Gut microbiome dynamics and Enterobacterales infection in liver transplant recipients: A prospective observational study.

Background & Aims: The aim of this study was to investigate gut microbiome (GM) dynamics in relation to carbapenem-resistant Enterobacterales (CRE) colonization, CRE infection, and non-CRE infection development within 2 months after liver transplant (LT). Methods: A single-center, prospective study was performed in patients undergoing LT from November 2018 to January 2020. The GM was profiled through 16S rRNA amplicon sequencing of a rectal swab taken on the day of transplantation, and fecal samples were collected weekly until 1 month after LT. A subset of samples was subjected to shotgun metagenomics, including resistome dynamics. The primary endpoint was to explore changes in the GM in the following groups: (1) CRE carriers developing CRE infection (CRE_I); (2) CRE carriers not developing infection (CRE_UI); (3) non-CRE carriers developing microbial infection (INF); and (4) non-CRE carriers not developing infection (NEG). Results: Overall, 97 patients were enrolled, and 91 provided fecal samples. Of these, five, nine, 22, and 55 patients were classified as CRE_I, CRE_UI, INF, and NEG, respectively. CRE_I patients showed an immediate and sustained post-LT decrease in alpha diversity, with depletion of the GM structure and gradual over-representation of Klebsiella and Enterococcus. The proportions of Klebsiella were significantly higher in CRE_I patients than in NEG patients even before LT, serving as an early marker of subsequent CRE infection. CRE_UI patients had a more stable and diverse GM, whose compositional dynamics tended to overlap with those of NEG patients. Conclusions: GM profiling before LT could improve patient stratification and risk prediction and guide early GM-based intervention strategies to reduce infectious complications and improve overall prognosis. Impact and implications: Little is known about the temporal dynamics of gut microbiome (GM) in liver transplant recipients associated with carbapenem-resistant Enterobacterales (CRE) colonization and infection. The GM structure and functionality of patients colonized with CRE and developing infection appeared to be distinct compared with CRE carriers without infection or patients with other microbial infection or no infection and CRE colonization. Higher proportions of antimicrobial-resistant pathogens and poor representation of bacteria and metabolic pathways capable of promoting overall host health were observed in CRE carriers who developed infection, even before liver transplant. Therefore, pretransplant GM profiling could improve patient stratification and risk prediction and guide early GM-based intervention strategies to reduce infectious complications and improve overall prognosis.

Development and validation of a prediction score for failure to casirivimab/imdevimab in hospitalized patients with COVID-19 pneumonia.

Introduction: Casirivimab and imdevimab (CAS/IMV) are two non-competing, high-affinity human IgG1 anti-SARS-CoV-2 monoclonal antibodies, that showed a survival benefit in seronegative hospitalized patients with COVID-19. This study aimed to estimate the day-28 risk of mechanical ventilation (MV) and death in individuals hospitalized for severe COVID-19 pneumonia and receiving CAS/IMV. Additionally, it aimed to identify variables measured at the time of hospital admission that could predict these outcomes and derive a prediction algorithm. Methods: This is a retrospective, observational cohort study conducted in 12 hospitals in Italy. Adult patients who were consecutively hospitalized from November 2021 to February 2022 receiving CAS/IMV were included. A multivariable logistic regression model was used to identify predictors of MV or death by day 28 from treatment initiation, and ß-coefficients from the model were used to develop a risk score that was derived by means of leave-one-out internal cross-validation (CV), external CV, and calibration. Secondary outcome was mortality. Results: A total of 480 hospitalized patients in the training set and 157 patients in the test set were included. By day 28, 36 participants (8%) underwent MV and 28 died (6%) for a total of 58 participants (12%) experiencing the composite primary endpoint. In multivariable analysis, four factors [age, PaO2/FiO2 ratio, lactate dehydrogenase (LDH), and platelets] were independently associated with the risk of MV/death and were used to generate the proposed risk score. The accuracy of the score in the area under the curve (AUC) was 0.80 and 0.77 in internal validation and test for the composite endpoint and 0.87 and 0.86 for death, respectively. The model also appeared to be well calibrated with the raw data. Conclusion: The mortality risk reported in our study was lower than that previously reported. Although CAS/IMV is no longer used, our score might help in identifying which patients are not likely to benefit from monoclonal antibodies and may require alternative interventions.

Predictors of bacteremia and death, including immune status, in a large single-center cohort of unvaccinated ICU patients with COVID-19 pneumonia.

BACKGROUND: We investigated the possible role of the immune profile at ICU admission, among other well characterized clinical and laboratory predictors of unfavorable outcome in COVID-19 patients assisted in ICU. METHODS: Retrospective analysis of clinical and laboratory data collected for all consecutive patients admitted to the ICUs of the General Hospital of Pescara (Abruzzo, Italy), between 1st March 2020 and 30th April 2021, with a confirmed diagnosis of COVID-19 respiratory failure. Logistic regressions were used to identify independent predictors of bacteremia and mortality. RESULTS: Out of 431 patients included in the study, bacteremia was present in N = 191 (44.3%) and death occurred in N = 210 (48.7%). After multivariate analysis, increased risk of bacteremia was found for viral reactivation (OR = 3.28; 95% CI:1.83-6.08), pronation (3.36; 2.12-5.37) and orotracheal intubation (2.51; 1.58-4.02). Increased mortality was found for bacteremia (2.05; 1.31-3.22), viral reactivation (2.29; 1.29-4.19) and lymphocytes < 0.6 × 103c/µL (2.32; 1.49-3.64). CONCLUSIONS: We found that viral reactivation, mostly due to Herpesviridae, was associated with increased risk of both bacteremia and mortality. In addition, pronation and intubation are strong predictors of bacteremia, which in turn together with severe lymphocytopenia due to SARS-CoV2 was associated with increased mortality. Most episodes of bacteremia, even due to Acinetobacter spp, were not predicted by microbiological evidence of colonization.

SOX-1 antibodies in a patient with Crohn's disease: a case report.

BACKGROUND: The anti-SOX-1 antibodies have been mainly associated with Lambert-Eaton Myasthenic Syndrome (LETMS) and Small-Cell Lung Cancer (SCLC). In this report, we describe the interesting case of a patient with serum anti-SOX-1 antibodies and Crohn's Disease (CD) with ensuing neurological symptoms. CASE PRESENTATION: A Caucasian 67-year-old female was admitted to the Emergency Department with seizures, vertigo, emesis, nausea, postural instability and recurrent falls, over a period of 10 days. She had been affected by Crohn's Disease since 1991. A CT scan failed to detect any ischemic or haemorrhagic lesion. A brain MRI revealed signs of leukoencephalopathy. Western blot analysis of her serum revealed a high titre of the onconeural antibody anti-SOX1, consistent with a neurological, cerebellar type, paraneoplastic syndrome. In spite of multiple efforts to unmask a possible underlying malignancy, no neoplastic lesion cropped up during hospitalization. Her clinical conditions progressively deteriorated, up to respiratory failure; a few days later she died, due to ensuing septic shock and Multiple Organ Failure. CONCLUSIONS: Our experience may usher and reveal a new role of anti-neural antibodies, so far reckoned an early indicator of associated malignancy, suggesting that neurological syndromes associated with such antibodies may complicate also chronic Gastrointestinal (GI) diseases. As of now, testing for anti-neuronal antibodies appeared unnecessary within the diagnostic assessment of gastroenterological disorders, which may lead to overlooking incident neurologic autoimmune diseases. Further exploration of such research hypothesis in clinical grounds appears intriguing.

The Gut Microbiota of Critically Ill Patients With COVID-19.

The SARS-CoV-2-associated COVID-19 pandemic has shaken the global healthcare system. Although the best-known symptoms are dry cough and pneumonia, viral RNA has been detected in the stool and about half of COVID-19 patients exhibit gastrointestinal upset. In this scenario, special attention is being paid to the possible role of the gut microbiota (GM). Fecal samples from 69 COVID-19 patients from three different hospitals of Bologna (Italy) were analyzed by 16S rRNA gene-based sequencing. The GM profile was compared with the publicly available one of healthy age- and gender-matched Italians, as well as with that of other critically ill non-COVID-19 patients. The GM of COVID-19 patients appeared severely dysbiotic, with reduced diversity, loss of health-associated microorganisms and enrichment of potential pathogens, particularly Enterococcus. This genus was far overrepresented in patients developing bloodstream infections (BSI) and admitted to the intensive care unit, while almost absent in other critically ill non-COVID-19 patients. Interestingly, the percentage of patients with BSI due to Enterococcus spp. was significantly higher during the COVID-19 pandemic than in the previous 3 years. Monitoring the GM of critically ill COVID-19 patients could help clinical management, by predicting the onset of medical complications such as difficult-to-treat secondary infections.

Breakthrough invasive fungal infection after liver transplantation in patients on targeted antifungal prophylaxis: A prospective multicentre study.

OBJECTIVE: To investigate the rate of and the risk factors for breakthrough-IFI (b-IFI) after orthotopic liver transplantation (OLT) according to the new definition proposed by Mycoses-Study-Group-Education-and-Research-Consortium (MSG-ERC) and the European-Confederation-of-Medical-Mycology (ECMM). METHODS: Multicenter prospective study of adult patients who underwent OLT at three Italian hospitals, from January 2015 to December 2018. Targeted antifungal prophylaxis (TAP) protocol was developed and shared among participating centers. Follow-up was 1-year after OLT. B-IFI was defined as infection occurring during exposure to antifungal prophylaxis. Risk factors for b-IFI were analyzed among patients exposed to prophylaxis by univariable analysis. RESULTS: We enrolled 485 OLT patients. Overall compliance to TAP protocol was 64.3%, 220 patients received antifungal prophylaxis, 172 according to TAP protocol. Twenty-nine patients were diagnosed of IFI within 1 year after OLT. Of them, 11 presented with b-IFI within 17 (IQR 11-33) and 16 (IQR 4-30) days from OLT and from antifungal onset, respectively. Then out of 11 patients with b-IFI were classified as having high risk of IFI and were receiving anti-mould prophylaxis, nine with echinocandins and one with polyenes. Comparison of patients with and without b-IFI showed significant differences for prior Candida colonization, need of renal replacement therapy after OLT, re-operation, and CMV infection (whole blood CMV-DNA >100 000 copies/mL). Although non-significant, a higher rate of b-IFI in patients on echinocandins was observed (8.2% vs 1.8%, P = .06). CONCLUSIONS: We observed 5% of b-IFI among OLT patients exposed to antifungal prophylaxis. The impact of echinocandins on b-IFI risk in this setting should be further explored.

Effective Containment of a COVID-19 Subregional Outbreak in Italy Through Strict Quarantine and Rearrangement of Local Health Care Services.

BACKGROUND: Since the beginning of the pandemic, the epidemiology of coronavirus disease 2019 (COVID-19) in Italy has been characterized by the occurrence of subnational outbreaks. The World Health Organization recommended building the capacity to rapidly control COVID-19 clusters of cases in order to avoid the spread of the disease. This study describes a subregional outbreak of COVID-19 that occurred in the Emilia Romagna region, Italy, and the intervention undertaken to successfully control it. METHODS: Cases of COVID-19 were defined by a positive reverse transcriptase polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on nasopharyngeal swab. The outbreak involved the residential area of a small town, with ~10 500 inhabitants in an area of 9 km2. After the recognition of the outbreak, local health care authorities implemented strict quarantine and a rearrangement of health care services, consisting of closure of general practitioner outpatient clinics, telephone contact with all residents, activation of health care units to visit at-home patients with symptoms consistent with COVID-19, and a dedicated Infectious Diseases ambulatory unit at the nearest hospital. RESULTS: The outbreak lasted from February 24 to April 6, 2020, involving at least 170 people with a cumulative incidence of 160 cases/10 000 inhabitants; overall, 448 inhabitants of the municipality underwent at least 1 nasopharyngeal swab to detect SARS-CoV-2 (positivity rate, 38%). Ninety-three people presented symptoms before March 11 (pre-intervention period), and 77 presented symptoms during the postintervention period (March 11-April 6). CONCLUSIONS: It was possible to control this COVID-19 outbreak by prompt recognition and implementation of a targeted local intervention.

Diffuse primary cutaneous infection by Alternaria alternata in a liver transplant recipient with pulmonary nocardiosis: Importance of prompt identification for clinical resolution.

Fungal infections are rare in the general population but are an emerging cause of disease in immunosuppressed patients, especially solid organ transplant recipients. Here, we report the case of a female Caucasian liver transplant patient who developed pulmonary nocardiosis two months after an episode of liver rejection. At the time of lung nocardiosis, she was being treated with tacrolimus and corticosteroids and suffered from diffuse papular skin lesions. She was initially suspected of having a cutaneous nocardial infection but culture examination revealed the presence of a dematiaceous fungus; Alternaria alternata. The prompt identification of the fungus and administration of oral Voriconazole resolved the skin infection with complete remission.

No progression of subclinical atherosclerosis in HIV-infected patients starting an initial regimen including tenofovir alafenamide/emtricitabine plus raltegravir, dolutegravir or elvitegravir/cobicistat during a two-year follow-up.

Objectives: Cardiovascular disease has become one of the most common comorbidities among HIV-infected patients, but available data about the correlation between antiretroviral drugs and progression rate of atherosclerotic disease are still limited. We evaluated the progression rate of carotid atherosclerosis in patients starting an initial antiretroviral regimen including one integrase strand transfer inhibitor (INSTI).Methods: Observational, prospective study involving HIV-1-infected, antiretroviral therapy-naive, adult patients who started an antiretroviral regimen including tenofovir alafenamide/emtricitabine (TAF/FTC) plus raltegravir (RAL group), elvitegravir/cobicistat (EVG/c group), or dolutegravir (DTG group). Patients with known cardiovascular disease or diabetes mellitus were excluded from the study. The progression rate of atherosclerosis has been assessed by carotid Doppler ultrasonography at baseline and after 24 months.Results: Overall, 102 patients were enrolled into the study: 73 males, with mean age of 48.7 years: 32, 36 and 34 patients were included in the RAL, EVG/c and DTG groups, respectively. The baseline features of the enrolled patients were comparable across the three groups. At 24 months, the mean intima-media thickness (IMT) increase at the carotid bifurcation was 0.026 mm in the RAL group, 0.029 mm in EVG/c group and 0.032 mm in DTG group. The mean IMT increases after 24 months were comparable across the three groups and statistically not significant in all the evaluated anatomical sites.Conclusions: The initial antiretroviral therapy with TAF/FTC plus RAL, EVG/c or DTG for 24 months led to a comparable and not significant effect on the progression rate of carotid atherosclerosis.

Improvement in liver steatosis after the switch from a ritonavir-boosted protease inhibitor to raltegravir in HIV-infected patients with non-alcoholic fatty liver disease.

Background: The ritonavir-boosted protease inhibitor (PI/r) use has been associated with several metabolic abnormalities, and the non-alcoholic fatty liver disease (NAFLD) is becoming a very frequent comorbidity among HIV-infected patients. Methods: We performed an observational, prospective study of HIV-infected patients with NAFLD, receiving one PI/r plus two nucleoside analogues, who switched from the PI/r to raltegravir or were treated only with lifestyle modification, maintaining antiretroviral therapy unchanged. Changes in liver steatosis after 12 months were evaluated by transient elastography and measurement of controlled attenuation parameter (CAP). Results: As a whole, 61 patients (46 males; median age, 55.4 years) were enrolled, and 32 of them have been switched from PI/r to raltegravir. At baseline, median CAP was 259 dB/m, 28 (45.9%) subjects had a moderate-to-severe hepatic steatosis (CAP ≥260 dB/m), and 19 patients (31.1%) had elevated aminotransferases. Type-2 diabetes mellitus was present in 5 persons, and chronic HCV coinfection in 4. At month 12, the median decrease in CAP values was -27 dB/m in patients switched to raltegravir and -11 dB/m in those with unchanged cART (p = .021). The number of patients with CAP ≥260 dB/m decreased from 16 to 6 (-62.5%) in patients switched to raltegravir and from 12 to 8 (-33.3%) in the other group (p = .037). Conclusion: After 12 months, HIV-infected patients with NAFLD switching from a PI/r to raltegravir showed a significantly greater decrease in the hepatic steatosis degreee in comparison with those with unchanged cART and treated only with lifestyle modification.

Improvement in insulin sensitivity and serum leptin concentration after the switch from a ritonavir-boosted PI to raltegravir or dolutegravir in non-diabetic HIV-infected patients.

OBJECTIVES: An observational, prospective, cohort study was performed to assess changes in insulin sensitivity and serum leptin level after a switch from a ritonavir-boosted PI (PI/r) to raltegravir or dolutegravir in HIV-infected adults on stable combination ART (cART). METHODS: Non-diabetic HIV-infected patients receiving suppressive cART including tenofovir disoproxil fumarate/emtricitabine plus one PI/r, who underwent a switch from the PI/r to raltegravir (group A) or dolutegravir (group B), were enrolled in the study. Serum levels of insulin, leptin and the homeostasis model assessment of insulin resistance (HOMA) index were evaluated during a 12 month follow-up. RESULTS: Overall, 86 patients were enrolled: 45 patients were included in group A and 41 were included in group B. The mean age was 45.7 years and 74 (86%) patients were male. After 12 months of follow-up, a significant reduction in the mean concentration of leptin and insulin was reported both in group A [-0.61 ng/mL (P < 0.001) and -2.5 mIU/L (P = 0.008), respectively] and in group B [-0.54 ng/mL (P = 0.005) and -2.1 mIU/L (P = 0.017), respectively], without a significant difference between the groups. A significant and comparable reduction in the mean HOMA index was reported both in group A [-0.55 (P = 0.004)] and in group B [-0.49 (P < 0.001)], as well as a significant decrease in lipid levels. CONCLUSIONS: In HIV-positive subjects on suppressive cART, the switch from a PI/r to raltegravir or dolutegravir led to a significant and comparable reduction in both HOMA index and serum leptin level, reflecting a similar and significant improvement in insulin sensitivity.

Cytokines, Hepatic Fibrosis, and Antiretroviral Therapy Role in Neurocognitive Disorders HIV Related.

The HIV may trigger a process of neuronal loss and axonal degeneration throughout the brain, which is carried on by the immune system releasing of proinflammatory cytokines, so that chronic inflammation associated with dysregulated innate immune response, glial cell dysfunction, and adverse antiretroviral therapy (ART) effect play an important role causing milder HIV-associated neurocognitive disorders or asymptomatic neurocognitive impairment. All patients have been tested for neurocognitive functioning through a comprehensive, five-domain neuropsychological battery performed in the study. Human cytokine (interleukin [IL]-6, IL-8, IL-18, and tumor necrosis factor [TNF]-α) and brain-derived neurotrophic factor serum levels were quantified using ELISAs, and the hepatic fibrosis was estimated using the noninvasive Fibrosis 4 (FIB-4) score. The study showed a group of 40 HIV-infected individuals and it was observed that almost 40% of HIV+ individuals, even if clinically asymptomatic, displayed some degree of neurocognitive dysfunction, compared to normative performance standards, at least in two cognitive areas. The functions affected the most were memory, attention, executive function, and psychomotor processing speed. Three cytokines (IL-6, IL-8, and IL-18) to be significantly linked to test results in specific neurocognitive domain were found. Treatments with nucleoside reverse transcriptase inhibitor plus non-nucleoside reverse transcriptase inhibitor alone were instead associated with poor neurocognitive outcome, especially in verbal fluency, fine motility, and Zung Depression Scale. Elevated value of FIB-4 score showed an opposite connection with cognitive performance as well, underlining the direct association between hepatic steatosis and neurocognitive deficit. The cytokine panel and the FIB-4 score can predict presence or worsening of neurocognitive functions in HIV-infected individuals. An ART switch can be suggested according to the neurocognitive domain involved the most, advising a therapy with protease inhibitors or/and integrase inhibitors to improve fluency, executive functions, and to prevent depression.