Predominantly defective CD8+ T cell immunity to SARS-CoV-2 mRNA vaccination in lung transplant recipients.

BACKGROUND: Although mRNA vaccines have overall efficacy preventing morbidity/mortality from SARS-CoV-2 infection, immunocompromised persons remain at risk. Antibodies mostly prevent early symptomatic infection, but cellular immunity, particularly the virus-specific CD8+ T cell response, is protective against disease. Defects in T cell responses to vaccination have not been well characterized in immunocompromised hosts; persons with lung transplantation are particularly vulnerable to vaccine failure with severe illness. METHODS: Comparison groups included persons with lung transplantation and no history of COVID-19 (21 and 19 persons after initial mRNA vaccination and a third booster vaccination respectively), 8 lung transplantation participants recovered from COVID-19, and 22 non-immunocompromised healthy control individuals after initial mRNA vaccination (without history of COVID-19). Anti-spike T cell responses were assayed by stimulating peripheral blood mononuclear cells (PBMCs) with pooled small overlapping peptides spanning the SARS-CoV-2 spike protein, followed by intracellular cytokine staining (ICS) and flow cytometry for release of cytokines in response to stimulation, including negative controls (no peptide stimulation) and positive controls (phorbol myristate acetate [PMA] and ionomycin stimulation). To evaluate for low frequency memory responses, PBMCs were cultured in the presence of the mRNA-1273 vaccine for 14 days before this evaluation. RESULTS: Ionophore stimulation of PBMCs revealed a less inflammatory milieu in terms of interleukin (IL)-2, IL-4, and IL-10 profiling in lung transplantation individuals, reflecting the effect of immunosuppressive treatments. Similar to what we previously reported in healthy vaccinees, spike-specific responses in lung transplantation recipients were undetectable (< 0.01%) when tested 2 weeks after vaccination or later, but were detectable after in vitro culture of PBMCs with mRNA-1273 vaccine to enrich memory T cell responses. This was also seen in COVID-19-recovered lung transplantation recipients. Comparison of their enriched memory responses to controls revealed relatively similar CD4+ T cell memory, but markedly reduced CD8+ T cell memory both after primary vaccination or a booster dose. These responses were not correlated to age or time after transplantation. The vaccine-induced CD4+ and CD8+ responses correlated well in the healthy control group, but poorly in the transplantation groups. CONCLUSIONS: These results reveal a specific defect in CD8+ T cells, which have key roles both in transplanted organ rejection but also antiviral effector responses. Overcoming this defect will require strategies to enhance vaccine immunogenicity in immunocompromised persons.

Optimizing COVID-19 Vaccination Strategy in Pediatric Kidney Transplant Recipients: Humoral and Cellular Response to SARS-CoV-2 mRNA Vaccination.

In this retrospective cohort study, we analyze the early humoral and cellular response in 64 adolescents KTx recipients, after two or three doses of mRNA vaccine BNT162b2 against different variants of COVID-19. After 2 doses, 77.8% % of children with no history of infection had a positive humoral response with a median anti-S IgG level of 1107 (IQR, 593-2,658) BAU/mL. All the patients with a history of infection responded with a higher median IgG level (3,265 (IQR, 1,492-8,178) BAU/mL). In non-responders after 2 doses, 75% responded after a third dose with a median Ab titer at 355 (IQR, 140-3,865 BAU/mL). Neutralizing activity was significantly lower against the delta and the omicron variants compared to the wild-type strain and did not improve after a 3rd dose, while infection did provide higher levels of neutralizations against the variants. T cell specific response correlated with humoral response and no patient displayed a cellular response without a humoral response. Adolescent KTx recipients exhibit a high seroconversion rate after only two doses. A third injection, induces a response in the majority of the non-responders patients but did not counterbalance the strong decrease in neutralizing antibody activities against variants highlighting the need for boosters with specific vaccines.

Efficacy and safety of a fourth dose of the COVID-19 vaccine in kidney transplant recipients: A systematic review and meta-analysis.

BACKGROUND: Kidney transplant recipients (KTRs) who become infected with SARS-CoV-2 are at greater risk of serious illness and death than the general population. To date, the efficacy and safety of the fourth dose of the COVID-19 vaccine in KTRs have not been systematically discussed. METHODS: This systematic review and meta-analysis included articles from PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wanfang Med Online published before May 15, 2022. Studies evaluating the efficacy and safety of a fourth dose of the COVID-19 vaccine in kidney transplant recipients were selected. RESULTS: Nine studies were included in the meta-analysis, with a total of 727 KTRs. The overall pooled seropositivity rate after the fourth COVID-19 vaccine was 60% (95% CI, 49%-71%, I2 = 87.83%, p > 0.01). The pooled proportion of KTRs seronegative after the third dose that transitioned to seropositivity after the fourth dose was 30% (95% CI, 15%-48%, I2 = 94.98%, p < 0.01). CONCLUSIONS: The fourth dose of the COVID-19 vaccine was well tolerated in KTRs with no serious adverse effects. Some KTRs showed a reduced response even after receiving the fourth vaccine dose. Overall, the fourth vaccine dose effectively improved seropositivity in KTRs, as recommended by the World Health Organization for the general population.

Blood unconjugated bilirubin and tacrolimus are negative predictors of specific cellular immunity in kidney transplant recipients after SAR-CoV-2 inactivated vaccination.

The immunogenicity of SARS-CoV-2 vaccines is poor in kidney transplant recipients (KTRs). The factors related to poor immunogenicity to vaccination in KTRs are not well defined. Here, observational study demonstrated no severe adverse effects were observed in KTRs and healthy participants (HPs) after first or second dose of SARS-CoV-2 inactivated vaccine. Different from HPs with excellent immunity against SARS-CoV-2, IgG antibodies against S1 subunit of spike protein, receptor-binding domain, and nucleocapsid protein were not effectively induced in a majority of KTRs after the second dose of inactivated vaccine. Specific T cell immunity response was detectable in 40% KTRs after the second dose of inactivated vaccine. KTRs who developed specific T cell immunity were more likely to be female, and have lower levels of total bilirubin, unconjugated bilirubin, and blood tacrolimus concentrations. Multivariate logistic regression analysis found that blood unconjugated bilirubin and tacrolimus concentration were significantly negatively associated with SARS-CoV-2 specific T cell immunity response in KTRs. Altogether, these data suggest compared to humoral immunity, SARS-CoV-2 specific T cell immunity response are more likely to be induced in KTRs after administration of inactivated vaccine. Reduction of unconjugated bilirubin and tacrolimus concentration might benefit specific cellular immunity response in KTRs following vaccination.

Two Cases of Possible Exacerbation of Chronic Rejection After Anti-SARS-CoV-2 Messenger RNA Vaccination: A Case Report.

In post-liver transplant recipients, SARS-CoV-2 infection is a health threat, and novel messenger RNA vaccines such as Pfizer BioNTech BNT162b2 and Moderna mRNA-1273 are aggressively recommended. However, there are few reports on their adverse effects, some of which may be potentially fatal. We have experienced 2 post-liver transplant recipients with exacerbated chronic rejection after vaccination, one of whom had to undergo retransplant and the other who is still in the process of liver function without improvement. These alarming cases will be presented as case reports.

Retrospective Evaluation of COVID-19 Infection and COVID-19 Vaccines in Heart Transplant Patients.

BACKGROUND: Patients who have performed solid organ transplantation in terms of COVID-19 infection are included in the high-risk group. In this study, it was aimed to evaluate the relationship between vaccination and retrospective evaluation of 32 patients who underwent a heart transplant in the clinic and tested positive for SARS-CoV-2 polymerase chain reaction. METHODS: In this study, demographic characteristics of the cases, comorbidities, timing of heart transplantation, immunosuppressive treatments, symptoms of COVID-19 infection, lung imaging findings, follow-up (outpatient/inpatient), treatments, 1-month mortality, and vaccination histories against COVID-19 infection were evaluated. The data obtained from the study were analyzed with SPSS version 25.0. RESULTS: The 3 most common symptoms are cough (37.5%), myalgia (28.1%), and fever (21.8%). COVID-19 infection was severe in 6.2% of the patients, moderate in 37.5%, and mild in 56.2%. Hospitalization was required in 5 patients (15.6%, 1 in the intensive care unit), and the other patients were followed up as an outpatient. Severe COVID-19 infection was seen more in 33% of unvaccinated patients; 93.5% were vaccinated. Nineteen patients (68%) were vaccinated before COVID-19 infection. Our patients received the CoronoVac (Sinovac, China) vaccine. CONCLUSION: COVID-19 infection is more likely to be severe and mortal in patients with heart transplant recipients. It is also crucial to comply with preventive measures other than immunization in this group of patients. This study is the largest series investigating COVID-19 infection in heart transplant recipient patients in our country.

Immunogenicity and safety of two-dose SARS-CoV-2 vaccination via different platforms in kidney transplantation recipients.

After kidney transplantation, patients exhibit a poor response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. However, the efficacy and adverse effects of vaccines based on different platforms in these patients remain unclear. We prospectively analyzed both anti-spike protein antibody and cellular responses 1 month after the first and second doses of SARS-CoV-2 vaccines in 171 kidney transplant patients. Four vaccines, including one viral vector (ChAdOx1 nCov-19, n = 30), two mRNA (mRNA1273, n = 81 and BNT162b2, n = 38), and one protein subunit (MVC-COV1901, n = 22) vaccines were administered. Among the four vaccines, mRNA1273 elicited the strongest humoral response and induced the highest interferon-γ levels in patients with a positive cellular response against the spike protein. Antiproliferative agents were negatively associated with both the antibody and cellular responses. A transient elevation in creatinine levels was noted in approximately half of the patients after the first dose of mRNA1273 or ChadOx1, and only one of them presented with borderline cellular rejection without definite causality to vaccination. In conclusion, mRNA1273 had better immunogenicity than the other vaccines. Further, renal function needs to be carefully monitored after vaccination, and vaccination strategies should be tailored according to the transplant status and vaccine characteristics.

Analysis of Acquisition of COVID-2019 Neutralizing Antibodies in Organ Transplant Recipients.

BACKGROUND: This study confirmed the kinetics of antibodies acquired by SARS-CoV-2 vaccination in solid-organ transplant recipients and examined their association with the development of COVID-19 and immunosuppressive status in organ transplant recipients. METHODS: We measured COVID-19 neutralizing antibody titer in 21 organ transplant recipients vaccinated with the COVID-19 vaccine and 14 nontransplant recipients (control group) 3 times before and at 1 and 6 months after the third dose of vaccine. By confirming the kinetics of the acquired antibodies, we examined the relevance of the background characteristics of organ transplant recipients, such as the development of infectious diseases and immunosuppressive status. RESULTS: The proportion of patients with neutralizing antibodies was significantly higher in the nontransplant group than in the transplant group. Neutralizing antibody titers were significantly lower in transplant recipients when they were compared before the third dose and 1 month later. In the transplant recipient group, 11 patients were positive, and 10 were negative for neutralizing antibodies. When the causal relationship between the neutralizing antibody titer and background was examined, a positive correlation was found between the antibody titer and the number of years since transplantation, and a negative correlation was found between the tacrolimus trough values, amount of mycophenolate mofetil or steroids taken internally, and antibody titer. CONCLUSION: This study suggests that the effectiveness of vaccination in transplant recipients is associated with the post-transplant period before vaccination and the dose of immunosuppressive agents.

Serologic response to COVID-19 infection or vaccination in pediatric kidney transplant recipients compared to healthy children.

BACKGROUND: Differences in serologic response to COVID-19 infection or vaccination were reported in adult kidney transplant recipients (KTR) compared to non-immunocompromised patients. This study aims to compare the serologic response of naturally infected or vaccinated pediatric KTR to that of controls. METHODS: Thirty-eight KTR and 42 healthy children were included; aged ≤18 years, with a previously confirmed COVID-19 infection or post COVID-19 vaccination. Serological response was measured by anti-spike protein IgG antibody titers. Response post third vaccine was additionally assessed in KTR. RESULTS: Fourteen children in each group had previously confirmed infection. KTR were significantly older and developed a 2-fold higher antibody titer post-infection compared to controls [median (interquartile range [IQR]) age: 14.9 (7.8, 17.5) vs. 6.3 (4.5, 11.5) years, p = 0.02; median (IQR) titer: 1695 (982, 3520) vs. 716 (368, 976) AU/mL, p = 0.03]. Twenty-four KTR and 28 controls were vaccinated. Antibody titer was lower in KTR than in controls [median (IQR): 803 (206, 1744) vs. 8023 (3032, 30,052) AU/mL, p < 0.001]. Fourteen KTR received third vaccine. Antibody titer post booster in KTR reached similar levels to those of controls post two doses [median (IQR) 5923 (2295, 12,278) vs. 8023 (3034, 30,052) AU/mL, p = 0.37] and to KTR post natural infection [5282 AU/mL (2583, 13,257) p = 0.8]. CONCLUSION: Serologic response to COVID-19 infection was significantly higher in KTR than in controls. Antibody level in KTR was higher in response to infection vs. vaccination, contrary to reports in the general population. Response to vaccination in KTR reached levels comparable to controls only after third vaccine.

Analysis of Antibody Responses After COVID-19 Vaccination in Liver Transplant Recipients: A Single-Center Study.

BACKGROUND: Liver transplant (LT) recipients were considered a vulnerable population during the coronavirus disease 2019 (COVID-19) pandemic. The clinical efficacy of the COVID-19 vaccine is unknown in immunocompromised patients. The purpose of this study was to provide evidence of antibody responses after COVID-19 vaccination in LT recipients. METHODS: This study enrolled 46 patients who underwent LT at Samsung Medical Center (Seoul, Korea) before implementation of the one-dose vaccine in Korea. Those who completed the two-dose COVID-19 vaccine between August 2021 and September 2021 were included and followed through December 2021. Semiquantitative anti-spike serologic testing was performed using the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (Roche Diagnostics, Rotkereuz, Switzerland) with a positive cutoff of at least 0.8 U/mL. RESULTS: Among all 46 participants, 40 (87%) demonstrated an antibody response after the second dose of a COVID-19 vaccine, while six (13%) had no antibody response after the second dose. Upon univariate analysis, patients with higher antibody titer had longer years since LT (2.3 ± 2.8 vs. 9.4 ± 5.0, P < 0.001). A lower median tacrolimus (TAC) level before vaccination and after the second dose of COVID-19 vaccine indicated a significantly higher antibody response (2.3 [1.6-3.2] vs. 7.0 [3.7-7.8], P = 0.006, 2.5 [1.6-3.3] vs. 5.7 [4.2-7.2], P = 0.003). Period between 2nd vaccination and serologic testing was significantly higher in the antibody-response group compared to the no-antibody-response group (30.2 ± 24.0 vs. 65.9 ± 35.0, P = 0.012). A multivariate analysis of antibody responses revealed TAC level before vaccination as a statistically significant factor. CONCLUSION: A higher TAC level before vaccination resulted in less effective vaccination in LT patients. Booster vaccinations are required, especially for patients in the early stage after LT who have compromised immune function.

A Pilot Single-Blinded, Randomized, Controlled Trial Comparing BNT162b2 vs. JNJ-78436735 Vaccine as the Third Dose After Two Doses of BNT162b2 Vaccine in Solid Organ Transplant Recipients.

Solid Organ Transplant (SOT) recipients are at significant higher risk for COVID-19 and due to immunosuppressive medication, the immunogenicity after vaccination is suboptimal. In the previous studies, booster method showed significant benefit in this population. In the current study, we compared using a mix-and-match method vs. same vaccine as a third dose in SOT recipients. This was a patient-blinded, single center, randomized controlled trial comparing BNT162b2 vs. JNJ-78436735 vaccine as the third dose after two doses of BNT162b2 vaccine. We included adult SOT recipients with functional graft who had received two doses of BNT162b2 vaccine. Participants were randomly assigned to receive either BNT162b2 or JNJ-78436735 in one-to-one ratio. Primary outcome was SARS-CoV-2 IgG positivity at 1 month after the third dose. Sixty SOT recipients, including 36 kidney, 12 liver, 2 lung, 3 heart, and 5 combined transplants, were enrolled, and 57 recipients were analyzed per protocol. There were no statistically significant differences between the two vaccine protocols for IgG positivity (83.3% vs. 85.2% for BNT162b2 and JNJ-78436735, respectively, p = 0.85, Odds Ratio 0.95, 95% Confidence Interval 0.23-4.00). Comparison of the geometric mean titer demonstrated a higher trend with BNT162b2 (p = 0.09). In this pilot randomized controlled trial comparing mix and match method vs. uniform vaccination in SOT recipients, both vaccines were safely used. Since this was a small sample sized study, there was no statistically significant difference in immunogenicity; though, the mix and match method showed relatively lower geometric mean titer, as compared to uniform vaccine. Further studies need to be conducted to determine duration of this immunogenicity. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05047640?term=20210641&draw=2&rank=1, identifier 20210641.

Kidney Transplant and Dialysis Patients Remain at Increased Risk for Succumbing to COVID-19.

BACKGROUND: Immunocompromised patients have been at an increased risk of succumbing to coronavirus disease 2019 (COVID-19) since the beginning of the pandemic. METHODS: Here, we analyzed mortality and case fatality data from dialysis and kidney transplant patients, and compared each with an age-matched subgroup of the general population. RESULTS: We found that both patients on dialysis and kidney transplant patients remain at increased risk of succumbing to COVID-19 despite all available countermeasures. CONCLUSIONS: The analyses underline the need for additional protection for this vulnerable population.

Hormone replacement therapy and COVID-19 outcomes in solid organ transplant recipients compared with the general population.

Exogenous estrogen is associated with reduced coronavirus disease (COVID) mortality in nonimmunosuppressed/immunocompromised (non-ISC) postmenopausal females. Here, we examined the association of estrogen or testosterone hormone replacement therapy (HRT) with COVID outcomes in solid organ transplant recipients (SOTRs) compared to non-ISC individuals, given known differences in sex-based risk in these populations. SOTRs ≥45 years old with COVID-19 between April 1, 2020 and July 31, 2022 were identified using the National COVID Cohort Collaborative. The association of HRT use in the last 24 months (exogenous systemic estrogens for females; testosterone for males) with major adverse renal or cardiac events in the 90 days post-COVID diagnosis and other secondary outcomes were examined using multivariable Cox proportional hazards models and logistic regression. We repeated these analyses in a non-ISC control group for comparison. Our study included 1135 SOTRs and 43 383 immunocompetent patients on HRT with COVID-19. In non-ISC, HRT use was associated with lower risk of major adverse renal or cardiac events (adjusted hazard ratio [aHR], 0.61; 95% confidence interval [CI], 0.57-0.65 for females; aHR, 0.70; 95% CI, 0.65-0.77 for males) and all secondary outcomes. In SOTR, HRT reduced the risk of acute kidney injury (aHR, 0.79; 95% CI, 0.63-0.98) and mortality (aHR, 0.49; 95% CI, 0.28-0.85) in males with COVID but not in females. The potentially modifying effects of immunosuppression on the benefits of HRT requires further investigation.

SARS-CoV-2 vaccine antibody response and breakthrough infections in transplant recipients.

Rates and modulators of SARS-CoV-2 vaccine nonresponse and breakthrough infections remain unclear in serially vaccinated transplant recipients. In a prospective, mono-centric, observational study, 1878 adult solid organ and hematopoietic cell transplant recipients, with prior SARS-CoV-2 vaccination, were included between March 2021 and February 2022. SARS-CoV-2 anti-spike IgG antibodies were measured at inclusion and details on SARS-CoV-2 vaccine doses and infection were collected. No life-threatening adverse events were reported after a total of 4039 vaccine doses. In transplant recipients without prior SARS-CoV-2 infection (n = 1636), antibody response rates ranged widely, from 47% in lung transplant to 90% in liver transplant and 91% in hematopoietic cell transplant recipients after third vaccine dose. Antibody positivity rate and levels increased after each vaccine dose in all types of transplant recipients. In multivariable analysis, older age, chronic kidney disease and daily dose of mycophenolate and corticosteroids were negatively associated with antibody response rate. Overall rate of breakthrough infections was 25.2% and mainly (90.2%) occurred after third and fourth vaccine dose. Lung transplant recipients had the highest rates of severe breakthrough infection (10.5%) and death (2.5%). In multivariable analysis, older age, daily dose of mycophenolate and corticosteroids were associated with severe breakthrough infection. Transplant recipients with infection before first vaccine dose (n = 160) had higher antibody response rates and levels after each vaccine dose, and a significantly lower overall rate of breakthrough infections compared to those without prior infection. Antibody response after SARS-CoV-2 vaccination and rate of severe breakthrough infections vary largely between different transplant types and are modulated by specific risk factors. The observed heterogeneity supports a tailored approach against COVID-19 in transplant recipients.

Heterologous versus homologous boosting elicits qualitatively distinct, BA.5-cross-reactive T cells in transplant recipients.

BackgroundThe SARS-CoV-2 Omicron BA.5 subvariant escapes vaccination-induced neutralizing antibodies because of mutations in the spike (S) protein. Solid organ transplant recipients (SOTRs) develop high COVID-19 morbidity and poor Omicron variant recognition after COVID-19 vaccination. T cell responses may provide a second line of defense. Therefore, understanding which vaccine regimens induce robust, conserved T cell responses is critical.MethodsWe evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective, observational trial (n = 75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or 2 doses of mRNA followed by Ad26.COV2.S (heterologous boosting).ResultsHomologous boosting with 3 mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated lower pseudo-neutralization against BA.5 compared with the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared with ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared with BNT162b2. IL-21+ cells correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting.ConclusionBoosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants in SOTRs, but alternative vaccine strategies are required to induce robust CD8+ T cell responses.FundingBen-Dov Family; NIH National Institute of Allergy and Infectious Diseases (NIAID) K24AI144954, NIAID K08AI156021, NIAID K23AI157893, NIAID U01AI138897, National Institute of Diabetes and Digestive and Kidney Diseases T32DK007713, and National Cancer Institute 1U54CA260492; Johns Hopkins Vice Dean of Research Support for COVID-19 Research in Immunopathogenesis; and Emory COVID-19 research repository.

Optimizing the use of nirmatrelvir/ritonavir in solid organ transplant recipients with COVID-19: A review of immunosuppressant adjustment strategies.

The coronavirus disease 2019 (COVID-19) pandemic has caused a significant burden of morbidity and mortality worldwide, with solid organ transplant recipients (SOTRs) being particularly vulnerable. Nirmatrelvir and ritonavir have demonstrated the potential for reducing the risk of hospitalization and death in patients with mild-to-moderate COVID-19. However, ritonavir has a strong drug-drug interaction with CYP3A-dependent drugs such as calcineurin inhibitors, potentially leading to rapid increases in blood concentration. As SOTRs are commonly prescribed immunosuppressants, co-administration with nirmatrelvir/ritonavir requires careful consideration. To address this issue, we conducted a literature review to evaluate the use and adverse effects of nirmatrelvir/ritonavir in SOTRs and explore feasible immunosuppressant adjustment regimens. Our findings suggest that nirmatrelvir/ritonavir could be a feasible treatment option for COVID-19 in SOTRs, provided that appropriate immunosuppressive drug management is in place during co-administration. Although prescribing the novel anti-SARS-CoV-2 drug to transplant recipients poses challenges, potential strategies to overcome these issues are discussed. Further studies are needed to determine the optimal dosing strategies of nirmatrelvir/ritonavir, immunosuppressant adjustment, and monitoring in this patient population.

Nirmatrelvir/ritonavir treatment in SARS-CoV-2 positive kidney transplant recipients - a case series with four patients.

BACKGROUND: Despite vaccination coronavirus disease 2019 (COVID-19)-associated mortality caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains high in kidney transplant recipients. Nirmatrelvir is a protease inhibitor with activity against SARS-CoV-2. Nirmatrelvir reduces the risk for mortality and hospitalization, which is approved for treating adults at risk for severe disease. Nirmatrelvir is metabolized by the cytochrome P-450 (CYP) 3A4 isozyme CYP3A4 and is therefore co-administered with the irreversible CYP3A4 inhibitor ritonavir, which results in a drug interaction with tacrolimus. A limited number of patients with nirmatrelvir/ritonavir and tacrolimus therapy after kidney transplantation have been reported to date. It has been reported that tacrolimus was paused during the five-day nirmatrelvir/ritonavir therapy and subtherapeutic tacrolimus levels were observed after finishing nirmatrelvir/ritonavir in two patients. Therefore, optimization of tacrolimus dosing is urgently needed in transplant recipients receiving nirmatrelvir/ritonavir treatment. CASE PRESENTATION: Here, we present our first-hand experience with four patients receiving tacrolimus therapy following kidney transplantation and nirmatrelvir/ritonavir therapy due to COVID-19. Tacrolimus was paused during nirmatrelvir/ritonavir therapy in all patients, which resulted in stable therapeutic tacrolimus levels. Tacrolimus was continued directly after finishing nirmatrelvir/ritonavir to avoid subtherapeutic levels in the first patient treated. This patient received his usual tacrolimus maintenance dose, which resulted in toxic levels. Based on this observation, tacrolimus therapy was continued 24 h after finishing nirmatrelvir/ritonavir treatment at a reduced dose in the subsequent patients. In these patients, therapeutic to supratherapeutic tacrolimus levels were observed despite the therapeutic break and dose reduction. DISCUSSION AND CONCLUSIONS: Based on altered CYP3A4 metabolism, tacrolimus levels have to be closely monitored after treatment with nirmatrelvir/ritonavir. Our study suggests that tacrolimus treatment should be paused during nirmatrelvir/ritonavir medication and be continued 24 h after completing nirmatrelvir/ritonavir therapy at a reduced dose and under close monitoring. Based on the limited number of patients in this study, results must be interpreted with caution.

Does Monocyte Chemoattractant Protein-1 Levels Determine the Prognosis of Covid-19 Disease in Kidney Transplant Recipients?

BACKGROUND: In the normal population, a high monocyte chemoattractant protein (MCP-1) level is an important biomarker for the progression of COVID-19. This study investigated whether MCP-1 level can determine the disease prognosis in kidney transplant (KT) patients with COVID-19. METHODS: A total of 89 patients, including 49 KT patients (group 1) diagnosed with COVID-19 who required hospitalization, and 40 KT patients who did not have COVID-19 disease (group 2), were included. Demographic characteristics and laboratory results of the patients were recorded. The serum reserved for MCP-1 was stored at -80°C and studied blindly by a single microbiologist at the end of the study. RESULTS: While the mean age of the patients was 51.0 years (40.0-59.50) in group 1, it was 48.0 years (40.75-54.75) in group 2 (P > .05). In terms of the female sex, it was 36 (73.5%) and 27 (67.5%) in group 1 and group 2, respectively (P > .05). Similarly, there was no significant difference between the 2 groups regarding primary disease and basal graft function (P > .05). There was a statistically significant difference in inflammation indicators in group 1 compared with group 2 (P < .05). A correlation was found between inflammation indicators and COVID-19 (P < .05). However, no significant correlation was detected between COVID-19 disease and MCP-1 levels in both groups (P > .05). Also, according to basal MCP-1 levels, we did not find a significant difference between survival and nonsurvival patients (164.0 pg/mL [146.0-202.0] vs 156.0 pg/mL [143.0-173.0], respectively (P > .05). CONCLUSION: Monocyte chemoattractant protein, an indicator of inflammation, was not found to predict the prognosis of COVID-19 disease in kidney recipients.