PET/CT Imaging of Infectious Diseases: Overview of Novel Radiopharmaceuticals.

Infectious diseases represent one of the most common causes of hospital admission worldwide. The diagnostic work-up requires a complex clinical approach, including laboratory data, CT and MRI, other imaging tools, and microbiologic cultures. PET/CT with 18F-FDG can support the clinical diagnosis, allowing visualization of increased glucose metabolism in activated macrophages and monocytes; this tracer presents limits in differentiating between aseptic inflammation and infection. Novel PET radiopharmaceuticals have been developed to overcome these limits; 11C/18F-labeled bacterial agents, several 68Ga-labeled molecules, and white blood cells labeled with 18F-FDG are emerging PET tracers under study, showing interesting preliminary results. The best choice among these tracers can be unclear. This overview aims to discuss the most common diagnostic applications of 18F-FDG PET/CT in infectious diseases and, as a counterpoint, to describe and debate the advantages and peculiarities of the latest PET radiopharmaceuticals in the field of infectious diseases, which will probably improve the diagnosis and prognostic stratification of patients with active infectious diseases.

Risk of Cardiovascular Events in People with HIV (PWH) Treated with Integrase Strand-Transfer Inhibitors: The Debate Is Not Over; Results of the SCOLTA Study.

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH.

COVID-19 vaccine related hypermetabolic lymph nodes on PET/CT: Implications of inflammatory findings in cancer imaging.

We observed several patients presenting 2-[18F]FDG uptake in the reactive axillary lymph node at PET/CT imaging, ipsilateral to the site of the COVID-19 vaccine injection. Analog finding was documented at [18F]Choline PET/CT. The aim of our study was to describe this source of false positive cases. All patients examined by PET/CT were included in the study. Data concerning patient anamnesis, laterality, and time interval from recent COVID-19 vaccination were recorded. SUVmax was measured in all lymph nodes expressing tracer uptake after vaccination. Among 712 PET/CT scans with 2-[18F]FDG, 104 were submitted to vaccination; 89/104 patients (85%) presented axillary and/or deltoid tracer uptake, related to recent COVID-19 vaccine administration (median from injection: 11 days). The mean SUVmax of these findings was 2.1 (range 1.6-3.3). Among 89 patients with false positive axillary uptake, 36 subjects had received chemotherapy due to lymph node metastases from somatic cancer or lymphomas, prior to the scan: 6/36 patients with lymph node metastases showed no response to therapy or progression disease. The mean SUVmax value of lymph nodal localizations of somatic cancers/lymphomas after chemotherapy was 7.8. Only 1/31 prostate cancer patients examined by [18F]Choline PET/CT showed post-vaccine axillary lymph node uptake. These findings were not recorded at PET/CT scans with [18F]-6-FDOPA, [68Ga]Ga-DOTATOC, and [18F]-fluoride. Following COVID-19 mass vaccination, a significant percentage of patients examined by 2-[18F]FDG PET/CT presents axillary, reactive lymph node uptake. Anamnesis, low-dose CT, and ultrasonography facilitated correct diagnosis. Semi-quantitative assessment supported the visual analysis of PET/CT data; SUVmax values of metastatic lymph nodes were considerably higher than post-vaccine lymph nodes. [18F]Choline uptake in reactive lymph node after vaccination was confirmed. After the COVID-19 pandemic, nuclear physicians need to take these potential false positive cases into account in daily clinical practice.

Durability of Dolutegravir-Based Regimens: A 5-Year Prospective Observational Study.

This study evaluates the frequency and causes of dolutegravir (DTG) discontinuation along 5 years of follow-up, in both antiretroviral treatment (ART)-naive and experienced people living with HIV (PLWH). This is a prospective multi-center cohort study enrolling PLWH on DTG from July 2014 until November 2020. DTG-durability was investigated using the Kaplan-Meier survival curve. The Cox proportional-hazards model was used for estimating the hazard ratio (HR) of DTG discontinuation for any cause, and for adverse events (AEs). Nine hundred sixty-three PLWH were included, 25.3% were women and 28.0% were ART-naive. Discontinuations for any causes were 10.1 [95% confidence interval (95% CI) 8.9-11.5] per 100 person-years, similar in most regimens, with the apparent exception of tenofovir alafenamide/emtricitabine+DTG (p < 0.0001). In the multivariable Cox regression model, non-Caucasian ethnicity, age ≥50 years, and lower estimated glomerular filtration rate (eGFR) were associated with a higher probability of DTG interruption. The incidence rate of virological failure was 0.4 (95% CI 0.2-0.7) per 100 person-years, while the estimated discontinuation rate for AEs was 4.0 (3.2-4.9) per 100 person-years. Thirty-four DTG interruptions were due to grade ≥3 events (10 central nervous system, 6 hypersensitivity, 3 renal, 3 myalgia/asthenia, 3 abdominal pain, 2 gastrointestinal, and 7 other events). People with lower body mass index, age ≥50 years, and lower eGFR were at higher risk of AEs, while dual combinations were protective (HR 0.41 compared with abacavir/lamivudine/DTG, 95% CI 0.22-0.77). In this prospective observational study, we found high DTG durability and a low rate of virological failures. Dual therapies seemed protective toward AEs and might be considered, when feasible, a suitable option to minimize drug interactions and improve tolerability.

Efficacy of ivabradine in HIV-associated dilated cardiomyopathy.

Ivabradine is a pure heart rate-lowering drug that acts directly on the sinus node and does not affect atrioventricular or intraventricular conduction times, myocardial contractility or ventricular repolarization. Ivabradine is used in the treatment of adults with New York Heart Association (NYHA) class II-IV chronic heart failure (CHF) with systolic dysfunction, in sinus rhythm, with a heart rate of ≥75 beats per minute (bpm). This report describes the beneficial effect of ivabradine on clinical parameters in a HIV-infected patient with dilated cardiomyopathy presenting with NYHA class III CHF symptoms. Ivabradine improved functional capacity and left ventricular (LV) systolic function in our patient with HIV-related dilated cardiomyopathy and CHF. This report also lists the summaries of potential clinically significant interaction, likely to require additional monitoring, alteration of drug dosage or timing of administration, between ivabradine and antiretroviral drugs.

How can we optimise antifungal use in a solid organ transplant centre? Local epidemiology and antifungal stewardship implementation: A single-centre study.

PURPOSE: We aimed to implement and to assess the impact of the antifungal stewardship programme (AFSp) on prescription appropriateness of antifungals, management and outcomes of candidaemia patients, and antifungal consumption and costs at our solid organ transplant (SOT) institute. METHODS: Local epidemiology of invasive fungal infections (IFIs) from 2009 to 2017 was analysed in order to prepare an effective AFSp, implemented in January 2018. It included suspension of empirical antifungal prescriptions after 72 hours (antifungal time-out), automated alert and infectious disease (ID) consult for empirical prescriptions and for every patient with IFI, and indication for step-down to oral fluconazole when possible. We used process measures and results measures to assess the effects of the implemented programme. RESULTS: The ASFp led to significant improvements in selection of the appropriate antifungal (40.5% in pre-AFS vs 78.6% in post-AFS), correct dosing (51.2% vs 79.8%), correct length of treatment (55.9% vs 75%) and better management of patients with candidaemia. Analysis of prescribed empirical antifungal revealed that defined daily doses (DDDs) per 100 patient days decreased by 36.7% in 2018 compared to the average of pre-AFSp period, with important savings in costs. CONCLUSION: This AFSp led to a better use of antifungal drugs in terms of appropriateness and consumption, with stable clinical and microbiological outcomes in patients with IFI.

Use of colistin in adult patients: A cross-sectional study.

OBJECTIVES: The aim of this study was to assess colistin use in a country endemic for multidrug-resistant Gram-negative bacteria (MDR-GNB). METHODS: Colistin prescription patterns were evaluated in 22 Italian centres. Factors associated with use of colistin in combination with other anti-MDR-GNB agents were also assessed. RESULTS: A total of 221 adults receiving colistin were included in the study. Their median age was 64 years (interquartile range 52-73 years) and 134 (61%) were male. Colistin was mostly administered intravenously (203/221; 92%) and mainly for targeted therapy (168/221; 76%). The most frequent indications for colistin therapy were bloodstream infection and lower respiratory tract infection. Intravenous colistin was administered in combination with at least another anti-MDR-GNB agent in 80% of cases (163/203). A loading dose of 9 MU of colistimethate was administered in 79% of patients receiving i.v. colistin and adequate maintenance doses in 85%. In multivariable analysis, empirical therapy [odds ratio (OR) = 3.25, 95% confidence interval (CI) 1.24-8.53;P = 0.017] and targeted therapy for carbapenem-resistant Enterobacterales infection (OR = 4.76, 95% CI 1.69-13.43; P = 0.003) were associated with use of colistin in combination with other agents, whilst chronic renal failure (OR = 0.39, 95% CI 0.17-0.88; P = 0.024) was associated with use of colistin monotherapy. CONCLUSION: Colistin remains an important option for severe MDR-GNB infections when other treatments are not available. Despite inherent difficulties in optimising its use owing to peculiar pharmacokinetic/pharmacodynamic characteristics, colistin was mostly used appropriately in a country endemic for MDR-GNB.

T-Cell Subsets (TCM, TEM, TEMRA) and Poly-Functional Immune Response in Patients with Human Immunodeficiency Virus (HIV) Infection and Different T-CD4 Cell Response.

OBJECTIVE: Dynamic changes of cytotoxic T cell responses against Human Immunodeficiency Virus 1 (HIV-1) infection have been the subject of an innovative investigation using antiretroviral therapy (ART). Currently, human CD8 naïve central memory (TCM), effector memory (TEM), and effector memory cells re-expressing CD45RA (TEMRA) T-cells have been thoroughly studied with ART. CD45RA is a marker usually found on naïve T-cells. MATERIALS AND METHODS: We performed a longitudinal study of mono-/polyfunctional T-cells in the peripheral blood while targeting three functionally distinct cell populations of CD4+ and CD8+ T-cells (single IL2 and IFN-γ, dual IL2/IFN-γ) in 50 HIV-1 patients. These patients consisted of 5 controllers, 15 non-controllers, 20 ART responders, and 10 highly active antiretroviral therapy (HAART) non-responders. RESULTS: We found that (1) non-controllers had the highest rate of IFN-γ-expressing CD4 or CD8, but the lowest rate of IL2-producing CD4 or CD8. (2) The control of HIV-1 infection was associated with polyfunctional Gag-specific T cell responses in controllers and responders. (3) Non-responders had high serum levels of IL2 and IFN-γ. There was a high percentage of CD4+ T cell response cells within the less differentiated phenotype in controllers. CD8+ T cell showed a high rate of TEM and TEMRA in responders. CONCLUSION: High levels of pro-inflammatory cytokines are typical in non-responders, exhausted T-cells may be associated with HIV-1 progression.

131I Uptake in Bronchiectasis Detected by Single Photon Emission Computed Tomography/Computed Tomography during Follow-up of Thyroid Cancer.

During follow-up of thyroid cancer, 131I whole-body scan showed intense tracer uptake in the right hemithorax of a patient previously submitted to thyroidectomy and radioiodine therapy for differentiated thyroid cancer. Thyroglobulin was undetectable at the time of the scan. Single-photon emission computed tomography/computed tomography (SPECT/CT) of the thorax correctly identified widespread bronchiectasis 131I-avid in the middle lobe of the right lung. After bronchoalveolar lavage, a bronchial specimen was positive for Mycobacterium avium infection. Hybrid imaging with SPECT/CT allowed to correctly identify a false-positive case of 131I uptake due to inflammation in a single diagnostic session, minimizing patient discomfort or misdiagnoses.

[Role of combination NK/KIRs in the natural history of viral infections.] / Ruolo dell'interazione NK/KIR nella storia naturale delle infezioni virali.

Immunological mechanisms involved in the genesis of the immune response against viral infections take into account the activation of both innate adaptative response. Innate immune defenses trigger a rapid local response, which is often sufficient to control viral infection, and promotes the subsequent activation of specific immune defenses. Natural killer (NK) cells that constitute a subpopulation of lymphocyte-related cells are a key factor of innate immune response and play a role in defense against viral infections by killing infected cells or by producing cytokines and interacting with adaptative immune system's cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leukocyte antigens (HLA). KIRs and HLA loci are highly polymorphic and certain HLA-KIRs combinations have been found to protect against viral infections. In this study we review how the KIRs/HLA repertoire may influence the course of hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV) and Herpes Simplex Virus 1 (HSV-1) infection. Results of our study suggest that a combination of KIRs/HLA gene/alleles is able to predict the outcome of viral infection and allows to plan successful customized therapeutic strategies.

Behavioral and clinical characteristics of people receiving medical care for HIV infection in an outpatient facility in Sicily, Italy.

AIM: The authors examined a cohort of HIV-positive outpatients at the AIDS Center of Palermo University in Italy in order to identify factors related to the frequency of their visits to the outpatient facility for health care services. METHODS: Two hundred and twenty-four HIV-infected subjects were enrolled in the study. Demographic and HIV disease characteristics were recorded and assessed with the number of days accessed to our outpatients unit in univariate and multivariate analyses. The potential relationship with immunological status was also analyzed stratifying the patients into groups according to their CD4(+) T-cell counts (≥500 vs <500/mm(3), and ≥200 vs <200/mm(3)). RESULTS: Both univariate and multivariate analyses showed that duration of antiretroviral therapy <5 years and hypertension were significantly associated with a CD4(+) T-cell count of <500/mm(3), whereas geographic origin (Africa) was associated with a CD4(+) T-cell count of <200/mm(3). Mean number of days the patients sought access to day-care services for laboratory tests was negatively associated with CD4(+) T-cell count. CONCLUSION: Patients with low CD4(+) T-cell counts showed higher use of health care services, demonstrating how early HIV diagnosis can help to reduce health care costs. The CD4(+) T-cell cut-off of 200 cells emphasizes the importance of identifying and managing HIV infection among hard-to-reach groups like vulnerable migrants. In our sample, the illegal status of immigrants does not influence the management of their HIV/AIDS condition, but the lack of European health card that documents the current antiretroviral status, could interfere with the efforts to eradicate AIDS. A better understanding of the major determinants of HIV treatment costs has led to appropriate large-scale actions, which in turn has increased resources and expanded intervention programs. Further guidance should be offered to hard-to-reach groups in order to improve early AIDS diagnosis, and procedures for identifying and managing these vulnerable subjects should be made available to care commissioners and service providers.

Delayed diagnosis of extrapulmonary tuberculosis in a 32-year-old man with knee pain.

A 32-year-old Bangladeshi male was admitted at our emergency department for trauma of the left knee. The radiographs showed absence of fracture, and presence of an indeterminate oval lucency in the proximal tibia. Further examinations were suggested, but the patient refused. 6 months later, the patient re-presented at our emergency department. A CT scan showed progression of musculoskeletal involvement and spread to the liver. This case underlines the importance of considering tuberculosis in the differential diagnosis of indeterminate bone lesions in immigrant patients.

Multimodal surgical and medical treatment for extensive rhinocerebral mucormycosis in an elderly diabetic patient: a case report and literature review.

Diabetes is a well-known risk factor for invasive mucormycosis with rhinocerebral involvement. Acute necrosis of the maxilla is seldom seen and extensive facial bone involvement is rare in patients with rhino-orbital-cerebral mucormycosis. An aggressive surgical approach combined with antifungal therapy is usually necessary. In this report, we describe the successful, personalized medical and surgical management of extensive periorbital mucormycosis in an elderly diabetic, HIV-negative woman. Mono- or combination therapy with liposomal amphotericin B (L-AmB) and posaconazole (PSO) and withheld debridement is discussed. The role of aesthetic plastic surgery to preserve the patient's physical appearance is also reported. Any diabetic patient with sinonasal disease, regardless of their degree of metabolic control, is a candidate for prompt evaluation to rule out mucormycosis. Therapeutic and surgical strategies and adjunctive treatments are essential for successful disease management. These interventions may include combination therapy. Finally, a judicious multimodal treatment approach can improve appearance and optimize outcome in elderly patients.

Surgical pathology and the diagnosis of invasive visceral yeast infection: two case reports and literature review.

Invasive mycoses are life-threatening opportunistic infections that have recently emerged as a cause of morbidity and mortality following general and gastrointestinal surgery.Candida species are the main fungal strains of gut flora. Gastrointestinal tract surgery might lead to mucosal disruption and cause Candida spp. to disseminate in the bloodstream.Here we report and discuss the peculiar clinical and morphological presentation of two cases of gastrointestinal Candida albicans lesions in patients who underwent abdominal surgery.Although in the majority of cases reported in the literature, diagnosis was made on the basis of microbiological criteria, we suggest that morphological features of fungi in histological sections of appropriate surgical specimens could help to detect the degree of yeast colonization and identify patients at risk of developing severe abdominal Candida infection.Better prevention and early antifungal treatments are highlighted, and relevant scientific literature is reviewed.

KPC - 3 Klebsiella pneumoniae ST258 clone infection in postoperative abdominal surgery patients in an intensive care setting: analysis of a case series of 30 patients.

BACKGROUND: Abdominal surgery carries significant morbidity and mortality, which is in turn associated with an enormous use of healthcare resources. We describe the clinical course of 30 Intensive Care Unit (ICU) patients who underwent abdominal surgery and showed severe infections caused by Klebsiella pneumoniae sequence type (ST) 258 producing K. pneumoniae carbapenemase (KPC-Kp). The aim was to evaluate risk factors for mortality and the impact of a combination therapy of colistin plus recommended regimen or higher dosage of tigecycline. METHODS: A prospective assessment of severe monomicrobial KPC-Kp infections occurring after open abdominal surgery carried out from August 2011 to August 2012 in the same hospital by different surgical teams is presented. Clinical and surgical characteristics, microbiological and surveillance data, factors associated with mortality and treatment regimens were analyzed. A combination regimen of colistin with tigecycline was used. A high dose of tigecycline was administered according to intra-abdominal abscess severity and MICs for tigecycline. RESULTS: The mean age of the patients was 56.6 ± 15 and their APACHE score on admission averaged 22.72. Twenty out of 30 patients came from the surgical emergency unit. Fifteen patients showed intra-abdominal abscess, eight anastomotic leakage, four surgical site infection (SSI) and three peritonitis. The overall crude ICU mortality rate was 40% (12 out of 30 patients). Twelve of the 30 patients were started on a combination treatment of high-dose tigecycline and intravenous colistin. A significantly lower mortality rate was observed among those patients compared to patients treated with approved dose of tigecycline plus colistin. No adverse events were reported with high doses of tigecycline. CONCLUSIONS: Critically-ill surgical patients are prone to severe post-surgical infectious complications caused by KPC-Kp. Timely microbiological diagnosis and optimizing antibiotic dosing regimens are essential to prevent worse outcomes. Further studies and well-controlled clinical trials are needed to define the optimal treatment of infections by KPC-Kp and, more generally, carbapenem-resistant bacteria.

High dose of trimethoprim-sulfamethoxazole and daptomycin as a therapeutic option for MRSA endocarditis with large vegetation complicated by embolic stroke: a case report and literature review.

Large cardiac vegetation carries a poor prognosis and high mortality risk, especially if associated with methicillin-resistant Staphylococcus aureus (MRSA) infection. We share our experience of a rare and complicated large cardiac vegetation which had a favourable outcome with combination antibiotic treatment alone. A 35-year-old HIV-negative, HCV-positive male patient with a previous history of methicillin-susceptible S. aureus endocarditis showed MRSA mitral valve endocarditis with large vegetation, complicated by embolic stroke. The strain was soon identified by PCR but only after culture did the patient receive efficacious antibiotics. A combination of daptomycin plus trimethoprim/sulfamethoxazole (TMP/SMX) was administered for six weeks, followed by a high dosage of TMP/SMX for a further six weeks. Effectiveness of the treatment was demonstrated by the patient's clinical improvement and instrumental evidence of cardiac mitral vegetation clearance. Innovative antibiotic strategies in patient management are needed to fight Staphylococcus aureus endocarditis because strains show varying antimicrobial susceptibility patterns in different geographic areas. Timely initiation of targeted antimicrobial therapy remains a crucial step to reduce morbidity and mortality but culture is crucial for appropriate fine-tuning of antibiotic therapy.