil (75.55%), and either cyclosporine or tacrolimus in 86.66% of COVID-positive patients. The use of either tacrolimus or cyclosporine was independently associated with acquiring COVID-19 infection on multivariate analysis (P <0.001) with an aOR (95% CI) of 1.703 (0.842–2.683) while diabetes was not associated with acquiring COVID-19 infection (P = 0.001) with an aOR (95% CI) of 0.513 (0.240–1.095) among other insignificant factors, as shown in [Table 1].
Table 1. Comparison of baseline data of the study population (n=159).
† indicates p-value calculated by independent t-test, * indicates chi-square test, ^indicates Fisher�s exact test. CVA: Cerebrovascular accident; ILD: Interstitial lung disease; COPD: Chronic obstructive pulmonary disease; CKD: Chronic kidney disease; OR: Odds ratio; aOR: adjusted odds ratio; COVID-19: Coronavirus disease 2019.


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[Table 2] summarizes the clinical profiles of COVID-19-infected patients including 12 patients admitted to intensive care facilities. The frequent symptoms were fever, dry cough, sore throat, dyspnea, and arthralgia/myalgia. The mean length of hospital stay was 15.25 ± 10.31 days while the mean duration of ICU stay was 8.01 ± 5.89 days. Only three patients were invasively ventilated, while 11 patients were managed with noninvasive modes. Bilateral pulmonary infiltrates were evident in 46.66% of infected patients and only 11.11% of them developed acute respiratory distress syndrome (ARDS). About 15.55% developed multiorgan dysfunction syndrome (MODS). Acute kidney injury was suffered by seven patients; four of them needed hemodialysis support. About five patients exhibited secondary bacterial infection including Pseudomonas aeruginosa (n = 2), Escherichiacoli (n = 1), Moraxella catarrhalis (n = 1), and Klebsiella pneumoniae being isolated organisms.
Table 2. Clinical profiles of COVID-19-infected renal transplant patients (n=45).
ICU: Intensive care unit; HDU: High-dependency unit; C/S: Culture and sensitivity, SD: Standard deviation; APACHE-II: Acute Physiology and Chronic Health Evaluation-II; SOFA: Sequential Organ Failure Assessment, ARDS: Acute respiratory distress syndrome.


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[Table 3] lists all the serial hematological parameters and biochemical and inflammatory markers of infected patients throughout the course of the disease. With respect to the development of bilateral pulmonary infiltrates, diabetes mellitus was associated with early onset of bilateral infiltrates (P = 0.031), while the use of mycophenolate mofetil (P = 0.008) and corticosteroids (P = 0.002) was associated with delayed onset of bilateral pulmonary infiltrates on Kaplan–Meier survival log, as shown in [Figure 2].
Table 3. Initial biochemical markers in COVID-19-infected renal transplant patients (n=45).
MCV: Mean corpuscular volume; BNP: B-type natriuretic peptide; LDH: Lactate dehydrogenase; CRP: C-reactive protein; TLC: Total leukocyte count; HCT: Hematocrit; ICU: Intensive care unit; HDU: High-dependency unit; COVID-19: Coronavirus disease 2019.


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Figure 2. Kaplan-Meier survival logs for onset of bilateral pulmonary infiltrates.

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   Discussion Top


The earliest case of reported COVID-19 pneumonia in a transplant recipient was presented with low-grade fever, generalized fatigue, and chills, while nasal stuffiness, chest tightness, nausea, vomited, dizziness, and loss of appetite were exhibited during the hospital course. Mild anemia, hypoalbuminemia, leukocytosis, elevated creatinine, and aminotransferase levels were documented during the hospital stay with an uneventful recovery.[8] Another case study presented with fever and gastrointestinal symptoms which then progressed to respiratory symptoms requiring mechanical ventilation. Elevated creatinine, persistent raised inflammatory markers, lymphopenia, and hyponatremia were reported during the hospital course.[15] A case series on solid organ transplant recipients showed more than 51% of renal transplant patients were COVID-19 infected with fever, cough, and dyspnea being predominant symptoms.[8] About 76% of them had mild-to-moderate disease and the rest 24% had severe disease. They reported mortality of 16 out of 90 patients, with serum procalcitonin correlating highest with disease severity. Another case study on 36 renal transplant recipients infected with coronavirus also presented predominantly with fever, cough, and dyspnea.[9] Leukopenia was reported in 21% of hospitalized patients, thrombocytopenia in 43%, hyperferritinemia in 36%, elevated C-reactive protein (CRP) in 46%, elevated D-dimer in 57%, elevated lactate dehydrogenase (LDH) in 36%, and raised procalcitonin in 43% of patients, with a reported mortality of 28%. While early reports from France reported 22.8% mortality in 279 COVID-19-infected renal transplant recipients.[10] Fever, cough, dyspnea, and diarrhea were the predominant symptoms in those patients. Increased age, body mass index, presence of cardiovascular comorbidities, fever, dyspnea, elevated CRP, and procalcitonin (PCT) were associated with significant mortality.[10]

Another case series showed 56% of renal transplant recipients been infected with COVID-19 among solid organ transplant patients. Fatigue and myalgia were also the predominant symptoms alongside fever, cough, and dyspnea. Neutrophilia, hepatic enzyme derangements, elevated CRP, LDH, and PCT were significantly associated with ICU admissions.[16] Coinfection was documented in 19% of hospitalized individuals, with a 16% mortality and 6% graft rejection also reported. While clinical variability was reported in transplant recipients with COVID-19 infection,[17] with fever in one half and cough being more common.[18] About 33% had normal chest radiographs in one study.[17] Renal injuries were common (40%), with a reported 13% mortality. While 50% mortality was reported according to one study in the elderly population,[19] with patients who expired were more likely anemic, lymphopenic, and had elevated CRP and D-dimer. Data from Spain suggested mortality of 28% in 18 solid organ transplant recipients with COVID-19 infection with elevated CRP, LDH, and lymphopenia reported during hospital stay. Renal organ transplants comprised 44% of their cohort and 15 patients presented with fever.[20] The largest COVID-19-infected organ transplant multicentric study had 318 patients from more than 50 centers, with cough being the most common symptom (73%). About 20.5% of them died during the disease course. Increased age, cardiopulmonary comorbidity, obesity, and lymphopenia were associated with mortality.[11]

Lymphopenia, elevated ferritin, D-dimer, and troponin levels are seen in severe disease according to one study, with one patient who died had AKI during hospital course.[13] Another study showed 69% of solid organ transplant patients having AKI during COVID-19 disease course, with 43% of them exhibited gastrointestinal symptoms.[21] Coinfection was highly reported with 4.8% mortality out of 21 studied patients.[21] While managing the patients with renal transplant, some studies have suggested a therapeutic regimen consisting of reduction of calcineurin inhibitors, and low-dose methylprednisolone is recommended with agents causing bone marrow suppression are withheld.[12] Cyclosporin A postulated to have an inhibitory effect on proliferation of coronavirus in vitro, through its action on cyclophilin A and B, while tacrolimus does not.[13] The selection of immunosuppressive treatment in COVID-19 is a complex issue, with only glucocorticoid therapy being reliable; on the other hand, discontinuation of immunosuppressants is controversial as some suggest that it might help in infection recovery and others pointed out on being exposing patients to graft rejection.[22] Many cytokines are gaining attraction of researches for potential COVID- 19 therapeutics including IL-1, IL-6, tumor necrosis factor, C-C Motif Chemokine Ligand 2, IL-37, and IL-38 that might also be overlappingly beneficial in the kinetics of transplant immunosuppression.[14] Finally, a French study on 49 renal transplant patients showcased gastrointestinal manifestations commonly. The 30-day mortality rate in hospitalized patients was 19.5%. CRP, high-sensitivity troponin I, and D-dimer were significantly associated with severe disease and mortality.[23]

There were a few limitations of our study, including a single center analysis with limited sample size, lack of serial biomarkers of all the patients, lack of treatment protocols defined for each patient, and indeterminate temporal associations of factors like comorbidities, use of immunosuppressants and other study variables.


   Conclusion Top


Our study was the first one to associate factors with harboring COVID-19 infection including comorbidities and use of immunosuppressants in postrenal transplant patients. Many biochemical markers were signifying the severity of disease. ICU severity scores such as Acute Physiology and Chronic Health Evaluation-II and Sequential Organ Failure Assessment were also calculated for patients managed intensively. Serial measurements of these markers must be paramount to improve clinical outcomes. Certain treatment protocols should be defined among the transplant recipients in the light of these findings with large sample study protocols and provision of immunosuppressants must be discussed in detail with respect to the management of these patients amid the ongoing pandemic.


   Ethical approval statement Top


Ethical approval was taken in this study from the institutional review board. The consent to participate from patients was not required as it was retrospective study.

Conflict of interest: None declared.



 
   References Top

1.
Fishman JA. Infection in organ transplantation. Am J Transplant 2013;17:1-10.  Back to cited text no. 1
    
2.
Fishman JA, Grossi PA. Novel Coronavirus-19 (COVID-19) in the immunocompromised transplant recipient: #Flatteningthecurve. Am J Transplant 2020;20:1765-7.  Back to cited text no. 2
    
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Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci 2020;63:364-74.  Back to cited text no. 3
    
4.
American Society of Transplantation. 2019-n-CoV (Coronavirus): FAQs for Organ Donation and Transplantation. Available from: https://www.my ast. org/sites/default/files/1 C O VID 19%20F AQ%20Tx%20Centers%2004.15. 2020.pdf. [Last accessed on 2020 Apr 22].  Back to cited text no. 4
    
5.
Guidance from the International Society of Heart and Lung Transplantation Regarding the SARS CoV-2 Pandemic. Available from: https://ishlt.org/covid-19-information. [Last accessed on 2020 Apr 22].  Back to cited text no. 5
    
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Fishman JA, Greenwald MA, Grossi PA. Transmission of infection with human allografts: Essential considerations in donor screening. Clin Infect Dis 2012;55:720-7.  Back to cited text no. 6
    
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Ning L, Liu L, Li W, et al. Novel coronavirus (SARS-CoV-2) infection in a renal transplant recipient: Case report. Am J Transplant 2020;20:1864-8.  Back to cited text no. 7
    
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Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant 2020;20:1800-8.  Back to cited text no. 8
    
9.
Akalin E, Azzi Y, Bartash R, et al. COVID-19 and kidney transplantation. N Engl J Med 2020;382:2475-7.  Back to cited text no. 9
    
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Caillard S, Anglicheau D, Matignon M, et al. An initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants. Kidney Int 2020;98:1549-58.  Back to cited text no. 10
    
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Kates OS, Haydel BM, Florman SS, et al. Coronavirus disease 2019 in solid organ transplant: A multicenter cohort study. Clin Infect Dis 2021;73:e4090-9.  Back to cited text no. 11
    
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Zhong Z, Zhang Q, Xia H, et al. Clinical characteristics and immunosuppressant management of coronavirus disease 2019 in solid organ transplant recipients. Am J Transplant 2020;20:1916-21.  Back to cited text no. 12
    
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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.  Back to cited text no. 13
    
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Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Antiinflammatory strategies. J Biol Regul Homeost Agents 2020;34:327-31.  Back to cited text no. 14
    
15.
Guillen E, Pineiro GJ, Revuelta I, et al. Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Am J Transplant 2020; 20:1875-8.  Back to cited text no. 15
    
16.
Roberts MB, Izzy S, Tahir Z, Al Jarrah A, Fishman JA, El Khoury J. COVID-19 in solid organ transplant recipients: Dynamics of disease progression and inflammatory markers in ICU and non-ICU admitted patients. Transpl Infect Dis 2020;22:e13407.  Back to cited text no. 16
    
17.
Columbia University Kidney Transplant Program. Early description of coronavirus 2019 disease in kidney transplant recipients in New York. J Am Soc Nephrol 2020;31:1150-6.  Back to cited text no. 17
    
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Fishman JA. The immunocompromised transplant recipient and SARS-CoV-2 infection. J Am Soc Nephrol 2020;31: 1147-9.  Back to cited text no. 18
    
19.
Crespo M, Pérez-Sáez MJ, Redondo-Pachón D, et al. COVID-19 in elderly kidney transplant recipients. Am J Transplant 2020;20: 2883-9.  Back to cited text no. 19
    
20.
Fernández-Ruiz M, Andrés A, Loinaz C, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant 2020;20:1849-58.  Back to cited text no. 20
    
21.
Yi SG, Rogers AW, Saharia A, Aoun M, Faour R, Abdelrahim M, et al. Early experience with COVID-19 and solid organ transplantation at a US high-volume transplant center. Transplantation 2020;104:2208-14.  Back to cited text no. 21
    
22.
Elens L, Langman LJ, Hesselink DA, et al. Pharmacologic treatment of transplant recipients infected with SARS-CoV-2: Considerations regarding therapeutic drug monitoring and drug-drug interactions. Ther Drug Monit 2020;42:360-8.  Back to cited text no. 22
    
23.
Benotmane I, Perrin P, Vargas GG, et al. Biomarkers of cytokine release syndrome predict disease severity and mortality from COVID-19 in kidney transplant recipients. Transplantation 2021;105:158-69.  Back to cited text no. 23
    

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Correspondence Address:
Dr Muhammad Sohaib Asghar
Renal Transplant Unit, National Institute of Solid Organ and Tissue Transplantation, Dow University Hospital, Ojha Campus, Karachi
Pakistan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.352430

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