Key words : Cytomegalovirus, Influenza, SARS-CoV-2, Solid-organ transplant recipients, Viral infections

Introduction

Solid-organ transplants are life-saving operations for patients with organ failure due to chronic diseases. To prevent organ rejection after surgery, transplant recipients typically receive intensive immunosup-pression therapy. However, immunosuppression increases bacterial, viral, parasitic, and fungal op-portunistic infections.^1,2 Although bacterial infections remain prominent after organ transplant, the incidence of viral infections is also increasing. Infections that are common among the general population can have a comparatively severe course in transplant recipients.³ In studies conducted during the COVID-19 pandemic (SARS-CoV-2, ie, severe acute respiratory syndrome-related coronavirus 2), organ transplant recipients were considered to be at higher risk for infection versus the general population.⁴ In addition to SARS-CoV-2, other common viral agents that affect organ transplant recipients include influenza, cytomegalovirus (CMV), enteric viruses, and BK virus.² We investigated viral infections seen in transplant patients during and before the COVID-19 pandemic period (2019-2023); our study is intended to be a guide in patient follow-up.

Materials and Methods

This retrospective and cross-sectional study was approved by the Baskent University Institutional Review Board (Project No. KA24/22, 16.01.2024) and supported by the Baskent University Research Fund. The protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration and the Declaration of Istanbul on Organ Trafficking and Transplant Tourism.

The first living-related kidney transplant in Turkey was performed by the transplant team of our hospital on November 3, 1975. The first deceased-related kidney transplant in Turkey was performed by our transplant team on October 10, 1978, and the first successful deceased donor liver transplant in Turkey, the Middle East, and North Africa was performed by our team on December 8, 1988. The transplant team performed a living-related liver transplant on an adult, which was the first in the world. In addition, on May 16, 1992, our transplant team performed the first combined transplant of liver and kidney from a living-related donor, which was the first operation of its kind anywhere in the world.⁵

Our transplant team performed 3520 kidney transplant procedures for the period 1975-2023 and 720 liver transplant procedures for the period 1988-2023. The first heart transplant was performed at our hospital in February 2003; 151 heart transplants were performed for the period 2003-2023.

Study design and patients
The study population consisted of patients over the age of 18 years who had undergone solid-organ transplant. Each living donor was a relative (up to the fourth degree) or spouse of the respective recipients. The sample group consisted of patients who had viral infections for the period 2019-2023. We obtained patient information from the hospital data system. We investigated variables associated with the participants, including age, sex, type of transplant, chronic diseases, laboratory values, viruses detected as causative agents, other foci of infection, duration of transfer and hospitalization, duration of stay in an intensive care unit (ICU), and mortality.

Statistical analyses
We used SPSS software (version 25.0) for statistical analyses. We examined conformity of the variables to the normal distribution using histogram charts and the Shapiro-Wilk test. We recorded descriptive variables as mean and standard deviation. The analysis of variance test was used for the comparison of normally distributed (parametric) variables between more than 2 groups. We used the Bonferroni method for multiple comparisons to investigate significant differences between the groups. We presented categorical variables as frequency and percentage and analyzed categorical variables with the chi-square test. P < .05 was considered statistically significant.

Results

The number of solid-organ transplants performed by the transplant team in our hospital up to 2023 was 4391 patients, with 3519 patients over the age of 18 years. Over the past 5 years, viral infection was detected in 238 patients over the age of 18 years. Of these patients with viral infection, 190 (79.8%) were kidney transplant recipients, 39 (16.4%) were liver transplant recipients, and 9 (3.8%) were heart transplant recipients. The most frequently detected viruses were SARS-CoV-2 (154 patients; 64.7%), influenza (43 patients; 18.1%), and CMV (18 patients; 7.6%). The BK virus was detected in 6 patients (2.5%), rotavirus in 5 (2.1%), norovirus in 5 (2.1%), rhinovirus in 3 (1.3%), sapovirus in 2 (0.8%), and respiratory syncytial virus in 2 patients (0.8%) (Figure 1).

When we examined changes in infection rates over the study period, influenza was prominent in 2019 but was replaced by SARS-CoV-2 in 2020-2022. Number of influenza infections increased again in 2023. Cytomegalovirus was the third most common viral agent (Figure 2).

The most frequently involved system was the respiratory system (213 patients, 89.5%). The gastro-intestinal system was involved in 13 patients (5.5%), the urinary system in 6 patients (2.5%), and the circula-tory system (ie, viremia) in 6 patients (2.5%) (Figure 3).

Mean age of the study group was 43.9 ± 14.9 years. The mean age for heart transplant patients was lower than the age for other transplant types (30.3 ± 13.7 years; P = .015). The number of male patients was 166 (69.7%). There were 158 patients (66.4%) who received transplants from living donors. Consistent with the transplant etiology of the patients, hypertension and renal failure were detected frequently in kidney transplant patients, heart failure in heart transplant patients, and malignancies in liver transplant patients (P < .05).

Elevated keratin levels were detected frequently in kidney transplant patients, whereas elevated liver enzymes, thrombocytopenia, and accompanying bacteremia were frequently detected in liver transplant patients (Table 1). Clinical symptoms varied by viral infection. Fever, cough, and sputum production were more frequent in influenza cases (P = .012, P = .041, and P = .009, respectively), and myalgia and dyspnea were more prominent in SARS-CoV-2 cases (P = .029 and P = .013, respectively). Thrombocytopenia was notably higher in influenza cases (P = .005), whereas CMV infections were significantly associated with bacteremia and ICU admissions (P = .002 and P = .031, respectively).

Empirical antibiotic treatment was started in 42 patients (17.2%). After the causative virus was identified, drugs such as favipiravir, molnupiravir, and remdesivir were used to treat SARS-CoV-2 infections, if such treatment options were available at that time. Oseltamivir has been used as a treatment option in cases of influenza, and ganciclovir and valganciclovir have been used in cases of CMV. Various supportive treatments were given for other viruses (Table 2).

Twenty-nine patients required ICU monitoring. The ICU admissions were significantly higher among patients older than 65 years and patients with bacteremia (P = .012 and P = .001, respectively)(Table 3).

Mortality was observed in 28 patients (12.1%). Mortality was found to be significantly higher in patients older than 65 years (P = .049), in patients with bacteremia (P = .001), and in patients admitted to the ICU (P = .001) (Table 3).

Discussion

Our findings underscore the substantial effect of SARS-CoV-2 on solid-organ transplant recipients, highlighting the clinical consequences of SARS-CoV-2 infection and the critical need for targeted preventive strategies. The CMV infections were associated with a higher likelihood of ICU admission, emphasizing the importance of proactive monitoring and timely interventions to mitigate complications.Solid-organ transplant recipients receive intensive immunosuppression treatments to prevent graft rejection. As a routine protocol in our hospital, the most commonly used immunosuppression treatments in solid-organ transplants are steroids, tacrolimus, and mycophenolate mofetil. These treatments increase susceptibility to bacterial and viral infections and cause infections in transplant patients to have a more complicated course than in the general population. All infections of patients should be closely monitored.⁶

Studies on viral infections in patients undergoing solid-organ transplant are fewer than the number of studies on bacterial infections. Diagnosis is more difficult in transplant patients than in the general population, and treatment options are limited. Such treatment mostly consists of support and symptomatic treatment and reduction of immunosuppression therapy.⁷ The respiratory tract is the system from which viruses are most frequently isolated.

In our research during the years 2019-2023, the 2 most frequently detected viral agents in 2019 were influenza and CMV. The first diagnosis of COVID-19 caused by SARS-CoV-2 in Turkey was made on March 11, 2020, when the COVID-19 pandemic was declared for the world. The most frequently detected virus in transplant patients during the 2-year period of 2022-2023 was the SARS-CoV-2 virus. As of November 2024, 776 754 317 cases of COVID-19 have been detected worldwide, and 7 073 466 people have died from COVID-19. In Turkey, 17 004 729 cases of COVID-19 and 101 419 deaths due to COVID-19 were reported.⁸ Solid-organ transplant patients constitute a risk group for COVID-19, as for many types of infection. For this reason, it may be vital for patients to pay attention to droplet and contact precautions and respiratory hygiene against the risk of contamination and to plan early diagnosis and treatment.⁹

Polymerase chain reaction tests are valuable diagnostic tests because these tests provide early results to facilitate early diagnosis patients and direction of treatment.¹⁰ We encountered polymerase chain reaction tests performed for our study patients.

Fever, headache, sore throat, muscle pain, cough, dyspnea, and diarrhea were the most common symptoms among patients in our study. Dyspnea was also common. Of note, fever and respiratory symptoms in patients may lead to misdiagnosis of the infection.¹¹ Diagnosed infections were treated with drugs such as remdesivir, favipiravir, and molnupiravir, which were available along with supportive treatment.¹² Nevertheless, we observed admission (10.4%) and mortality (11%) in our patients, which indicated that careful follow-up remains crucial. Mortality rates, which are around 1% to 2% for the general population, have been reported to be around 9% to 30% in patients in the risk group and in patients with comorbidities.^13,14

Influenza was the second most common virus during the study period. Influenza was detected in 43 patients. Fever, headache, sore throat, myalgia, cough, and sputum are the most common symptoms of influenza. Thrombocytopenia was detected more frequently in influenza cases versus other viral infections. In the treatment of influenza infection, oseltamivir was given along with supportive treatments. Eight of the patients with influenza were monitored in the ICU, and 4 of these patients died. Therefore, all organ transplant patients should be vaccinated against seasonal influenza. Effective antiviral treatment should be started when the diagnosis is made.¹⁵ Nevertheless, empirical antibiotic treatment was frequently started in influenza patients before the causative agent was identified.

Cytomegalovirus was the third most frequently detected viral agent and was detected in 18 patients. Symptoms for CMV appear to be similar to SARS-CoV-2 and influenza, except for the absence of myalgia and headache.^16,17 However, the association of bacteremia and admission to the ICU were more commonly associated with CMV infections than with SARS-CoV-2 and influenza. Ganciclovir and valgan-ciclovir were used in the treatment of patients with CMV, and empirical antibiotic treatment was not initiated in any patient with CMV. Five patients with CMV infection died. Posttransplant prophylaxis, monitoring of patients, and early diagnosis and treatment can be vital.

Other viruses were detected less frequently, including rhinovirus and respiratory syncytial virus, which are respiratory viruses, and rotavirus, norovirus, and sapovirus, which are diarrheal agents, and BK virus was detected in the urinary system. These are some of the most frequently encountered viruses reported in the literature for solid-organ transplant recipients.^17,18 Patients diagnosed with these other viral infections were given supportive treat-ments. Admission to the ICU was not needed for these other viral infections, and no deaths were reported. It is important to identify the causative agent before proceeding with an individualized treatment plan.

Limitations
This was a retrospective, cross-sectional study, which inherently limits the ability to establish causal relationships and to fully capture dynamic changes over time. Data were extracted from hospital information systems, which may contain incomplete or inaccurate records and may potentially limit the comprehensiveness of the findings. In addition, the sample size of our study was limited to 238 patients, which restricts the ability to generalize the results to broader populations.

Future studies with larger sample sizes and prospective designs could provide more robust, generalizable, and longitudinal insights into the patterns and outcomes of viral infections in solid-organ transplant recipients.

Conclusions

The most frequently detected viral agent among solid-organ transplant recipients during the study period was SARS-CoV-2 (the virus that causes COVID-19), followed by influenza viruses (influenza A and influenza B) and CMV. Some patients required admission to the ICU, and some patients died, highlighting the critical role of managing chronic conditions in this vulnerable population.

Vaccination against COVID-19 and influenza has proved efficacious to reduction of hospitalizations and mortality, and so vaccinations should be prioritized for organ transplant recipients. Pretransplant eva-luations should encompass tailored vaccination programs, prophylaxis, and regular surveillance to minimize infection risks.

Further research aligned with these findings will help improve the understanding, diagnosis, and management of viral infections in transplant recipients, which will thereby contribute to the development of more effective care strategies.

Moreover, early detection of viral pathogens can reduce the reliance on empirical antibiotic treatments. Such measures could mitigate challenges such as anti-biotic resistance, adverse drug effects, prolonged hos-pital stays, and the higher financial cost of health care.

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