SARS-CoV-2 Vaccination in Solid-Organ Transplant Recipients

The coronavirus disease 2019 (COVID-19) pandemic has posed significant global challenges for solid organ transplant (SOT) recipients. Mortality rates of COVID-19 in this patient population remain high, despite new available therapeutic options and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination. Priority access to SARS-CoV-2 vaccination for waitlisted candidates and for SOT patients and their family members is recommended since the advantage from vaccination reduces the risk of COVID-19-related complications. However, immunogenicity and efficacy of COVID-19 vaccines are lower in waitlisted candidates and SOT recipients than in the general population. Routine systematic assessment of humoral and cellular immune responses after SARS-CoV-2 vaccination is controversial, although highly recommended for investigation and improvement of knowledge. SOT recipients should continue to adhere to preventive protective measures despite vaccination and may undergo passive antibody prophylaxis. This article seeks to provide an update on SARS-CoV-2 vaccination and preventive measures in SOT recipients based on existing literature and international guidelines

Kidney, kidney-pancreas and liver-kidney transplantation in HIV infected individuals: the Italian experience

Until a few years ago, HIV infection was considered an exclusion criteria for organ transplantation. However, more recently, because of the significant increase in life expectancy of HIV-infected persons with highly active antiretroviral therapy (HAART), kidney, kidney-pancreas, heart, lung and liver transplantation have been introduced in this patients population in several centers around the world. To evaluate the possible extension of the indications of kidney transplantation to HIV-infected individuals, the Italian National Centre for Transplantation has designed a protocol to be applied on a national basis. Inclusion criteria required a CD4 count ≥200/mm3 and undetectable HIV viral load for at least 3 months for patients on HAART.The program was voluntarily adopted by 4 transplant centres. From January 2006 through November 2007 a total of 13 HIV infected patients (9 male and 4 female, mean age 46.4 years, range 35-56) underwent cadaveric kidney transplantation (including two kidney-pancreas and two liver-kidney) after a median waiting time of 142 days (range 58-650). Median CD4 cells count at the time of transplantation was 449 (range 210-782) and the HIV-RNA was undetectable in all recipients. HAART was started in all recipients after transplantation and HIV-RNA remain undetectable in all patients. Five patients (38.4%) experienced an episode of biopsy proven acute rejection (steroid resistant in one). Drug-drug interactions between antiretrovirals and immunosuppressive agents required frequent dosage modifications. Graft and patient survival was 100% at a median follow-up of 161 days after transplantation (range 8-669). Despite the limited number of patients and the shortness of the follow-up, our study confirms excellent short term results of kidney transplantation in HIV-infected individuals

Management of infections pre- and post-liver transplantation: Report of an AISF consensus conference

The burden of infectious diseases both before and after liver transplantation is clearly attributable to the dysfunction of defensive mechanisms of the host, both as a result of cirrhosis, as well as the use of immunosuppressive agents. The present document represents the recommendations of an expert panel commended by the Italian Association for the Study of the Liver (AISF), on the prevention and management of infectious complications excluding hepatitis B, D, C, and HIV in the setting of liver transplantation. Due to a decreased response to vaccinations in cirrhosis as well as within the first six months after transplantation, the best timing for immunization is likely before transplant and early in the course of disease. Before transplantation, a vaccination panel including inactivated as well as live attenuated vaccines is recommended, while oral polio vaccine, Calmette-Guerin's bacillus, and Smallpox are contraindicated, whereas after transplantation, live attenuated vaccines are contraindicated. Before transplant, screening protocols should be divided into different levels according to the likelihood of infection, in order to reduce costs for the National Health Service. Recommended preoperative and postoperative prophylaxis varies according to the pathologic agent to which it is directed (bacterial vs. viral vs. fungal). Timing after transplantation greatly determines the most likely agent involved in post-transplant infections, and specific high-risk categories of patients have been identified that warrant closer surveillance. Clearly, specifically targeted treatment protocols are needed upon diagnosis of infections in both the pre- as well as the post-transplant scenarios, not without considering local microbiology and resistance patterns

Influence of Vitamin D in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab

Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug metabolism and elimination. Immune system regulation and immunodeficiency is frequent in non-small cell lung cancer patients. To date, no data have been reported about the relationship between nivolumab and VD. The aim of this study was to quantify plasma 25-hydroxyVD (25-VD) and 1,25-VD, nivolumab, and its anti-antibody before starting treatment (baseline) and at 15, 45 and 60 days of therapy. VD-pathway-associated gene single nucleotide polymorphisms (SNPs) were also evaluated. Molecules were quantified through enzyme-linked immunosorbent assay, and SNPs through real-time PCR. Forty-five patients were enrolled. Median nivolumab concentrations were 12.5 ug/mL, 22.3 ug/mL and 27.1 ug/mL at 15, 45 and 60 days respectively. No anti-nivolumab antibodies were found. Correlations were observed between nivolumab concentrations and 25-VD levels. Nivolumab concentrations were affected by VD-pathway-related gene SNPs. VDBP AC/CC genotype and baseline 25-VD < 10 ng/mL predicted a nivolumab concentration cut-off value of <18.7ug/mL at 15 days, which was associated with tumor progression. This is the first study showing VD marker predictors of nivolumab concentrations in a real-life context of non-small cell lung cancer treatment

Efficacy and safety of reparixin in patients with severe covid-19 Pneumonia. A phase 3, randomized, double-blind placebo-controlled study

Introduction: Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia. Methods: In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200 mg three times daily or placebo for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28. Results: Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment. Conclusions: This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated. Trial registration: ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51

Refractory CMV infection in post-transplant phase: epidemiological framing in the Italian context, current patient management and unmet needs

Background: Cytomegalovirus (CMV) infection usually occurs asymptomatically but can represent an important cause of morbidity and mortality in patients with compromised immune system such as transplant patients. Infection may not respond to standard therapies leading to refractoriness (with or without resistance) which jeopardizes transplant successful outcome. Objective: Since refractoriness represents a critical point, a project has been conducted to verify the epidemiology in the Italian context and to convey the current patients’ unmet medical needs. Methods: The project included: literature analysis, expert interviews and results’ validation through expert opinion. Based on literature data, a questionnaire was built and submitted to 8 experts with proven experience in the management of post-transplant CMV infection. Topics included epidemiology, patient management, unmet needs and future perspective. Outcomes were validated by 3 additional national experts in solid organ transplantation, hematopoietic stem cell transplantation and infectious diseases. Results: Epidemiological rates from literature applied to current transplantation numbers in Italy estimate approximately 109 adults and 8 children with refractory post-transplant CMV infection in 2021. If valganciclovir/ganciclovir are ineffective, foscarnet is predominantly used. When foscarnet fails, patients have no therapeutic alternatives. Despite being a minority, this represents a high medical need. Therefore, the introduction of new therapeutic options with a better efficacy/safety profile would lead to a significant improvement in refractory CMV infection management. Conclusion: Although refractory infections represent a minority, they are the most critical issue that can occur in post-transplant patients resulting in a high unmet need due to the lack of specific treatment options and the toxicity of current treatments used

Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer

Background Bone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy. Methods Pretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM. Results Cohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p < 0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p < 0.0001; Cohort B: 2.7 versus 5.2 months, p < 0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p < 0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78). Conclusions BoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy

Failure of levofloxacin treatment in community-acquired pneumococcal pneumonia

BACKGROUND: Streptococcus pneumoniae is the leading cause of community-acquired pneumonia (CAP). High global incidence of macrolide and penicillin resistance has been reported, whereas fluoroquinolone resistance is uncommon. Current guidelines for suspected CAP in patients with co-morbidity factors and recent antibiotic therapy recommend initial empiric therapy using one fluoroquinolone or one macrolide associated to other drugs (amoxicillin, amoxicillin/clavulanate, broad-spectrum cephalosporins). Resistance to fluoroquinolones is determined by efflux mechanisms and/or mutations in the parC and parE genes coding for topoisomerase IV and/or gyrA and gyrB genes coding for DNA gyrase. No clinical cases due to fluoroquinolone-resistant S. pneumoniae strains have been yet reported from Italy. CASE PRESENTATION: A 72-year-old patient with long history of chronic obstructive pulmonary disease and multiple fluoroquinolone treatments for recurrent lower respiratory tract infections developed fever, increased sputum production, and dyspnea. He was treated with oral levofloxacin (500 mg bid). Three days later, because of acute respiratory insufficiency, the patient was hospitalized. Levofloxacin treatment was supplemented with piperacillin/tazobactam. Microbiological tests detected a S. pneumoniae strain intermediate to penicillin (MIC, 1 mg/L) and resistant to macrolides (MIC >256 mg/L) and fluoroquinolones (MIC >32 mg/L). Point mutations were detected in gyrA (Ser81-Phe), parE (Ile460-Val), and parC gene (Ser79-Phe; Lys137-Asn). Complete clinical response followed treatment with piperacillin/tazobactam. CONCLUSION: This is the first Italian case of community-acquired pneumonia due to a fluoroquinolone-resistant S. pneumoniae isolate where treatment failure of levofloxacin was documented. Molecular analysis showed a group of mutations that have not yet been reported from Italy and has been detected only twice in Europe. Treatment with piperacillin/tazobactam appears an effective means to inhibit fluoroquinolone-resistant strains of S. pneumoniae causing community-acquired pneumonia in seriously ill patients

Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Enterobacterales Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study)

Background. Few data are reported in the literature about the outcome of patients with severe extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) infections treated with ceftolozane/tazobactam (C/T), in empiric or definitive therapy.Methods. A multicenter retrospective study was performed in Italy (June 2016-June 2019). Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to ESBL-E infection and lack of microbiological evidence of infection. The primary end point was to identify predictors of clinical failure of C/T therapy.Results. C/T treatment was documented in 153 patients: pneumonia was the most common diagnosis (n = 46, 30%), followed by 34 cases of complicated urinary tract infections (22.2%). Septic shock was observed in 42 (27.5%) patients. C/T was used as empiric therapy in 46 (30%) patients and as monotherapy in 127 (83%) patients. Favorable clinical outcome was observed in 128 (83.7%) patients; 25 patients were considered to have failed C/T therapy. Overall, 30-day mortality was reported for 15 (9.8%) patients. At multivariate analysis, Charlson comorbidity index >4 (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-3.5; P = .02), septic shock (OR, 6.2; 95% CI, 3.8-7.9; P < .001), and continuous renal replacement therapy (OR, 3.1; 95% CI, 1.9-5.3; P = .001) were independently associated with clinical failure, whereas empiric therapy displaying in vitro activity (OR, 0.12; 95% CI, 0.01-0.34; P < .001) and adequate source control of infection (OR, 0.42; 95% CI, 0.14-0.55; P < .001) were associated with clinical success.Conclusions. Data show that C/T could be a valid option in empiric and/or targeted therapy in patients with severe infections caused by ESBL-producing Enterobacterales. Clinicians should be aware of the risk of clinical failure with standard-dose C/T therapy in septic patients receiving CRRT

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant

BACKGROUND: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. METHODS: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. RESULTS: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. CONCLUSIONS: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level