Key words : COVID-19, Infection, Kidney transplant, Liver transplant, Pneumonia

Introduction

In every aspect, the COVID-19 pandemic has created a big problem for the human race, with World Health Organization data showing the effects of the COVID-19 pandemic on every part of the world. As of September 22, 2021, approximately 176 million people were diagnosed with COVID-19, and 830 thousand people have died due to this disease. These numbers continue to increase every day.¹
The most prevalent symptoms of COVID-19 include flu-like symptoms, such as high fever, sore throat, difficulty breathing, cough, and fatigue, which can be accompanied by shortness of breath and loss of smell.^2-4 As reported in 1 study, hospitalization is required in 20% of patients with COVID-19 and 5% of patients require intensive care and mechanical ventilation.⁵ Elderly individuals and patients with comorbidities, such as hypertension, diabetes, lung or cardiac failure, chronic kidney disease (CKD), cancer, renal replacement therapy, and immunosuppression, have been reported to be affected more by COVID-19.^6,7
Solid-organ transplant (SOT) recipients, who usually have comorbidities and long-term immunosuppression, are considered a high-risk group for SARS-CoV-2 infection.⁸ About 50% to 75% of organ transplant recipients encounter infections within the first year after transplant.⁹ The most important factors determining risk of posttransplant infection are the intensity of exposure to potential pathogens and the patient’s sensitivity to infection (related to the degree of immunosuppression). Presently, data are scarce on whether the course of COVID-19 infection in SOT recipients is different from that shown in the healthy population in terms of mortality, response to treatment, and disease severity. Thus, there are uncertainties on management of COVID-19 infection in these patients. Despite the increasing disease incidence, questions on differences in terms of sensitivity to disease, clinical severity, antiviral treatment, and immunosuppression management have not been clearly answered.^10-12 In this study, we investigated the clinical course and outcomes of COVID-19 infection in SOT recipients at our center in Turkey with an aim to reduce negative outcomes.

Materials and Methods

Study design and population
Our study received approval from the Ethics Committee of the Baskent University Medical and Health Sciences Research Committee (project no: KA20/453) and the R. T. Ministry of Health. Between March 2020 and January 2021, 23 SOT recipients and 336 nontransplant individuals were followed and treated for COVID-19 pneumonia in our center (the Baskent University Faculty of Medicine Hospital COVID-19 isolation ward). The diagnosis of COVID-19 pneumonia was confirmed by polymerase chain reaction (PCR) tests for SARS-CoV-2 and radiological findings on computed tomography of thorax.
Electronic medical records were retrospectively analyzed. We collected demographic characteristics, laboratory data, radiological findings, antiviral and anticytokine treatments, management of immuno-suppressive therapy, and clinical course of patients for comparisons between SOT recipients and nontransplant individuals. Among nontransplant individuals, 193 patients with comorbid diseases were excluded from the nontransplant group to exclude confounders. After that, a specific subgroup analysis was also performed between SOT recipients and 143 previously healthy patients.

Patient management
To diagnose COVID-19, nasopharyngeal swab specimens were tested with Bioeksen reverse transcriptase PCR tests for SARS-CoV-2. Most hospitalized patients received radiological imaging at the time of initial diagnosis with low-dose computed tomography of thorax. The patients were categorized as having mild disease (ambulatory treatment alone), moderate disease (admission to the COVID-19 isolation ward), or severe disease (mechanical ventilation, hospitalization in the intensive care unit [ICU], or death). All patients with SARS-CoV-2 infection were cared for in single rooms in line with the droplet and contact measures, and visits to patient rooms were not allowed. Medical staff wore personal protective equipment in line with the institutional protocols.

Antiviral, anticytokine, anticoagulant, and immunomodulatory therapy protocols
All patients received a standard treatment regimen for COVID-19 based on the national guidelines.¹³ Patients without complications received treatment with the antiviral favipiravir for 5 to 10 days for those with mild and moderate pneumonia and for 10 days for those with severe pneumonia (1600 mg twice daily for the first day, followed by 600 mg twice daily for 4 days; oral administration). Treatment with remdesivir was given for 5 to 10 days to selected patients (200 mg/day, followed by 100 mg intravenously). Unless they had active bleeding or thrombocytopenia, anticoagulant therapy was used in all of the patients hospitalized with COVID-19. For those with ongoing signs of inflammation, no response to glucocorticoid treatment, and rapidly progressive cytokine release syndrome, the anticytokine drugs tocilizumab (400 mg/day for 2 days; intravenously) or anakinra (100 mg/day for 7-14 days or until hospital discharge; subcutaneously) were used under the supervision of rheumatologists and immunologists. Intravenous immunoglobulin (IVIG) infusion was also used in selected cases.

At the time of hospitalization, all SOT recipients were under routine immunosuppressive therapy in accordance with the general approach for immunosuppression. Immunosuppressive therapy protocols in our center for liver transplant recipients include a triple-drug immunosuppression consisting of tacrolimus/cyclosporine/mechanistic target of rapamycin (mTOR) inhibitor + mycophenolate mofetil (MMF) + prednisolone in the first year, double-drug immunosuppression (tacrolimus/-cyclosporine/mTOR inhibitor + MMF) in the second year, and single-drug immunosuppression (tacrolimus/cyclosporine/mTOR inhibitor) in the third year. Kidney transplant recipients receive lifetime triple-drug immunosuppressive therapy (tacrolimus/cyclosporine/mTOR inhibitor + MMF + prednisolone).

Our center followed the recommendations of the Turkish Transplantation Society and Turkic World Transplantation Society for the continuity of immunosuppressive therapy in SOT recipients with COVID-19 pneumonia; the immunosuppressive therapy regimen was given according to the decision of the transplant physician.¹⁴ In line with these recommendations, the use of antimetabolite immunosuppressive agents was discontinued during the disease. Calcineurin inhibitor doses were decreased in patients with mild clinical severity; however, the use of calcineurin inhibitors was completely discontinued in patients with severe pneumonia and those who may require intubation. Depending on the patient’s clinical condition, steroid therapy was increased from a low dose of methylprednisolone (5 mg/day) to a high dose of steroid (1 mg/kg/day methylprednisolone, 6 mg/day dexamethasone). In patients who did not respond to this treatment or who had macrophage activation syndrome, methylprednisolone was used for 3 days at a dose of 250 mg/day. These patients received plasma therapy at the same time.

Statistical analyses
Quantitative data are presented as mean ± SD or as median with IQR. Qualitative variables are presented as relative frequencies. Intergroup comparisons were made using chi-square and Mann-Whitney U tests. For statistical analysis, SPSS version 20.0 software (IBM Corporation) was used. P < .05 was considered statistically significant.

Results

Demographics and clinical characteristics
Table 1 presents the sociodemographic characteristics of the patients. Mean age of SOT recipients was 49.8 ± 13.7 years, 78.3% of them were male, and 21.7% were female. Among the 23 transplant recipients, 17 (73.9%) had kidney transplants and 6 (26.1%) had liver transplants. Of these patients, 11 (48%) received a transplant from a relative (2 fathers, 1 mother, 1 sister, 1 child, 1 uncle, and 5 spouses). Mean age of nontransplant individuals was 57.5 ± 19.8 years, 57.6% were male, and 42.4% were female. Among the 336 nontransplant recipients, 143 were previously healthy patients(45.4 ± 11.6 years, with 64% male and 36% female patients).

In both the transplant and nontransplant groups, the most commonly observed symptoms were fever, cough, and dyspnea, respectively (Table 1). Comorbid diseases that were observed in SOT recipients were previous history of CKD (82.6%), hypertension (60.9%), diabetes mellitus (39.1%), and coronary artery disease (21.7%). Comorbid diseases in the nontransplant group included hypertension (43.5%), coronary artery disease (3.0%), and diabetes mellitus (22.0%). There were no significant differences between the SOT and the nontransplant group in terms of additional diseases, other than the history of CKD (P = .001).

Laboratory and radiological findings
Table 2 presents the laboratory findings in the 2 study groups. Hemoglobin and platelet counts, neutrophil-to-lymphocyte ratio, and creatinine, procalcitonin, C-reactive protein, troponin, and ferritin levels were found to be higher in the SOT recipients, with a statistically significant difference detected between the SOT and nontransplant groups (P < .05).

Table 3 presents the radiological data in the 2 study groups. Radiologically, lung involvement was observed in 91.3% of SOT recipients and 76.8% of nontransplant individuals. In both groups, the dominant radiological finding was bilateral lung involvement with multiple foci and peripheral ground-glass density. There were more cavitary lesions in the SOT group than in the nontransplant group (P < .05).

In the subgroup analysis of SOT recipients versus a previously healthy group, bilateral involvement was more significantly common in the SOT recipients (87% and 37%, respectively; P < .001). Consolidation and multiple foci rates were also higher in SOT recipients than in the healthy patient group (P < .05) (Table 4).

Of note, although PCR positivity of 11 patients was detected in the first PCR sample, PCR positivity of 2 patients was detected at the second or third tests.

Clinical course and management
In the follow-up of SOT recipients, antimetabolite treatment was discontinued in 73.9% (n = 17) of the patients, calcineurin inhibitors were either discontinued or their doses were decreased in 21.7% (n = 5) of patients, and mTOR inhibitors were either discontinued or their doses were decreased in 26% (n = 6) of patients. Of these patients, 15 (65.21%) received 1 mg/kg per day methylprednisolone therapy, whereas 39% (n = 9) needed a high dose methylprednisolone (250 mg/day for 3 consecutive days) (Table 4). Of SOT recipients, 17.4% (n = 4) needed noninvasive mechanical ventilation, 9% (n = 2) needed high flow nasal oxygen, and 9% (n = 2) needed mechanical ventilation (Table 5).
Ten of the SOT recipients needed ICU follow-up, with mean time to respiratory failure of 6.08 ± 1.50 days. The mean ICU stay was 2.26 ± 4.42 days in these patients (Table 5). Of these, 9% (n = 2) of the patients needed invasive mechanical ventilation. The remaining clinical data of the patients are presented in Table 5. The mean ICU length of stay and need for noninvasive mechanical ventilation, tocilizumab, steroid, and plasma use were higher in SOT recipients, with significant differences shown between the groups (P < .05).
When we compared SOT recipients with previously healthy patients with COVID-19, the ICU length of stay and need for noninvasive mechanical ventilation, tocilizumab, steroid, and plasma use were higher in SOT recipients than in healthy patients with COVID-19 (P < .05) (Table 4).

Antiviral therapy was used in all patients, and antiviral therapies were generally well tolerated in both groups, with no side effects. With regard to antiviral agents, 19 patients received favipiravir and 6 patients received remdesivir because of lack of good clinical and laboratory responses after favipiravir. Tocilizumab was used against the cytokine storm in a total of 6 patients, 3 of whom were SOT recipients (13.0%) and 3 of whom were nontransplant individuals (0.89%).

Of 23 SOT recipients, 6 recipients (26.1%) were diagnosed with secondary infections. Isolated agents are shown in Table 6. Empiric therapies were changed to agent-based antibiotics after the causative agent was isolated in treatment of secondary infections in SOT recipients. Antibiotics and antifungals were used in 13 patients (56.5%) and 2 patients (8.6%), respectively. Of 336 nontransplant individuals, 29 (8.6%) were diagnosed with secondary infections (Table 6). Antibiotics and antifungals were used in 30 patients (8.9%) and 12 patients (3.5%), respectively. The secondary infection rate was 2% in the healthy patients with COVID-19 disease, and all were successfully treated.

Four of the SOT recipients had outpatient follow-up after 1 day of hospitalization. Of these patients, 2 had decreased urine output and mild elevation of creatinine levels; however, these levels returned to normal in the follow-ups, and no other disease-related complications were observed.

Acute kidney injury developed in 8 SOT recipients (34.8%) and 14 nontransplant individuals (4.2%) during the course of the disease and hemodialysis was required. One patient had acute kidney rejection after COVID-19. After resolution of COVID-19 symptoms (up to 75 days), 2 SOT recipients (8.7%) had prolonged RT-PCR positivity.
In our study, 298 nontransplant individuals (88.7%) had mild/moderate disease and 38 (11.3%) had severe disease. In the SOT group, 18 recipients (78.3%) had mild/moderate disease and 5 recipients (21.7%) had severe disease (P = .224). Invasive mechanical ventilation was required in 5.4% of the nontransplant group and in 8.7% of the SOT group (P = .380). In the 30-day follow-up, mortality was observed in 28 nontransplant individuals (8.3%) and 3 SOT recipients (13.0%) (P = .439). Mortality was significantly different between SOT patients and previously healthy patients with COVID-19 (P < .001) (Table 4).

Discussion

An atypical course and worse outcomes of viral infections in immunosuppressed patients are known because of experiences acquired via previous viral infections.¹⁵ In this patient group, long-term use of immunosuppressive agents and especially the disruption in the T-cell immune response can cause this problem.¹⁶ It has been proposed that, in SOT recipients, immunosuppression can increase the disease severity in the early stage of COVID-19 and decrease mortality by inhibiting an excessive host inflammatory response in the late stage of COVID-19.¹⁷ Because of concerns regarding infection control and uncertainties in immunosuppression management, anxiety about COVID-19 has increased among SOT recipients. This has caused a significant decrease in or even the complete halt of transplant procedures in many centers around the world.

The rapid global spread of COVID-19 has led to the development of continuously changing and different protocols in the diagnosis, treatment, and management of the disease. Data on COVID-19 prevalence and disease severity among SOT recipients are still limited, and antiviral therapy and immunosuppressive therapy protocols are not yet clear. In this study, our aim was to evaluate and compare the demographic, radiological, laboratory, and clinical course data of 23 SOT recipients versus 336 nontransplant individuals.

We know that clinical symptoms and radiological findings are diminished because of decreased inflammatory responses from immunosuppressive therapy in SOT recipients. The general opinion for these patients is that fever is neither a sensitive nor a specific predictor of infection.¹⁸ However, our study showed that fever and cough were cardinal symptoms of COVID-19 infection and were similar in both SOT recipients and nontransplant individuals as reported previously.^16,20,21 We also suggest that fever and cough are important warning signs for the suspicion of COVID-19 infection in SOT patients.

Although the world has been battling with the COVID-19 pandemic for more than 1.5 years, the uncertainty in antiviral therapy strategies continues. Uncertainty has also continued for transplant patients. Favipiravir, although used in a limited number of COVID-19 therapies, is a therapeutically studied antiviral agent.²² In Turkey, the Ministry of Health has recommended favipiravir as the antiviral for use in COVID-19 infections. Therefore, in our hospital, all SOT recipients and all nontransplant patients, except for 4 patients, had received favipiravir, and no major or minor side effects were observed. Moreover, there were no statistically significant differences between the groups in terms of side effects.

It has been reported that remdesivir, the most promising antiviral drug tested for COVID-19 treatment, has no effect on the mortality rate.²³ However, in Turkey, access to remdesivir is only possible in a limited number of patients with the permission of the Provincial Directorate of Health and only if there is no response to favipiravir. In our study group, remdesivir was obtained via off-label use approval for 4 of our patients; no significant side effects were observed in these patients.

Tocilizumab, during development of its second clinical phase, has been characterized by its release of inflammatory cytokines in COVID-19 and has been shown to decrease inflammatory parameters; however, no decrease in mortality with tocilizumab has been shown.²⁴ So far, data on its use are scarce in immunosuppressed patients. In our study, increased inflammatory parameters and clinical and radiological worsening in patients were generally observed in the second week. In our cohort, tocilizumab was used in 3 of the SOT recipients (13.0%) and was well-tolerated by the patients. Although use of this agent was significantly higher in SOT recipients than in nontransplant individuals, patient numbers were insufficient to investigate its effect on survival.

Experiences acquired on COVID-19 pneumonia have shown that the use of dexamethasone ensures a decrease of 17% in mortality, and steroids must be used in all COVID-19 patients who need oxygen and/or mechanical ventilation.²³ However, there are no studies that have specifically evaluated the outcomes of SOT recipients with COVID-19 who are treated with corticosteroids. Recently, it has been recommended to continue steroids at a low dose rather than completely discontinuing them in SOT recipients.¹⁴ In our study, 65% of SOT recipients required systemic steroids. High-dose systemic steroids (100-250 mg/day methylprednisolone) were administered to 9 patients with advanced hypoxemia and radiological findings. Three of our patients who were receiving high-dose corticosteroids died. These patients died from septic shock due to secondary infections. Two of these patients underwent IVIG replacement due to low immunoglobulin G/immunoglobulin A levels at the time of hospitalization. Therefore, we suggest that the use of corticosteroids at a high dose increased the long-term immunosuppression already existing in the background, especially in SOT recipients with COVID-19. However, further studies are needed to investigate whether there is a relationship between corticosteroid use and mortality in these patients.

A preclinical study in China showed that convalescent plasmas from COVID-19 patients can accelerate clinical recovery.¹⁴ Convalescent plasma has been recognized as a safe therapy with relatively few side effects, including in SOT recipients. In studies that investigated convalescent plasma for COVID-19, side effects included fever, shivering, anaphylaxis, and transfusion-related acute lung injury.²² Convalescent plasma was used in 5 of our SOT recipients. One of the patients who received convalescent plasma was lost to sepsis later. In addition, pulse steroid therapy (pulse of ≥250 mg/day methylprednisolone) was used. For these therapies, strategies for their indication and the optimum timing have not yet been determined.

Viral shedding and infectivity have been found to be associated with disease severity and viral load in the general population. In that study, although PCR tests were negative on day 10 in 90% of the mild cases, positivity had continued on day 10 in severe cases.²⁴ Corsini Campioli and colleagues defined immuno-suppressive therapy as a factor that contributed to delayed viral clearance.²⁵ In the study from Decker and colleagues,²⁶ SARS-CoV-2 viral culture collected from pharyngeal swabs confirmed the presence of active viral replication, even on day 35. From these results, the investigators stated that continuing immuno-suppressive therapy in transplant recipients could contribute to prolonged reverse transcriptase PCR positivity, potential long-term infectivity, and communicability.²⁶ We also detected prolonged SARS-CoV-2 RNA positivity (up to 75 days) after clinical recovery from COVID-19 in 2 patients (8.7%).

The optimum dose and timing to restart immuno-suppressive therapy after recovery from COVID-19 are not yet clear in SOT recipients. In our center, immunosuppressive agents were rapidly restarted after discharge to prevent the development of allograft rejection.

Acute kidney injury is a frequently observed complication of COVID-19 and is detected in 30% to 89% of hospitalized kidney transplant recipients. Acute kidney injury, which can also be transiently observed during the course of COVID-19, is potentially related to many factors, including decreased renal perfusion, multiple organ failure, and cytokine storm.^23,27 In 14 nontransplant individuals (4.2%) and 8 SOT recipients (34.8%), acute kidney injury developed during the course of the disease in our study. Temporary dialysis was applied to these patients as needed. On the other hand, acute kidney rejection developed in only 1 of our patients after COVID-19 treatment. We believe that the low rejection rate in our study was due to the administration of high doses of steroids to our patients and discontinuation or reduction of immunosuppressive agents in a way that would not cause disease progression.

The incidence of invasive pulmonary aspergillosis in nontransplant patients with COVID-19 has been shown to vary between 19.6% and 33.3% and has a mortality rate as high as 64.7%. Treatment with tocilizumab can decrease the interleukin 6 immune response and can potentially lead to Aspergillus infection.²⁸ In our study, 1 patient developed invasive pulmonary aspergillosis, and this patient had been infected immediately after renal transplant, that is, in the early posttransplant period. This patient, who did not have hypoxemia during the course of COVID-19, did not receive tocilizumab but received long-term steroid treatment for immunosuppressive therapy. The patient, who had suspicious cavitary lesions, was diagnosed via bronchoalveolar lavage and was lost to invasive pulmonary aspergillosis 1 month after recovering from COVID-19 pneumonia. Urinary system infection developed in 3 of our patients. These 3 patients had sepsis and septic shock during follow-up, and their clinical presentation became severe. Secondary infection was detected in 3 of 143 healthy patients and did not affect survival in any of them. We believe that physicians must be alert and careful with regard to urinary system infections in cases of acute clinical worsening that cannot be explained by respiratory system findings, especially in SOT recipients infected with COVID-19 who have received high-dose steroids and tocilizumab.
The rate of respiratory failure requiring invasive mechanical ventilation was reported as 29% in SOT recipients with COVID-19 in the study from the TANGO International Consortium, which included 144 kidney transplant recipients from 12 centers across the United States, Italy, and Spain,²⁹ as 30% to 35% in 5 studies from the United States,^11,30-33 and as 22% in a Swedish study on 53 SOT recipients.³⁴ In a multicenter study from Turkey,³⁵ the need for mechanical ventilation in SOT recipients was reported as 15%. In our study, mechanical ventilation was needed in 5.4% of nontransplant patients and in 8.7% of SOT recipients. We suggest that our relatively low rate of respiratory failure requiring mechanical ventilation can be a result of our strategy of hospitalizing all SOT recipients with COVID-19 pneumonia. In this way, we can detect poor clinical course earlier and manage treatment strategies without delay regarding the effective use of the prone position, steroids, high-flow oxygen therapies, and noninvasive/invasive mechanical ventilation. However, our subgroup analysis showed significantly decreased need for mechanical ventilation in healthy patients versus SOT recipients. We suggest that this result can be associated with the fact that all SOT patients have at least 1 comorbid disease associated with poor prognosis for COVID-19.

Initial reports from transplant centers in New York concerning SOT recipients have stated that mortality rates are between 13% and 30%.^20,36-39 Studies found that mortality occurred mostly in elderly patients who were obese or frail and in patients who had underlying heart disease.^33,40 In a study that included 482 SOT recipients with COVID-19 from more than 50 transplant centers, the 28-day mortality rate was reported as 20.5%, and advanced age, heart failure, chronic lung disease, obesity, lymphopenia, and radiographic abnormalities were found to be associated with mortality. Multiple measurements of immunosuppression intensity were found to not be associated with mortality. Recent administration of increased immunosuppressive therapy and the type or number of maintenance immunosuppression agents were found to not be associated with mortality.⁴¹ Although mortality risk is thought to be higher in transplant recipients than the general population, this belief has not been universally verified.²³ In a multicenter study conducted in Turkey, mortality rate was reported as 12.5% in SOT recipients, which is similar to that shown in our study.³⁵ We found mortality to be significantly higher when we compared SOT recipients with nontransplant patients, confirming that comorbidities in SOT recipients can increase mortality after COVID-19 infection.

In our center, we have adopted a strategy of following all our SOT recipients with pneumonia, regardless of the indication, by hospitalizing them in an isolated unit as a treatment approach for COVID-19 infection. We believe that our cautious approach gave us the opportunity to closely observe our SOT recipients to detect worsening parameters early and to initiate the necessary treatments without delay. We also had the opportunity to catch opportunistic infections at an early stage and to start treatment per the detected agent in the patient specimens. Although the mean ICU length of stay, need for nasal oxygen and noninvasive mechanical ventilation, and use of tocilizumab, steroids, and convalescent plasma were higher in our SOT study group, we did not find a difference between SOT recipients and nontransplant patients in terms of mortality. However, our study showed that SOT recipients had more severe COVID-19 disease compared with the nontransplant group. We concluded that these results corroborate the accuracy of our strategy of hospitalization and close observation of SOT recipients with COVID-19 pneumonia.

Our study has some limitations. First, the sample size was too small for many subgroup analyses, including treatment modalities. Second, only inpatients were included in our study. There is a need for studies with larger numbers of patients, including both inpatients and outpatients.

Conclusions

Solid-organ transplant recipients with COVID 19 infection had more severe symptoms and outcomes than our nontransplant study group. Secondary infections during COVID-19 disease had a poor effect on the prognosis of the SOT recipients. We believe that preventive strategies to reduce secondary infections could reduce mortality in SOT recipients with COVID-19 disease.

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