Solid Organ Transplantation Research Articles

MiRNAs, dd-cf-DNA, and Chemokines as Potential Noninvasive Biomarkers for the Assessment of Clinical Graft Evolution and Personalized Immunosuppression Requirement in Solid Organ Transplantation.

The use of noninvasive biomarkers may reduce the need for biopsy and guide immunosuppression adjustments during transplantation. The scientific community in solid organ transplantation currently considers that chemokines, T- and B-cell immunophenotypes, and gene expression, among other molecular biomarkers, have great potential as diagnostic and predictive biomarkers for graft evolution; however, in clinical practice, few valid early biomarkers have emerged. This review focuses on the most relevant scientific advances in this field in the last 5 years regarding the role of 3 biomarkers: miRNAs, chemokines, and ddcf-DNA, in both adult and pediatric populations. An update was provided on the scores based on the combination of these biomarkers. The most-featured articles were identified through a literature search of the PubMed database. This review provides a comprehensive analysis of the potential clinical applications of these biomarkers in the diagnosis and prediction of graft outcomes and discusses the reasons why none have been implemented in clinical practice to date. Translating these biomarkers into routine clinical practice and combining them with pharmacogenetics and pharmacokinetic monitoring is challenging; however, it is the key to present/future individualized immunosuppressive therapies. It is essential that they be shown to be applicable and robust in real-life patient conditions and properly evaluate their added value when combined with the standard-of-care factor monitoring for graft clinical assessment. Partnership strategies among scientists, academic institutions, consortia, including expert working groups and scientific societies, and pharmaceutical and/or biotechnology companies should promote the development of prospective, randomized, multicenter intervention studies for adequate clinical validation of these biomarkers and their monitoring frequency, and their commercialization to make them available to transplant physicians.

Quadrivalent HPV (4vHPV) vaccine immunogenicity and safety in women using immunosuppressive drugs due to solid organ transplant

IntroductionImmunocompromised persons are at high risk of persistent Human Papilloma Virus (HPV) infection and associated diseases. Few studies evaluated HPV vaccines in immunocompromised persons. This study aimed to evaluate the quadrivalent HPV vaccine (4vHPV) immunogenicity and safety in solid organ transplant (SOT) recipients, in comparison to immunocompetent women (IC).MethodsOpen-label clinical trial that enrolled SOT recipients and immunocompetent women aged 18 to 45 years. All participants received three doses of 4vHPV vaccine. Blood samples were drawn for evaluation of immune responses at baseline and one month after the third vaccination. Seroconversion rates and antibody geometric mean concentration (GMC) against HPV 6, 11, 16, 18, 31, 35, 52 and 58 were measured with in-house multiplexed serology assay (xMAP technology). Follow-up for the local and systemic adverse events (AEs) continued for seven days after each vaccination. Severe AEs were evaluated throughout the study.Results125 SOT and 132 immunocompetent women were enrolled; 105 (84%) SOT and 119 (90%) immunocompetent women completed the study. At baseline, HPV seropositivity was not significantly different between groups. Seroconversion rates were significantly lower in SOT (HPV18, 57%; HPV6 and 16, 69%; and HPV11, 72%) than in immunocompetent women (100% seroconversion to all vaccine types) (p<0.001). Antibody GMCs of all four HPV vaccine types were also significantly lower in SOT (p<0.001). Pain in the injection site and headache were the most frequent adverse event in both groups. Local pain was more frequent in immunocompetent women than in SOT recipients. Rates of other AEs were comparable in both groups.Conclusion4vHPV vaccine was well-tolerated by SOT recipients. We found strong evidence of lower humoral immune responses to 4vHPV vaccine in SOT compared to immunocompetent women, which strengthen recommendation of routine cervical cancer screening in SOT recipients regardless of HPV vaccination status.

Long-term treatment outcomes of complicated acute diverticulitis in immunocompromised patients

PurposeThe main aim of this study was to determine the short- and long-term outcomes of the non-operative management of acute left-sided complicated diverticulitis (ALCD) in severely immunocompromised patients (IMS group) and compare them with immunocompetent patients (IC group). The secondary aim was to assess the necessity of an elective surgery following a successful prior non-operative management in the IMS group after a non-operative management of the first episode of ALCD.MethodsPatients presented with their first episode of ALCD between 2012 and 2018 were retrospectively reviewed. Only severely immunosuppressed patients were considered for the analysis, including the following: long-term oral or intravenous steroid intake, current malignancy undergoing chemotherapy, chronic kidney disease on hemodialysis, or solid organ transplant with immunosuppressive medication. For each group, demographic data, severity of the episode, management decisions (conservative or operative), and short- and long-term outcomes were recorded and compared. A sub-analysis of patients with ALCD associating and abscess (modified Hinchey classification Ib/II) was performed.ResultsA total of 290 patients were included in the study: 50 among the IMS and 240 among the IC group. The rate of emergent surgery was higher in the IMS group (50.0% vs. 22.5%, p < 0.001) and was associated with increased morbidity (72.4% vs. 50.0%, p = 0.041) and mortality (24.1% vs. 4.3%, p = 0.003). The duration of the hospital stay was significantly longer in the IMS group (15 vs. 8 days, p < 0.001). The final stoma rate was significantly higher in the IMS group (82.1% vs. 22.9, p < 0.001), with a median follow-up of 51.4 months. A total of 141 patients presented ALCD with an abscess; 25 in the IMS and 116 in the IC group. There was a higher rate of surgical intervention among the IMS group as the initial treatment approach (24.0% vs. 5.2%, p = 0.002), even though the conservative treatment had a similar rate of success (81.3% vs. 92.0%, p = 0.178). The recurrence rate following a non-operative approach was similar (IMS: 31.2% vs. 35.4% in the IC group, p = 0.169). Furthermore, 81.2% of non-operatively managed IMS patients (13 out of 16) did not require a surgical intervention at the end of the follow-up, with similar findings in the IC group (78/96, 81.2%, p = 0.148).ConclusionMedical treatment of immunosuppressed patients during their first ALCD episode associated with an abscess is feasible, with a high success rate and results comparable with the IC group. Moreover, taking into account the readmission rates, the need for emergent surgery of the recurrence, and the perioperative mortality and morbidity in the IMS group, conservative management with no differed scheduled surgery seems to be a safe option in this subgroup of patients.

Serum antigen tests for the diagnosis of invasive aspergillosis: a retrospective comparison of five Aspergillus antigen assays and one beta-D-glucan assay.

Invasive aspergillosis (IA) is a life-threatening infection. Early and specific diagnosis is pivotal to ensure adequate therapy. Antigen testing from blood is a widespread and convenient diagnostic approach. Various tests for the detection of Aspergillus antigen as well as for the panfungal antigen β-1,3-D-glucan (BDG) are available, for which comprehensive comparisons are still lacking. Blood samples of 82 proven/probable (11/71) IA patients and 52 controls were tested using two enzyme-linked immunosorbent assays (ELISAs) (Bio-Rad and Euroimmun), one chemiluminescent immunoassay (CLIA) (Vircell), one BDG assay (Fujifilm Wako), and two point of care (PoC) assays (Immy sōna and OLM). PoC assays were evaluated visually and used automated read out systems. Of the 82 IA patients, 37 had received solid organ transplantation (SOT) and 25 hematopoietic stem cell transplant (HSCT). Sensitivities and specificities for the eight test systems ranged from 27% to 71% and from 64% to 100%. Estimating a 10% prevalence of IA, test performance would have resulted in positive and negative predictive values of 14%-100% and 91%-95%. Areas under the curve (AUCs) for all tests except GM were below 0.7. When the cut-off values for quantitative tests were normalized to a specificity close to 95%, sensitivities ranged from 14% to 40%. The use of automated read out systems for the PoC assays had a significant impact. Combining different tests did not result in better test strategies. Sensitivity of Aspergillus antigen testing from single serum samples is low. Due to specificity issues, the majority of tests is not suited for screening purposes. The different assays can meet different needs in different diagnostic settings.

Current and future strategies for the prevention and treatment of cytomegalovirus infections in transplantation.

Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ and allogeneic hematopoietic cell transplantation. Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. Observational studies and interventional trials of commercially-available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.

A Scoping Review of Arthropod-Borne Flavivirus Infections in Solid Organ Transplant Recipients.

Arthropod-borne flaviviruses (ABFs), transmitted by mosquitoes or ticks, are increasing due to climate change and globalization. This scoping review examines the epidemiology, clinical characteristics, diagnostics, treatment, and outcomes of ABF infection in solid organ transplant recipients (SOTRs). A database search up to January 25, 2024, focused on ABFs such as West Nile virus (WNV), dengue virus (DENV), Japanese encephalitis virus (JEV), Powassan virus (POWV), yellow fever virus (YFV), and Zika virus (ZIKV), limited to SOTRs. We identified 173 WNV cases from 84 studies, with 28 donor-derived infections (DDIs). Common clinical features included fever (78.5%), altered mental status (65.1%), and weakness or paralysis (45.6%). Treatment involved reducing immunosuppression (IS) in 93 cases, with intravenous immunoglobulin (IVIG), interferon alfa-2b, and ribavirin used in 75 cases. Seven cases involved graft loss or rejection post-infection. WNV infection had a 23.7% mortality rate, with severe neurological complications in 43.9% For DENV infection, 386 cases from 47 studies were identified, including 14 DDI cases. Symptoms included fever (85%), myalgias (56.4%), and headache or retro-orbital pain (34.6%). Severe dengue occurred in 50 cases (13.0%). IVIG was administered in six cases. Reduction in IS was reported in 116 patients. DENV mortality rate was 4.9%. Additionally, 26 cases of less common ABFs such as JEV, POWV, YFV, and ZIKV were described. In summary, ABF infections among SOTRs are associated with higher morbidity and mortality compared to the general population, emphasizing the need for improved preventive strategies, timely diagnosis, and optimized management protocols.

Comment on: Safety of penile prosthesis implantation in solid organ transplant recipients: a systematic review.

Comment on: Safety of penile prosthesis implantation in solid organ transplant recipients: a systematic review.

Risk factors for SARS-CoV-2 infection and severe COVID-19 in unvaccinated solid organ transplant recipients

The role of immunosuppressive therapy on SARS-CoV-2 infection risk and COVID-19 severity remains unclear in unvaccinated solid organ transplant recipients. We included 1957 organ transplant recipients between July 2020 and April 2021 to analyze whether baseline immunosuppressive therapy and other risk factors are associated with SARS-CoV-2 infection and severe COVID-19. In total, 247 (12.6%) had SARS-CoV-2 (defined as positive nasopharyngeal swab and/or positive antibody titer). Of these, 57 (23.1%) had severe COVID-19, defined as oxygen supplementation, intensive care unit admission or death. Multivariable analysis identified diabetes (hazard ratio (HR) 1.39 (95% confidence interval (CI) 1.05–1.83)), chronic lung disease (HR 1.71 (95% CI 1.13–2.60)) and contact with a COVID-19 positive individual (HR 3.61 (95% CI 2.61–4.99) as independent risk factors for SARS-CoV-2 infection. There was no association between immunosuppressive therapy and infection risk. Severe COVID-19 was multivariably associated with hypertension (OR 5.45 (95% CI 1.66–17.84)), chronic kidney disease (OR 3.55 (95% CI 1.75–7.19)), corticosteroid use (OR 2.93 (95% CI 1.03–2.55)) and having a COVID-19 positive housemate (OR 6.77 (95% CI 2.65–17.28)). In conclusion, baseline corticosteroid use, but no other immunosuppressive agent, is independently associated with severe COVID-19 in unvaccinated SOT recipients after correction for hypertension, chronic kidney disease, housemates affected by COVID-19 and transplant type.

Risk Factors of Post-Traumatic Stress in Pediatric Solid Organ Transplant Recipients.

Life with end-stage organ failure is accompanied by an accumulation of traumatic medical or surgical experiences. Despite recovery after solid organ transplantation (SOT), many children and adolescents develop post-traumatic stress symptoms (PTSS). PTSS remain underappreciated as a major comorbidity in SOT programs, despite their association with decreased quality of life. We conducted a retrospective, cross-sectional study of 86 pediatric SOT recipients (17 heart, 44 kidney, and 25 liver) to evaluate potential determinants of PTSS. Trauma symptoms were measured by the Child Trauma Screening Questionnaire (CTSQ). Demographic, baseline, and contemporaneous factors were tested for independent association with CTSQ scores. The median post-transplant CTSQ score was 2 (IQR 1-4), and 22% were identified as high risk (score ≥5) for PTSD. Higher CTSQ scores were independently associated with the number of ICU days within the previous 12 months, the number of medications (complexity), and involvement with foster care in the primary model (R2 [adj.] = 0.26). The addition of the Family Impact Module improved the overall model (R2 [adj.] = 0.33), wherein higher family functioning was independently associated with lower CTSQ scores. An exploratory analysis of pre-transplant patients (n = 34) found a median pre-transplant CTSQ of 2 (IQR 1-6), suggesting that PTSS are onset before transplant and persist afterward. PTSS are highly prevalent in the SOT population. Risk factors include recent adverse medical experiences and complexity, whereas family stability may be protective. Additional research is needed to improve early ascertainment and support for patients at high risk of developing PTSS throughout their transplant journey.

Suspicious of Acute Kidney Graft Rejection: Tacrolimus Pharmacokinetics Under Methylprednisolone Therapy.

Acute rejection remains one of the main complications in the first months after transplantation and may influence long-term outcomes. Tacrolimus has proven its usefulness in solid organ transplants and its monitoring through the application of pharmacokinetic concepts to optimize individual drug therapy. This research proposes to evaluate the tacrolimus pharmacokinetic parameters in patients suspected of acute kidney graft rejection under methylprednisolone pulse therapy. Eleven adult tacrolimus-treated renal recipients were selected from a prospective, single-arm, single-center cohort study, with suspicion of acute rejection although in use of methylprednisolone pulses therapy. They were followed up for three months posttransplantation, being tacrolimus trough serum concentrations determined using a chemiluminescent magnetic immunoassay, and pharmacokinetic parameters were estimated by using a nonlinear mixed-effects model implemented by Monolix 2020R1. A tacrolimus trough serum concentration range of 8 to 12 ng.mL-1 was considered therapeutic. Six patients showed acute cellular rejection, and two of them in addition had an antibody- mediated rejection. Tacrolimus trough serum concentration was below the reference range in eight patients. Most patients showed a high tacrolimus concentration intrapatient and pharmacokinetic parameters variability. The obtained pharmacokinetics parameters helped in understanding the kidney recipient patients' tacrolimus behavior, assisting in the improvement of individual drug therapy and reducing the risk of acute rejection episodes.

Outcomes and inflammation changes in different types of immunocompromised patients with critically ill COVID-19 admitted to ICU: a national multicenter study

BackgroundImmunocompromised patients face higher risks of Severe Acute Respiratory Syndrome Coronavirus 2 infection and co-infections, leading to a possibility of high disease severity and poor outcomes. Conversely, immunosuppression can mitigate the excessive inflammatory response induced by the virus, potentially reducing disease severity. This study aims to investigate the prognostic differences and early inflammatory response characteristics in various types of immunocompromised patients with severe coronavirus disease 2019 (COVID-19) admitted to intensive care unit (ICU), summarize their clinical features, and explore potential mechanisms.MethodsA retrospective analysis was conducted on critically ill COVID-19 patients admitted to the ICU of 59 medical centers in mainland China during the Omicron outbreak from November 2022 to February 2023. Patients were categorized into two groups based on their immunosuppression status: immunocompromised and immunocompetent. Immunocompromised patients were further subdivided by etiology into cancer patients, solid organ transplant (SOT) patients, and other immunocompromised groups, with immunocompetent patients serving as controls. The mortality rates, respiratory support, complications, and early inflammatory cytokine dynamics upon ICU admission among different populations were analyzed.ResultsA total of 2030 critically ill COVID-19 patients admitted to ICU were included, with 242 in the immunocompromised group and 1788 in the immunocompetent group. Cancer patients had a higher median age of 69 years (IQR 59, 77), while SOT patients were generally younger and had less severe illness upon ICU admission, with a median APACHE II score of 12.0 (IQR 8.0, 20.0). Cancer patients had a twofold increased risk of death (OR = 2.02, 95% CI 1.18–3.46, P = 0.010) compared to immunocompetent patients. SOT and cancer patients exhibited higher C-reactive protein and serum ferritin levels than the immunocompetent group in their early days of ICU admission. The CD8+ T cells dynamics were inversely correlated in cancer and SOT patients, with Interleukin-6 levels consistently lower in the SOT group compared to both immunocompetent and cancer patients.ConclusionCritically ill COVID-19 patients admitted to the ICU exhibit distinct clinical outcomes based on their immunosuppression status, with cancer patients facing the highest mortality rate due to variations in inflammatory responses linked to their immunosuppression mechanisms. Monitoring dynamic changes in inflammatory markers and immune cells, particularly CD8+ T lymphocytes and IL-6, may offer valuable prognostic insights for these patients.

Donor-Specific Blood Transfusion in Lung Transplantation

Lung transplantation is still hindered by a high rate of chronic rejection necessitating profound immunosuppression with its associated complications. Donor-specific blood transfusion is a pre-transplant strategy aimed at improving graft acceptance. In contrast with standard stored blood or donor-specific regulatory T cells transfusions, this approach utilizes fresh whole blood from the donor prior to allograft transplantation, encompassing all cell types and plasma. The precise mechanisms underlying donor-specific blood transfusion-induced tolerance remain incompletely understood. Associations with regulatory/helper T cells, modulation of mononuclear phagocytic cells or microchimerism have been suggested. While numerous (pre-)clinical studies have explored its application in solid organ transplants like liver, kidney, and intestine, limited attention has been given to the setting of lung transplantation. This comprehensive review summarizes existing knowledge on the mechanisms and outcomes of donor-specific blood transfusion in solid organ transplants both in preclinical and clinical settings. We also address the potential benefits and risks associated with donor-specific blood transfusion in the field of lung transplantation, offering insights into future research directions.

Proceedings of the Conference “CMV Vaccine Development—How Close Are We?” (27–28 September 2023)

Congenital cytomegalovirus (cCMV) is the most common infectious cause of disability in children, including sensorineural hearing loss. There is interest in developing a pre-conception vaccine that could confer protective immunity on a woman of child-bearing age, hence resulting in a reduced cCMV disease burden. Other populations, including solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) patients, could also benefit from CMV vaccination. To review and discuss vaccines that are in clinical development, a workshop, sponsored by the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID), was empaneled. At this workshop, correlates of protective immunity against CMV, epidemiologic features of CMV transmission, and vaccine platforms in development were reviewed. Representatives from academia, pharma, and the NIH engaged in discussion on the current state-of-the-art in CMV vaccinology. A summary of the presentations from this is provided in this report.

Draft genomes of the bile duct microbiome strains Klebsiella pneumoniae and Enterococcus lactis isolated from bilioenteric drainages with biofilm-forming abilities.

We describe the genetic properties of two strains isolated from the elusive bile duct microbiome from solid organ transplant patients. Bacterial strains Enterococcus lactis (MS-STENT-08-E-001) and Klebsiella pneumoniae (MS-STENT-01-M-001) were isolated from the biofilms of bile duct catheters.

Beyond Awareness: Hope for a CMV Vaccine! An Introduction to the Conference, “CMV Vaccine Development—How Close Are We?” (27–28 September 2023)

Congenital cytomegalovirus (cCMV) is the most common infectious cause of disability in children. The major theme of this National Institute of Allergy and Infectious Diseases (NIAID) workshop, “CMV Vaccine Development—How Close Are We?”, was to report progress on the development of a pre-conception vaccine that could confer protective immunity for women of child-bearing age. Such a vaccine could result in a reduced cCMV disease burden, although other populations, including solid organ transplant and hematopoietic stem cell transplant patients, could benefit as well. To frame the compelling need for a cCMV vaccine, a keynote lecture by Dr. Megan Pesch, immediate past-president of the National CMV Foundation and a leading cCMV researcher from the University of Michigan, was given. This manuscript provides a summary of Dr. Pesch’s presentation from this workshop, which was written as the introductory conference report for the meeting.

Epstein-Barr virus positive post-transplant lymphoproliferative disorder with significantly decreased T-cell chimerism early after transplantation: A case report

BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation (allo-HCT) or solid organ transplantation (SOT). Unlike SOT, PTLD after allo-HCT usually originates from the donor and is rarely accompanied by a loss of donor chimerism. CASE SUMMARY We report a case of Epstein-Barr virus positive PTLD manifesting as diffuse large B-cell lymphoma (DLBCL) with significantly decreased T-cell chimerism early after allo-HCT. A 30-year-old patient with acute myeloid leukemia underwent unrelated allo-HCT after first complete remission. Nearly 3 mo after transplantation, the patient developed cervical lymph node enlargement and gastric lesions, both of which were pathologically suggestive of DLBCL. Meanwhile, the patient experienced a significant and persistent decrease in T-cell chimerism. A partial remission was achieved after chemotherapy with single agent rituximab and subsequent R-CHOP combined chemotherapy. CONCLUSION The loss of T-cell chimerism and the concomitant T-cell insufficiency may be the cause of PTLD in this patient.

Post-Transplant Vitamin D Deficiency in Lung Transplant Recipients: Impact on Outcomes and Prognosis

Despite the recognized clinical significance of vitamin D deficiency in other solid organ transplant recipients, its specific relevance in lung transplantation remains to be fully understood. In this study, we performed a retrospective observational study on the impact of vitamin D deficiency on clinical outcomes and prognosis in 125 lung transplant recipients (LTRs) from October 2014 to March 2020 at a university hospital in Seoul, South Korea. Among 125 LTRs, 51 patients (40.8%) were vitamin D deficient. LTRs in the vitamin D-deficient group exhibited a higher incidence of post-transplant pneumonia and overall mortality than those with normal vitamin D levels during the follow-up period. This trend persisted when subjects were stratified into vitamin D tertiles. Furthermore, post-transplant vitamin D levels and C-reactive protein (CRP) significantly impacted pneumonia incidence and survival outcomes. Prognosis also varied based on cumulative vitamin D supplementation after transplantation, with patients receiving higher cumulative supplementation demonstrating improved prognosis. Our findings underscore the importance of assessing and maintaining optimal vitamin D levels post-transplantation, suggesting a potential avenue for improving outcomes in lung transplant recipients, especially in mitigating infection risk and enhancing long-term survival. Further research into optimal vitamin D levels and supplementation strategies in this population is warranted.

A Narrative Review of Chromatographic Bioanalytical Methods for Quantifying Everolimus in Therapeutic Drug Monitoring Applications

Background: Methods for measuring drug levels in the body are crucial for improving therapeutic drug monitoring (TDM) and personalized medicine. In solid-organ transplants, TDM is essential for the management of immunosuppressive drugs to avoid toxicity and organ rejection. Everolimus is a commonly used immunosuppressant with a small range of safe doses; therefore, it is important to adjust the dose according to each patient's needs. Therefore, reliable methods are required to accurately measure everolimus levels. This study aims to conduct a comprehensive and updated narrative review of chromatographic bioanalytical methods for everolimus quantification. Methods: The authors searched for original research articles published between 2013 and 2023 in Scopus and PubMed and found 295 articles after removing duplicates. Based on their titles and summaries, 30 articles were selected for a detailed review and 25 articles were included in the final analysis. Results: Among the 25 studies, 16 used protein precipitation, mainly with methanol, to prepare the samples, 12 used high-performance liquid chromatography, 11 used ultra-performance liquid chromatography, and 2 used both. Almost all the studies (24 of 25) used tandem mass spectrometry for detection, whereas only 1 used ultraviolet. Conclusions: This comprehensive review of bioanalytical methods for measuring everolimus using chromatography is a useful resource for researchers developing bioanalytical methods for TDM applications. Future trends in everolimus measurement include achieving lower detection limits, owing to the trend of reducing drug doses in therapy by improving sample extraction techniques and using more sensitive methods.

Atypical presentation of PJP: hypercalcemia and kidney injury in an allogeneic stem cell transplant recipient

BackgroundPneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that primarily affects immunocompromised individuals. Typical symptoms of PJP include the subacute onset of dyspnea, nonproductive cough, and low-grade fever. In hematology patients, particularly those who are allogeneic stem cell transplant recipients, the disease often presents with a more aggressive clinical course. While hypercalcemia has been documented as a manifestation of PJP in some solid organ transplant recipients, it has not been reported in hematology or stem cell transplant patients.Case presentationHere, we present a case of PJP in a 56-year-old male allogeneic stem cell transplant recipient, who developed hypercalcemia and renal failure during the late post-transplant period. The patient had a history of allogeneic stem cell transplantation due to acute myeloid leukemia. He presented with symptoms of fatigue and weakness. Laboratory tests revealed hypercalcemia (13.8 mg/dL) and elevated serum creatinine levels (2.3 mg/dL). The patient was hospitalized, and despite initial treatment with hydration and furosemide, the hypercalcemia persisted, leading to the administration of denosumab. During follow-up, hypoxia was detected, and a chest CT scan revealed mosaic attenuation and ground-glass opacities. Bronchoscopy was performed, and PCR testing confirmed the presence of Pneumocystis jirovecii. Other causes of hypercalcemia were ruled out, with PTH measured at 13.8 pg/mL (normal range 15–65 pg/mL), albumin at 3.71 g/dL, 1.25-dihydroxy vitamin D3 at 96 ng/dL (normal range 26–95 ng/dL), and 25-hydroxy vitamin D at 32.5 ng/mL (normal range 20–40 ng/mL). A PET-CT scan demonstrated no pathological FDG uptake, with the exception of findings suggestive of a pulmonary infection. Following treatment with trimethoprim-sulfamethoxazole and denosumab, the patient’s hypercalcemia and infection resolved.Conclusions Although rare, PJP can present with hypercalcemia and kidney injury in allogeneic stem cell transplant recipients. Early diagnosis and treatment can improve both PJP and hypercalcemia.

Tremor after solid organ transplantation: Results from the TransplantLines Biobank and Cohort Study.

Tremor is a frequent complaint of solid organ transplant recipients. We report on the largest population investigated with clinical neurophysiological methods. Our aim is to objectively establish the tremor prevalence and syndrome in the largest population of solid organ transplant recipients. Tremor was measured in heart, kidney, liver, and lung recipients, using accelerometers during rest, postural, and weight-loaded conditions. The 95th percentile of healthy kidney donors' tremor amplitude was used as the cutoff to determine the presence of tremor in transplant recipients. Tremor frequency, frequency variability, and effect of loading were used to investigate enhanced physiological tremor as the likely tremor syndrome. Impact on activities of daily life was assessed, and correlations with tacrolimus blood levels were investigated. Tremor was present in 52% of 246 transplant recipients, typically in postural positions. Mean tremor frequency was 6.1 (±2.0) Hz; mean tremor variability was 2.6 (±1.8) Hz. A frequency decrease upon loading was found in 83% of patients with tremor. Sixty-five percent of patients met formal clinical neurophysiological criteria for enhanced physiological tremor. Tremor-related impairment was present in 55% and correlated with tremor amplitude (ρ = 0.23, p ≤ 0.001). In a binominal regression analysis, tacrolimus blood levels were independently associated with tremor prevalence (p = 0.009). More than half of solid organ transplant recipients experience a tremor that best fits the syndrome of enhanced physiological tremor. This is the first objective study on tremor that has established a better understanding of the neurophysiological mechanisms of tremor in a large population of solid organ transplant recipients.