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Background: Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab–cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab–cilgavimab in preventing progression to severe COVID-19 or death. Methods: TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab–cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394. Findings: Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab–cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab–cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6–71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1–8·0; p Interpretation: A single intramuscular tixagevimab–cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab–cilgavimab might lead to more favourable outcomes.

[Background] Piacenza is the closest city to the first coronavirus disease 2019 (COVID-19) cluster in Italy and has the highest national COVID-19 death rates per population. The objective of this study is to present characteristics and outcomes of patients admitted to medical departments of the Hospital of Piacenza during the first wave of the epidemic., [Methods] A total of 218 patients with confirmed or suspect COVID-19 and severe pneumonia were included from February 21st to May 15th, 2020. Routinely-collected clinical and laboratory data were retrospectively retrieved from electronic medical files. A Cox proportional-hazards model was fit to assess the association of treatment and other variables with death., [Results] Median age of patients was 68 years; 150 patients (69%) had comorbidities, mainly hypertension (107, 49%). Overall, 185 (85%) patients had acute respiratory distress syndrome (ARDS) on admission, including 103 (47%) with moderate or severe ARDS. Chest computed tomography scan showed bilateral disease in 201 (98%) and extensive lung involvement in 79 (50%) patients. Most patients received antiviral treatment (187, 86%) and corticosteroids (134, 61%). All patients received respiratory support and 64 (29%) were admitted to intensive care unit. As of June 30th, 100 patients (46%) died, 109 patients (50%) were discharged, and 9 patients (4%) were still hospitalized. In multivariable Cox analysis, age above 65 years, having more than one comorbidity, severe ARDS, low platelet counts, and high LDH levels at admission were associated with mortality, while having diarrhea at admission was associated with survival. The use of antivirals or corticosteroids was not associated with survival., [Conclusions] Overall case fatality rates were high and associated with comorbidities, extensive lung involvement, ARDS at admission, and advanced age. The use of antivirals was not associated with increased survival.

North Italy emerged as an epicenter of COVID-19 in the Western world. The majority of studies of patients with COVID-19 have focused on hospitalized patients, and data on early outpatient treatment are limited. This research retrospectively examines consecutive symptomatic adults who did not present to a hospital but who experience laboratory confirmed (nasopharyngeal swabs) or probable COVID-19 infection. From March 12 to April 12, 2020, 124 consecutive patients with laboratory-confirmed COVID-19 infection (84%) or with epidemiologically linked exposure to a person with confirmed infection (16%) were managed at home. The diagnosis of pneumonia was made with a portable ultrasound. COVID-19 treatment was based on low-dose hydroxychloroquine with or without darunavir/cobicistat or azithromycin and enoxaparine for bedridden patients. The patients were monitored by telemedicine. The primary endpoints were clinical improvement or hospitalization, and the secondary endpoints were mortality at day 30 and at day 60. Forty-seven (37.9%) patients had mild COVID-19 infection, 44 (35.5%) had moderate COVID-19 infection, and 33 (26.6%) had severe COVID-19 infection. Four patients (3.2%) were hospitalized and there were no deaths at day 30 and at day 60. Only mild side effects were reported. Early home treatment of COVID-19 patients resulted in a low hospitalization rate with no deaths, with the limitations of the small sample size and that it was conducted within a single geographic area. We believe that this model may be easily reproduced in both cities and rural areas around the world to treat COVID-19 infection.

RationalePulse glucocorticoid therapy is used in hyperinflammation related to coronavirus disease 2019 (COVID-19). We evaluated the efficacy and safety of pulse intravenous methylprednisolone in addition to standard treatment in COVID-19 pneumonia.MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, 304 hospitalised patients with COVID-19 pneumonia were randomised to receive 1 g of methylprednisolone intravenously for three consecutive days or placebo in addition to standard dexamethasone. The primary outcome was the duration of patient hospitalisation, calculated as the time interval between randomisation and hospital discharge without the need for supplementary oxygen. The key secondary outcomes were survival free from invasive ventilation with orotracheal intubation and overall survival.ResultsOverall, 112 (75.4%) out of 151 patients in the pulse methylprednisolone arm and 111 (75.2%) of 150 in the placebo arm were discharged from hospital without oxygen within 30 days from randomisation. Median time to discharge was similar in both groups (15 days, 95% CI 13.0–17.0 days and 16 days, 95% CI 13.8–18.2 days, respectively; hazard ratio (HR) 0.92, 95% CI 0.71–1.20; p=0.528). No significant differences between pulse methylprednisolone and placebo arms were observed in terms of admission to intensive care unit with orotracheal intubation or death (20.0%versus16.1%; HR 1.26, 95% CI 0.74–2.16; p=0.176) or overall mortality (10.0%versus12.2%; HR 0.83, 95% CI 0.42–1.64; p=0.584). Serious adverse events occurred with similar frequency in the two groups.ConclusionsMethylprenisolone pulse therapy added to dexamethasone was not of benefit in patients with COVID-19 pneumonia.

The aims of this study were to characterize new SARS-CoV-2 genomes sampled all over Italy and to reconstruct the origin and the evolutionary dynamics in Italy and Europe between February and June 2020. The cluster analysis showed only small clusters including

The aim of this study was the reconstruction of SARS-CoV-2 evolutionary dynamics in time and space in Italy and Europe between February and June 2020. The cluster analysis showed that pure Italian clusters were observed mainly after the lockdown and distancing measures were adopted. Lineage B and B.1 spread between late January and early February 2020, from China to Veneto and Lombardy, respectively. Lineage B.1.1 most probably evolved within Italy and spread from central to south Italian regions, and to European countries. The lineage B.1.1.1 entered Italy only in the second half of March and remained localized in Piedmont until June 2020. In conclusion, the reconstructed ancestral scenario suggests a central role of China and Italy in the widespread diffusion of the D614G variant in Europe in the early phase of the pandemic and more dispersed exchanges involving several European countries from the second half of March 2020.

Data on the burden of Clostridioides difficile infection (CDI) in Coronavirus Disease 2019 (COVID-19) patients are scant. We conducted an observational, retrospective, multicenter, 1:3 case (COVID-19 patients with CDI)-control (COVID-19 patients without CDI) study in Italy to assess incidence and outcomes, and to identify risk factors for CDI in COVID-19 patients. From February through July 2020, 8402 COVID-19 patients were admitted to eight Italian hospitals, 38 CDI cases were identified, including 32 hospital-onset-CDI (HO-CDI) and 6 community-onset, healthcare-associated-CDI (CO-HCA-CDI). HO-CDI incidence was 4.4 × 10,000 patient-days. The percentage of cases recovering without complications at discharge (i.e., pressure ulcers, chronic heart decompensation) was lower than among controls (p = 0.01), in-hospital stays was longer among cases, 35.0 versus 19.4 days (p = 0.0007). The presence of a previous hospitalisation (p = 0.001), previous steroid administration (p = 0.008) and the administration of antibiotics during the stay (p = 0.004) were risk factors associated with CDI. In conclusions, CDI complicates COVID-19, mainly in patients with co-morbidities and previous healthcare exposures. Its association with antibiotic usage and hospital acquired bacterial infections should lead to strengthen antimicrobial stewardship programmes and infection prevention and control activities.

IMPORTANCE: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. OBJECTIVE: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao(2)/Fio(2)) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. INTERVENTIONS: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. MAIN OUTCOME AND MEASURES: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao(2)/Fio(2) ratio less than 150 mm Hg, whichever came first. RESULTS: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao(2)/Fio(2) ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37

Objectives: We aimed to develop and validate a risk score to predict severe respiratory failure (SRF) among patients hospitalized with coronavirus disease-2019 (COVID-19). Methods: We performed a multicentre cohort study among hospitalized (>24 hours) patients diagnosed with COVID-19 from 22 February to 3 April 2020, at 11 Italian hospitals. Patients were divided into derivation and validation cohorts according to random sorting of hospitals. SRF was assessed from admission to hospital discharge and was defined as: SpO2 30 breaths/min or respiratory distress. Multivariable logistic regression models were built to identify predictors of SRF, β-coefficients were used to develop a risk score. Trial Registration NCT04316949. Results: We analysed 1113 patients (644 derivation, 469 validation cohort). Mean (±SD) age was 65.7 (±15) years, 704 (63.3%) were male. SRF occurred in 189/644 (29%) and 187/469 (40%) patients in the derivation and validation cohorts, respectively. At multivariate analysis, risk factors for SRF in the derivation cohort assessed at hospitalization were age ≥70 years (OR 2.74; 95% CI 1.66–4.50), obesity (OR 4.62; 95% CI 2.78–7.70), body temperature ≥38°C (OR 1.73; 95% CI 1.30–2.29), respiratory rate ≥22 breaths/min (OR 3.75; 95% CI 2.01–7.01), lymphocytes ≤900 cells/mm3 (OR 2.69; 95% CI 1.60–4.51), creatinine ≥1 mg/dL (OR 2.38; 95% CI 1.59–3.56), C-reactive protein ≥10 mg/dL (OR 5.91; 95% CI 4.88–7.17) and lactate dehydrogenase ≥350 IU/L (OR 2.39; 95% CI 1.11–5.11). Assigning points to each variable, an individual risk score (PREDI-CO score) was obtained. Area under the receiver-operator curve was 0.89 (0.86–0.92). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 71.6% (65%–79%), 89.1% (86%–92%), 74% (67%–80%) and 89% (85%–91%), respectively. PREDI-CO score showed similar prognostic ability in the validation cohort: area under the receiver-operator curve 0.85 (0.81–0.88). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 80% (73%–85%), 76% (70%–81%), 69% (60%–74%) and 85% (80%–89%), respectively. Conclusion: PREDI-CO score can be useful to allocate resources and prioritize treatments during the COVID-19 pandemic.

Background: We describe cancer patients with coronavirus disease-2019 (COVID-19) infection treated at the Piacenza’s general hospital (north Italy). Materials & methods: 25 cancer patients infected by COVID-19 admitted at the Piacenza’s general hospital from 21 February to 18 March 2020. Outcome from the infection were compared with infected noncancer patients. Results: 20 patients (80%) were treated with antiviral therapy and hydroxychloroquine and five (20%) received hydroxychloroquine alone. Nine (36%) patients died, while 16 (64%) overcome the infection. In the control group the mortality was 16.13% and the overcome from infection was 83.87%. Conclusion: Mortality for COVID-19 was greater in cancer patients when compared with noncancer patients, worse prognosis for older age, women and patients treated with hydroxychloroquine alone. However, the comparisons did not reach statistical significance in most cases. This could be due to the small sample size that is the main limitation of the study.

Background: A significant spread of Coronavirus Disease 19 (COVID-19) has been observed in Western countries. The aim of the study was to analyze whether obesity (BMI ≥ 30 kg/m2) was a risk factor for respiratory failure and death. Methods: Retrospective multicentric cohort study of 296 COVID-19 patients admitted to the hospital between February 28 and March 28, 2020. Demographic characteristics, laboratory findings and clinical scores were compared in obese and non-obese patients. Multivariable analysis was carried out to identify the risk factors for respiratory failure and mortality. Findings: Of 296 patients, 70 (23·6%) had a BMI ≥ 30 kg/m2. Obese patients were significantly older (68±13·5 vs. 63±16·8, p=0·0052) and reported a higher rate of hypertension (77.9% vs. 40.2%, p

Background: Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-associated coronavirus disease-2019 (COVID-19) is spreading worldwide challenging healthcare resources. To provide the best possible care for patients, efficient prognosis is needed. Methods: We performed a multicentre cohort study to develop and validate a risk score for severe respiratory failure (SRF) among hospitalized patients diagnosed with COVID-19. Study population included all adult patients with RT-PCR on nasopharyngeal swab positive for SARS-CoV-2, hospitalized from February 22 to April 3 2020, at 11 hospitals from four Italian Regions. Exclusion criteria were early ( 30bpm, or respiratory distress. Findings: Of the 1265 included patients, 1044 patients were analyzed, (581 derivation, 463 validation cohort). Mean age was 65.7±15 years, 661 (63·3%) were male. SRF rates were 29% and 38% in derivation and validation cohort, respectively. At multivariate analysis, risk factors for SRF in the derivation cohort were age ≥70 years, obesity, body temperature ≥38°C, RR ≥22bpm, lymphocytes ≤900/mm3, creatinine ≥ 1 mg/dl, C-reactive protein ≥10mg/dl, and lactate dehydrogenase ≥350IU/L at hospitalization. Area under receiver-operator curve (AUROC) was 0·90 (95%CI 0.86-0.93). Assigning points to each variable an individual risk score (PREDICO score) was obtained. At risk score of >3, sensitivity, specificity, positive and negative predictive values were 71·6% (64-78), 89·1% (85-92), 72·9% (65-79), and 88·4% (85-91), respectively; positive and negative likelihood ratios were 6·56 (95% CI 4·9-8·77) and 0·31 (95%CI 0·25-0·40), respectively. PREDICO score showed similar prognostic ability in the validation cohort: AUROC 0·80 (0·74-0·88). Interpretation: Using eight variables, easy to obtain at hospitalization, patients with COVID-19 could be classified according to their probability of developing SRF during hospitalization. PREDICO score can be useful to allocate resources and prioritize treatments during COVID-19 pandemic. Trial Registration: NCT04316949. Funding Statement: None. Declaration of Interests: Authors state no conflict of interest related to the content of the present study. Ethics Approval Statement: The study was approved by the Ethic Committee of the promoting center (Comitato Etico Indipendente di Area Vasta Emilia Centro, n. 283/2020/Oss/AOUBo).

Human echinococcosis is among the 17 neglected tropical diseases recognized by the World Health Organization. It is responsible for over $3 billion of health costs every year being endemic in large areas worldwide, and liver is affected in 70% of the cases. Surgery associated to medical treatment is the gold standard and robotic approach may be a valuable tool to achieve safe, parenchyma sparing resections. We retrospectively analyzed the outcomes of patients that underwent robotic radical surgical treatment for hydatid liver disease, from prospectively maintained databases of three Italian centers. 15 patients were included in this study, median age 51 years (24–76). 1 right hepatectomy, 2 left lateral sectionectomies, 5 segmentectomies (including 1 caudatectomy), 3 wedge resections and 5 cyst-pericystectomies were performed. Median estimated blood loss was of 100 ml (50–550 ml), and median operative time including docking was 210 min (95–590 min), with no need for conversion to open. Median hospital stay was 4 days, with only one readmission for fever. Only one patient experienced recurrence in a different liver segment. In our experience, robotic approach for cystic echinococcosis of the liver proved to be a safe and effective strategy also in the so-called “difficult segments”, with short post-operative stay and quick return to daily activities, along with the absence of surgical site recurrences. To the best of our knowledge, this is the largest report of robotic approach to hydatid liver disease.

Rhodococcus equi is a gram-positive coccobacillus responsible for severe infections in patients with weakened immune systems. R equi generally causes pnumonia that may evolve into fatal systemic infection if left untreated. Here, we present a case of a 67-year-old woman affected by acute intermittent porphyria (AIP) who developed R equi pneumonia 7 months after kidney transplantation. Although clinical features at presentation were nonspecific, lung computed tomography showed right perihilar consolidation with a mass-like appearance causing bronchial obstruction. Appropriate antibiotic including intravenous meropenem and oral azithromycin that was then switched to oral levofloxacin and oral azithromycin along with reduction of immunosuppressive therapy resolved pneumonia without provoking an acute attack of porphyria. AIP limited the choice of antibiotics for the treatment of R equi infection because some potentially porphyrinogenic antibacterial agents were avoided. Based on this experience, azithromycin and meropenem can be safely administered for the treatment of R Equi infection in patients with AIP.

Mammary tuberculosis is exceptional in developed countries. It can mimic an abscess or a granulomatous mastitis. In subjects coming from endemic areas, it is necessary to suspect a tuberculosis infection in case of recurrent mastitis refractory to antibiotics. Positivity of Quantiferon‐TB Gold assay can help to confirm the clinical suspicion.

Introduction: Aim of the study is to evaluate the prevalence of HBV, HIV, HCV, tuberculosis and syphilis infection among immigrants assigned to the immigrant centre of the province of Modena. Methods: At the time of arrival all immigrant were tested for: HBsAg, HBsAb, HBcAb, Ag p24/HIVAb, HCVAb, RPR, TPPA, Mantoux test (>10 mm diameter of induration was considered to be positive), Chest X-rays. In case of positive samples, second level tests were performed (HbeAg, HBeAb, HDVAb, and baseline management and treatment of the infection detected). Results: A total of 304 immigrant people were enrolled in the study. HBsAg positivity was 12.2%, HCVAb 3.3%, HIVAb 1.6%, TPPA + RPR positivity in the 0.7%; 10.2% had a positive Mantoux test; 5.6% had Chest X-rays positive for signs of infection and 6 patients had an active tuberculosis. 83.8% HBsAg were HBeAb positive/HBeAg negative. HDVAb resulted positive in 1 patient (2.7%). Previous HBV infection was detected in 28.6% of cases, isolated HBcAb in 2.3%; 5.6% of patients resulted to be positive to HbsAb alone (probable vaccinated). Conclusion: Our study confirms the high prevalence of HBsAg positivity and latent tuberculosis among immigrants, underlying the importance of screening for infections in this special population. Keywords: Immigrant population, Sexually transmitted infections, Tuberculosis, Screening

Mucormycosis is an uncommonly encountered fungal infection in solid organ transplantation. The infection is severe and often results in a fatal outcome. The most common presentations are rhino-sino-orbital and pulmonary disease. We describe a rare case of gastric mucormycosis in a patient with a combined liver-kidney transplant affected by glycogen storage disease type Ia. A 42-year-old female patient presented with gastric pain and melena 26 days after transplantation. Evaluation with upper endoscopy showed two bleeding gastric ulcers. Histological examination of gastric specimens revealed fungal hyphae with evidence of Mucormycetes at subsequent molecular analysis. Immunosuppressive therapy was reduced and antifungal therapy consisting of liposomal amphotericin B and posaconazole was promptly introduced. Gastrointestinal side effects of posaconazole and acute T-cell rejection of renal graft complicated management of the case. A prolonged course of daily injections of amphotericin B together with a slight increase of immunosuppression favored successful treatment of mucormycosis as well as of graft rejection. At 2-year follow-up, the woman was found to have maintained normal renal and liver function. We conclude that judicious personalization of antimicrobial and antirejection therapy should be considered to resolve every life-threatening case of mucormycosis in solid organ transplantation.

Background Posttransplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality in solid organ transplants. Epstein Barr virus (EBV) plays a major role in PTLD development. Guidelines recommend EBV viral load (VL) monitoring in high-risk populations in the first year. Methods Retrospective observational study in all adult patients who had at least 1 EBV-VL performed in the postkidney transplant (KT) period from January 2005 to December 2014 at the Policlinico Modena Hospital. We compared patients with negative EBV-DNA to patients with positive EBV-DNA and we described PTLD developed in the study period. Results One hundred ninety (36.3%) KT patients of 523 were screened for EBV-DNA with 796 samples. One hundred twenty-eight (67.4%) of 190 tested patients presented at least 1 positive sample for EBV. Older age, the use of sirolimus, everolimus, and steroids were associated with EBV-DNA positivity in the univariate analysis. Nine (1.7%) of 523 patients had PTLD. Incidence rate of PTLD in the KT cohort was 0.19/100 person year follow-up (95% confidence interval, 0.09-0.37). One of 9 patients developed early PTLD and was a high-risk patient. Only this PTLD case was positive for EBV. No PTLD case had an EBV-VL superior to 4000 copies/mL. Conclusions Our results suggest that the keystone of PTLD diagnosis is the clinical suspicion. Our study suggests that, in line with guidelines, EBV-VL assays may be avoided in low-risk patients in the absence of a strong clinical PTLD suspicion without increasing patients' risk of developing PTLD. This represents a safe and cost-saving clinical strategy for our center.

The diagnosis of visceral leishmaniasis (VL) remains challenging, due to the limited sensitivity of microscopy, the poor performance of serological methods in immunocompromised patients and the lack of standardization of molecular tests. The aim of this study was to implement a combined diagnostic workflow by integrating serological and molecular tests with standardized clinical criteria. Between July 2013 and June 2015, the proposed workflow was applied to specimens obtained from 94 in-patients with clinical suspicion of VL in the Emilia-Romagna region, Northern Italy. Serological tests and molecular techniques were employed. Twenty-one adult patients (22%) had a confirmed diagnosis of VL by clinical criteria, serology and/or real-time polymerase chain reaction; 4 of these patients were HIV-positive. Molecular tests exhibited higher sensitivity than serological tests for the diagnosis of VL. In our experience, the rK39 immunochromatographic test was insufficiently sensitive for use as a screening test for the diagnosis of VL caused by L. infantum in Italy. However, as molecular tests are yet not standardized, further studies are required to identify an optimal screening test for Mediterranean VL.

Purpose: We investigated the clinical performance of (1 → 3)-β-d-glucan (BG), as an early marker of invasive fungal infections (IFI), in different clinical settings. Methods: BG serum levels were assessed by Fungitell (Associates of Cape Cod, Inc), in parallel with galactomannan (GM) when requested by clinicians. By a prospective monocentric study, 270 episodes at risk or with suspect of IFI were enrolled, namely 58 proven-probable invasive aspergillosis (IA), 27 proven invasive candidiasis (IC), 11 possible IC, 16 P.jirovecii pneumonia (PJP), 4 episodes of other IFI and 154 non-IFI controls. Results: We found that (a) the BG overall sensitivity, specificity, positive predictive value and negative predictive value (NPV) were 87.9, 80.5, 76.7 and 89.9 %, respectively; (b) the highest sensitivity was found in the IC groups, followed by PJP, IA and other IFI groups; (c) an association was observed between BG kinetics and patients outcome; (d) in the IA episodes, the combination of BG or GM vs GM alone increased sensitivity from 60.0 to 83.3 % in the haematological patients; (e) false-positive BG results were related to Gram-negative infections or infusion of polyclonal IgM-enriched immunoglobulins, where high levels of BG were indeed detected. Conclusion: Besides strengthening its overall good clinical performance, we provide evidence that serum BG correlates with clinical outcome and that, once used in combination with GM, BG allows to enhance IFI diagnosis rate. The high sensitivity and NPV, observed in the Intensive Care Unit setting, open to BG validation as a marker for assessment of antifungal treatment.

Background. Visceral leishmaniasis (VL) caused byLeishmania infantumis endemic in the Mediterranean area. In the last decades a northward spread of the parasite has been observed in Italy. This paper describes a VL outbreak in Modena province (Emilia-Romagna, Northern Italy) between 2012 and 2015.Methods. Retrospective, observational study to evaluate epidemiological, microbiological characteristics, and clinical management of VL in patients referring to Policlinico Modena Hospital.Results. Sixteen cases of VL occurred in the study period. An immunosuppressive condition was present in 81.3%. Clinical presentation included anemia, fever, leukopenia, thrombocytopenia, and hepatosplenomegaly. Serology was positive in 73.3% of cases, peripheral blood PCR in 92.3%, and bone marrow blood PCR in 100%. Culture was positive in 3/6 cases (50%) and all the isolates were identified asL. infantumby ITS1/ITS2 sequencing. The median time between symptom onset and diagnosis was 22 days (range 6–131 days). All patients were treated with liposomal amphotericin b. 18.8% had a VL recurrence and were treated with miltefosine. Attributable mortality was 6.3%.Conclusions. VL due toL. infantumcould determine periodical outbreaks, as the one described; thus it is important to include VL in the differential diagnosis of fever of unknown origin, even in low-endemic areas.

Fusarium is an opportunistic fungal pathogen which is emerging as a significant cause of morbidity and mortality in immunocompromised hosts. We present a rare case of F. verticillioides fungemia that occurred in a patient who underwent a second orthotopic liver transplantation for chronic rejection and completely responded to treatment with voriconazole.

Mucorales-specific T cells were investigated in 28 hematologic patients during the course of their treatment. Three developed proven invasive mucormycosis (IM), 17 had infections of known origin but other than IM, and 8 never had fever during the period of observation. Mucorales-specific T cells could be detected only in patients with IM, both at diagnosis and throughout the entire course of the IM, but neither before nor for long after resolution of the infection. Such T cells predominantly produced IL-4, IFN-γ, IL-10, and to a lesser extent IL-17 and belonged to either CD4+ or CD8+ subsets. The specific T cells that produced IFN-γ were able to directly induce damage to Mucorales hyphae. None of the 25 patients without IM had Mucorales-specific T cells. Specific T cells contribute to human immune responses against fungi of the order Mucorales and could be evaluated as a surrogate diagnostic marker of IM.

Although human immunodeficiency virus (HIV) infection has been a major global health problem for almost 3 decades, with the introduction of highly active antiretroviral therapy in 1996 and effective prophylaxis and management of opportunistic infections, mortality from acquired immunodeficiency syndrome has decreased markedly. In developed countries, this condition is now being treated as a chronic condition. As a result, rates of morbidity and mortality from other medical conditions leading to end-stage liver, kidney, and heart disease are steadily increasing in individuals with HIV. Because the definitive treatment for end-stage organ failure is transplantation, the demand for it has increased among HIV-infected patients. For these reasons, many transplant centers have eliminated HIV infection as a contraindication to transplantation, as a result of better patient management and demand.

Background: Immunocompromised persons infected with Mycobacterium tuberculosis (MTB) have increased risk of tuberculosis (TB) reactivation, but their management is hampered by the occurrence of false-negative results of the tuberculin skin test (TST). The T-cell interferon (IFN)-γ release blood assays T-SPOT.TB (TS.TB) [Oxford Immunotec; Abingdon, UK] and QuantiFERON-TB Gold In-Tube (QFT-IT) [Cellestis Ltd; Carnegie, VIC, Australia] might improve diagnostic accuracy for latent TB infection (LTBI) in high-risk persons, although their performance in different groups of immunocompromised patients is largely unknown. Methods and results: Over a 1-year period, we prospectively enrolled patients in three different immunosuppressed groups, as follows: 120 liver transplantation candidates (LTCs); 116 chronically HIV-infected persons; and 95 patients with hematologic malignancies (HMs). TST, TS.TB, and QFT-IT were simultaneously performed, their results were compared, and intertest agreement was evaluated. Overall, TST provided fewer positive results (10.9%) than TS.TB (18.4%; p < 0.001) and QFT-IT (15.1%; p = 0.033). Significantly fewer HIV-infected individuals had at least one positive test (9.5%) compared with LTCs (35.8%; p < 0.001) and patients with HMs (29.5%; p < 0.001). Diagnostic agreement between tests was moderate (κ = 0.40 to 0.65) and decreased in the HIV-infected group when the results of the TS.TB were compared with either TST (κ = 0.16) or QFT-IT (κ = 0.19). Indeterminate blood test results due to low positive control values were significantly more frequent with QFT-IT (7.2%) than with TS.TB (0.6%; p < 0.001). Conclusions: Blood tests identified significantly more patients as being infected with MTB than TST, although diagnostic agreement varied across groups. Based on these results, we recommend tailoring application of the new blood IFN-γ assays for LTBI in different high-risk groups and advise caution in their current use in immunosuppressed patients.

Background Infectious complications still represent a major cause of morbidity and mortality in patients with organ transplantation. In particular, small bowel or multivisceral transplantation is complicated to a greater extent than other grafts as a consequence of infectious complications including sepsis. Methods This prospective study assessed outcome, incidence, and timing of infections in sequential patients undergoing small bowel or multivisceral transplantation (SB/MVTx) performed at a university transplant center between January 2001 and October 2003. Nineteen patients underwent transplantation during this period, 13 of whom (68%) undergoing isolated SB and 6 (32%) MV grafts with or without liver. Results The median follow up was 524 days (interquartile range=252-730) with an overall 24.4 person/year of observation. Postoperative mortality rate was 0.1 death/person/year; all patients, except one who died intraoperatively, were alive 6 months postsurgery. There were 100 documented infections including: 59 bacterial (2.4 events/person/year), 35 viral (1.4 events/person/year) and 6 fungal (0.2 events/person/year). Patients developed at least one episode of bacterial infection in 94% of the cases, viral infection in 67%, and fungal infection in 28%. Conclusions This cohort describes the very common and complex nature of infectious complications in this challenging group of transplantation patients. Larger cohorts are needed to specifically address infection risk factors and longer term outcomes.

To the Editor: Legionella pneumophila serogroups (SGs) 1–16 cause pneumonia in humans. Although SG 1 is the serogroup most commonly associated with disease (1), we report a case of community-acquired legionellosis caused by SG 11. In November 2010, a 42-year-old man was admitted to Modena University Hospital, Modena, Italy, with a 4-day history of fever, dyspnea, and cough. His vital signs were as follows: temperature 40.0°C, pulse 135 beats/min, blood pressure 110/60 mm Hg, respiratory rate 30 breaths/min, and oxygen saturation 85% in room air. Inspiratory crackles were heard in the left lower lung lobe. Chest radiographs and successive high-resolution computerized tomography revealed left lobar infiltrates (Figure, panels A and B). Blood count documented severe pancytopenia together with high levels of inflammation markers: fibrinogen (1,031 mg/dL), C-reactive protein (33 mg/dL), and procalcitonin (28.5 ng/mL). The patient’s medical history was unremarkable; however, results of tests conducted at the time of hospital admission led to the diagnosis of acute leukemia. Figure Imaging studies of 42-year-old man with severe pneumonia caused by Legionella pneumophila serogroup 11, showing lobar consolidation of the left lower lung lobe, with an air-bronchogram within the homogeneous airspace consolidation. Consensual mild pleural ... Empirically prescribed antimicrobial treatment for neutropenic patients was initiated and consisted of meropenem (3 g/day) and levofloxacin (500 mg/day), combined first with vancomycin (2 g/day) and later with linezolid (1,200 mg/day). A few days later, antifungal therapy was empirically added to the treatment regimen (liposomal amphotericin B at 3 mg/kg/day). The patient received continuous positive airway pressure, which resulted in progressive improvement of blood gas exchange, until normalization was achieved. Serologic and molecular examination and culture of bronchoalveolar lavage fluid, blood, urine, and feces produced negative results for fungal, viral, and bacterial pathogens. Test results for L. pneumophila urinary antigen (Biotest AG, Dreieich, Germany) and IgM and IgG against L. pneumophila (Serion-Immundiagnostica GmbH, Wurzburg, Germany) were negative. Culture of sputum collected at the time of hospital admission showed growth of legionella-like colonies on buffered charcoal yeast extract, with and without the addition of antimicrobial drugs (Oxoid, Basingstoke, UK). The colonies were identified as L. pneumophila SGs 2–14 by the Legionella latex test (Oxoid). The strain was further characterized as L. pneumophila SG 11, according to a polyclonal latex reagent set (Biolife, Milan, Italy). Environmental investigations were conducted in the patient’s house and workplace, but L. pneumophila SG 11 was not detected in any of the locations tested. A week after hospital admission, the patient was persistently febrile and experienced pain in the left thorax. High-resolution computerized tomography of the chest was repeated and showed increased pulmonary infiltrate (Figure, panels C and D) that was consistent with L. pneumophila pneumonia (2). Highly potent antimicrobial therapy against L. pneumophila was administered, consisting of high-dosage levofloxacin (1 g/day) combined with azithromycin (500 mg/day), while the other antimicrobial agents were progressively reduced (3). The fever subsided 14 days after the onset of targeted antimicrobial drug treatment; at that time, the sputum culture and test results for urinary L. pneumophila antigen were negative, but serologic assay results were positive for IgG and negative for IgM against L. pneumophila. Subsequent computerized tomographic scans of the chest documented progressive improvement of lung infiltrates, and nearly complete resolution was obtained 3 months after hospital admission. L. pneumophila SG 11 infection has, thus far, been reported only rarely in humans. The first SG 11 strain was isolated in the United States in 1982 from a patient with multiple myeloma (4). Since then, few other cases of SG 11 strains have been reported in Europe (5,6); it is conceivable that this strain is not as widely distributed and is less pathogenic than other SGs, especially SG 1. It can be argued that infections caused by SG 11 have been underdiagnosed. L. pneumophila SG 11 cannot be detected by Legionella urinary antigen or serologic tests, the assays most frequently used to diagnose legionellosis (7–9). The negative urinary antigen test result for this patient is consistent with a non–SG 1 infection. The single positive serologic result for IgG was probably caused by cross-reactivity because the commercial assay kit was designed to recognize only L. pneumophila SGs 1–7. Culture is the only useful diagnostic tool for identifying SGs. However, this tool is not always feasible because it requires specialized media and skills to identify the organism. In addition, sensitivity is low, depending on the severity of the disease and the availability of adequate respiratory specimens (9). Despite these limitations, culture is needed to detect all SGs of L. pneumophila, especially in immunocompromised patients, who are more susceptible to infections caused by strains of non–SG 1 L. pneumophila (10).

We determined the in vitro antifungal activity of liposomal amphotericin B (L-AmB) against 604 clinical yeast isolates. Amphotericin B deoxycholate (D-AmB) was tested in parallel against all the isolates. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) M27-A3 method. Overall, L-AmB was highly active against the isolates (mean MIC, 0.42 µg ml−1; MIC90, 1 µg ml−1; 97.2 % of MICs were ≤1 µg ml−1) and comparable to D-AmB (mean MIC, 0.48 µg ml−1; MIC90, 1 µg ml−1; 97.3 % of MICs were ≤1 µg ml−1). The in vitro activity of D-AmB and L-AmB was correlated (R 2 = 0.61; exp(b), 2.3; 95 % CI, 2.19–2.44, PCandida albicans (mean MICs of D-AmB and L-AmB, 0.39 µg ml−1 and 0.31 µg ml−1, respectively) and Candida parapsilosis (mean MICs of D-AmB and L-AmB, 0.38 µg ml−1 and 0.35 µg ml−1, respectively) were the species most susceptible to the agents tested, while Candida krusei (currently named Issatchenkia orientalis) (mean MICs of D-AmB and L-AmB, 1.27 µg ml−1 and 1.13 µg ml−1, respectively) was the least susceptible. The excellent in vitro activity of L-AmB may have important implications for empirical treatment approaches and support its role in treatment of a wide range of invasive infections due to yeasts.

The pharmacokinetic interaction between highly active antiretroviral therapy (HAART) and immunosuppressive drugs is a critical element in the management of patients with human immunodeficiency virus infection who undergo orthotopic liver transplantation (OLT). We describe the effect of the coadministration of Amprenavir/Ritonavir (APV/r) and FosAmprenavir (FosAPV) on cyclosporine (CsA) concentrations in two patients receiving OLT for end-stage liver disease due to hepatitis C Virus. Patient 1, who was maintained on 300 mg CsA twice a day with a trough concentration (C(trough)) around 250 ng/mL, restarted HAART 12 days after transplantation with 300 mg APV/r twice a day with corresponding APV C(trough) of 5293 ng/mL and RTV C(trough) of 186 ng/mL. Forty-eight hours after initiation of HAART, C(trough) of CsA was 1200 mg/mL, so it was necessary to reduce the CsA dosage 12-fold (50 mg every day) to achieve a therapeutic effect. In Patient 2, who was maintained on 300 mg CsA twice a day and a corresponding C(trough) of 400 ng/mL, HAART was restarted 12 days post-OLT with FosAPV 1400 mg twice a day. After 48 hours C(trough) of CsA was around 600 ng/mL and C(trough) of FosAPV, 1221 ng/mL. In this case it was necessary to reduce the CsA administration 3.5-fold (175 mg every day). In conclusion, therapeutic drug monitoring was necessary to monitor HAART and CsA post-OLT to prevent toxicity due to both therapies. The use of FosAPV without ritonavir boostering is sufficient to maintain adequate CsA blood concentrations, avoiding any event of toxicity.

A Burkholderia cepacia complex outbreak occurred among ventilated non-cystic fibrosis patients in an intensive care unit (ICU) in Italy: 33 colonized and 13 infected patients were included in a retrospective study aimed at investigating factors related to clinical infection and mortality. Demographic/clinical conditions and mortality did not vary significantly between colonized and infected patients, both groups showing high mortality rates compared with the overall ICU population and similar to that observed in patients with other infections. In multivariate regression analysis, disease severity (defined by the Simplified Acute Physiology Score II) and age were the only independent predictors of early mortality (odds ratio: 1.12; 95% confidence interval: 1.02-1.26; and 1.07; 1.01-1.15, respectively).

Background: Immune-compromised patients incur a high risk of surgical wound dehiscence and colonization by multidrug resistant organisms. Common treatment has been debridement and spontaneous secondary healing.We report on the results obtained in nine such patients whose wounds were treated by debridement, negative pressure dressing and direct closure.Methods: All immune-compromised patients referred to our Institution between March 1, 2010 and November 30, 2011 for dehiscent abdominal wounds growing multidrug resistant organisms were treated by serial wound debridements and negative pressure dressing. They were primarily closed, despite positive microbiological cultures, when clinical appearance was satisfactory.As a comparison, records from patients treated between March 1, 2008 and February 28, 2010 who, according to our Institution's policy at that time, had been left to heal by secondary intention, were retrieved and examined.Results: Nine patients were treated by direct wound closure, five had been treated previously by secondary intention healing.Overall, ten patients had received liver transplant, 1 kidney transplant, 1 was HIV infected, 1 suffered from multi-organ failure, 1 was undergoing hemodialysis.Wound dehiscence involved skin and subcutaneous layers in all patients, in two the muscular layer was also involved.Mean healing time was significantly shorter in patients treated more recently by primary intention in comparison with historical patients (28 vs 81 days). The only complication observed was a small superficial abscess that developed around a non-absorbable stitch 10 months after closure in a patient treated by primary closure. Conclusions: According to our results, fast healing can be safely obtained by closure of a clinically healthy wound, despite growth of multidrug resistant organisms, even in immune-compromised patients. © 2013 Pignatti et al.; licensee BioMed Central Ltd.

We report a case of gastric localization of Leishmania in a 29-year old man affected by AIDS. Gastric biopsies revealed macrophages infected with intracytoplasmic organisms attributable to Leishmania amastigotes. The authors emphasize the importance of performing random biopsies in the absence of endoscopic abnormalities.