Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS-CoV-2 infection: A retrospective cohort study.

As it has been shown that lopinavir (LPV) and hydroxychloroquine (HCQ) have in vitro activity against coronaviruses, they were used to treat COVID-19 during the first wave of the epidemic in Lombardy, Italy. To compare the rate of clinical improvement between those who started LPV/ritonavir (LPV/r)+HCQ within 5 days of symptom onset (early treatment, ET) and those who started later (delayed treatment, DT). This was a retrospective intent-to-treat analysis of the hospitalized patients who started LPV/r + HCQ between 21 February and 20 March 2020. The association between the timing of treatment and the probability of 30-day mortality was assessed using univariable and multivariable logistic models. The study involved 172 patients: 43 (25%) in the ET and 129 (75%) in the DT group. The rate of clinical improvement increased over time to 73.3% on day 30, without any significant difference between the two groups (Gray's test P = .213). After adjusting for potentially relevant clinical variables, there was no significant association between the timing of the start of treatment and the probability of 30-day mortality (adjusted odds ratio [aOR] ET vs DT = 1.45, 95% confidence interval 0.50-4.19). Eight percent of the patients discontinued the treatment becausebecause of severe gastrointestinal disorders attributable to LPV/r. The timing of the start of LPV/r + HCQ treatment does not seem to affect the clinical course of hospitalized patients with COVID-19. Together with the severe adverse events attributable to LPV/r, this raises concerns about the benefit of using this combination to treat COVID-19.

Virological response and retention in care according to time of starting ART in Italy: data from the Icona Foundation Study cohort.

OBJECTIVES: To describe: (i) factors associated with rapid and delayed ART initiation; (ii) rates of 12 week virological response; and (iii) virologically controlled retention in care by 1 year from ART initiation according to timing of start in a real-life setting. METHODS: All individuals in the Icona cohort diagnosed with HIV in 2016-17 who initiated ART were grouped according to the time between HIV diagnosis and ART initiation: Group 1, ≤7 days; Group 2, 8-14 days; Group 3, 15-30 days; Group 4, 31-120 days; and Group 5, >120 days. Multivariable logistic regression models were used to identify factors associated with: (i) the probability of rapid (Group 1) and very delayed (Group 5) ART initiation; (ii) the 12 week virological response (by a modified snapshot algorithm); and (iii) the probability of retention in care at 1 year (on ART with HIV-RNA <50 copies/mL). RESULTS: A total of 1247 individuals were included [82 (6.6%) in Group 1, 115 (9.2%) in Group 2, 267 (21.4%) in Group 3, 641 (51.4%) in Group 4 and 142 (11.4%) in Group 5]. Main predictors of rapid ART start (Group 1) were low CD4 cell count and high HIV-RNA at first contact with the infectious diseases centre. There was no association between probability of virological response and timing of ART initiation. Overall, 90% of individuals remained on ART after 1 year, 91% with undetectable HIV-RNA. Participants of Italian nationality, those with higher CD4 cell count and lower HIV-RNA at ART initiation were more likely to be retained in care after 1 year. CONCLUSIONS: In our high-income observational setting, we did not observe differences in the 1 year rate of virological response and retention in care according to timing of ART initiation.

Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders.

Despite optimal suppression of HIV replication, restoration of CD4(+) T cells is not always achieved in antiretroviral therapy-treated individuals. Defective CD4 recovery in immunologic nonresponders is possibly associated with TLR-mediated immune activation driven by alterations of gut permeability. Hydroxychloroquine (HCQ) reduces endosomal TLR signaling; thus, we verified whether HCQ could dampen immune activation and be associated with an increase in CD4(+) T cells. To this end, we enrolled in a prospective study 20 HIV-infected immunologic nonresponders (CD4 count < 200 cells/mL or CD4 increase < 5% in the last 12 months) who received 400 mg/day HCQ for 6 months. HCQ had a notable impact on immune activation as shown by significant modifications of the following parameters: (1) reduced plasma lipopolysaccharide; (2) decreased TLR4-expressing CD14(+) cells, TLR4-mediated signal transduction, and mRNA synthesis; (3) reduced percentages of activated CD4(+) (CD4(+)/Ki67(+)) and CD14(+) (CD14(+)/CD69(+)) cells; (4) increased T-regulatory cells (Tregs), naive Tregs, and TLR4-expressing Tregs; (5) augmented plasmacytoid dendritic cells and reduced IFNα-secreting plasmacytoid dendritic cells; and (6) reduced IL-6 and TNFα production. HCQ-induced immune modulation was associated with increased percentages of circulating CD4(+) T cells and was mostly retained 2 months after therapy interruption. HCQ reduces lipopolysaccharide/TLR-mediated immune activation; this compound could be a useful immunomodulant in HIV-infected patients. This study is registered at EutraCT as 2009-012499-28 with study number HLS01/2009-1-16-03-2009.

Immunological effects of sublingual immunotherapy: clinical efficacy is associated with modulation of programmed cell death ligand 1, IL-10, and IgG4.

Sublingual immunotherapy (SLIT) is an alternate route of administration of allergen-specific immunotherapy with an improved safety profile; to clarify the immune mechanisms elicited by this therapy, we analyzed the clinical and immunologic effects of SLIT in patients with a clinical history of ragweed sensitization. To analyze possible difference among immunotherapeutic protocols, we also compared patients receiving preseasonal, seasonal, or prolonged sublingual therapy (≥ 3 y); patients receiving symptomatic therapy alone were enrolled as well in the study. Clinical and immunological parameters were measured twice in and out of the pollination period. Clinical benefits, as measured by the visual analog scale for symptoms and for use of drugs, were evident in all three groups of individuals receiving immunotherapy, but were significantly better in patients undergoing prolonged SLIT. Immunologically, SLIT resulted in increased IL-10 production, programmed cell death ligand 1 expression, and concentration of allergen-specific IgG4, as well as in the reduction of CD80 and CD86 expression and IL-4 production. SLIT, thus, is associated with modulation of programmed cell death ligand 1 expression and IL-10 synthesis and favors the production of allergen-specific IgG4. These effects are evident from the first pollen season, independently from therapeutic regimen (preseasonal or seasonal) even if a prolonged treatment is necessary to obtain full clinical efficacy. A more detailed understanding of the interaction of allergen and APCs within the oral mucosa will allow improved targeting of allergy vaccine.

Disseminated Cryptococcosis in a Patient With Metastatic Prostate Cancer Who Died in the Coronavirus Disease 2019 (COVID-19) Outbreak.

We report the case of a 61-year-old patient with a history of prostate cancer affected by bone metastasis. He presented to our attention for ulcerous and necrotic cutaneous lesions unresponsive to antibiotics. The spread of cutaneous lesions and the onset of neurological symptoms suggested a cryptococcal disease, which was confirmed by lumbar puncture and cutaneous biopsy. We present the diagnostic and therapeutic approach to this case.

Imported dengue fever: a 16-years retrospective analysis in Milan (Italy) and a brief review of the European literature.

Dengue Fever (DF), transmitted by Aedes mosquitoes, is the most common arthropod-borne infection, it is almost ubiquitous in tropical and subtropical areas with an estimate of 360 million infections per year. A competent vector (A. albopictus) is present in most of Southern Europe and is endemic in Italy. We conducted a 16-year retrospective study of probable/confirmed dengue fever observed at the Department of Infectious Diseases of Luigi Sacco Hospital in Milan, Italy. Overall 122 patients were included in the study, 106 with probable and 16 with proven diagnosis of dengue fever. Most patients (91%) were Italian, with a median age of 35 years (IQR 29-46 years) and similar gender distribution, travelling for tourism (80%). Asia (mainly South East Asia and Indian Subcontinent) was the most frequent travel destination (55%), followed by Central America and the Caribbeans (22%). August-September was the peak season of presentation (42.6%). The majority of our diagnoses were based on serology alone. The most common signs and symptoms were fever (99,2%), maculopapular rash (50,8%), headache (50,8%), arthralgias (50,8%) and myalgias (46,7%). Leukopenia (77%), thrombocytopenia (81%) and altered LDH, AST and ALT (respectively 60,6%, 54,1% and 45,9%) were the most common laboratory test's abnormalities. No cases of severe DF were recorded. Our epidemiological and clinical findings are largely in accordance with most recent studies about imported DF in Europe. Although very similar in presentation to other arthropod-borne illnesses, some clinical features may help in differentiating DF from other causes of fever in the returning traveler.

The Effect of Switching from Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide (TAF) on Liver Enzymes, Glucose, and Lipid Profile.

OBJECTIVE: We aimed to investigate the effect of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) on the hepatic safety and metabolic profile. METHODS: Consecutive HIV patients, enrolled in the Surveillance Cohort Long-term Toxicity Antiretrovirals/Antivirals (SCOLTA) project, switching from TDF to TAF were included. Changes from baseline (T0) to 6-month follow-up (T1) were evaluated using paired t-test and signed rank test. RESULTS: A total of 190 patients switched from TDF to TAF and had one 6-month follow-up visit. They were 80% male, 74.2% at CDC stage A-B, 93.7% with undetectable HIV-viral load. Mean age was 46.7±10.7 years, body mass index was 25.0±3.9 kg/m2, median CD4 cell count was 634 cell/µL (interquartile range [IQR]=439-900), aspartate aminotransferase (AST) was 23 (IQR=19-30) IU/L, and alanine aminotransferase (ALT) was 24 (IQR=17-34) IU/L. At T1, both AST (median=-1, IQR=-5-2 IU/L, P=0.004) and ALT (median=-2, IQR=-7-3 IU/L, P=0.0004) showed a significant decrease. Among 28 patients with ALT >40 at baseline, reduction was significant both clinically (-17, IQR=-32--1) and statistically (P=0.0003). Total cholesterol levels (TC) increased (+13.4±3.8 mg/dL, P=0.0006), as well as HDL-cholesterol (HDL-C) (+3.8±1.2 mg/dL, P=0.02), LDL Cholesterol (LDL-C) (+7.6±3.4, P=0.03) and glucose (+4.0±1.8 mg/dL, P=0.02). D:A:D: and Framingham risk score did not change at 6 months after switch. CONCLUSION: A significant reduction of liver enzymes was observed after switching from TDF to TAF, especially in subjects with initial level of ALT >40 IU/L. Glucose, TC, HDL-C, and LDL-C increased, with no effect on cardiovascular risk scores.

Exploring healthcare providers' mental models of the infection prevention "patient zone" - a concept mapping study.

Background: Pathogen transmission plays a major role in the development of healthcare-associated infections. The "patient zone" concept developed as part of the World Health Organization's "Five moments of hand hygiene" aims to distinguish surfaces primarily contaminated by flora of a single patient, i.e. inside the patient zone, from those outside the patient zone containing foreign and potentially harmful microorganisms. Discrepancies in healthcare provider (HCP) internal conceptual representations (i.e. mental models) of the patient zone may lead to missed infection prevention measures that could result in patient harm. We explored HCPs' mental models of the patient zone that shape how they interact with the work environment. Methods: We conducted individual concept mapping interviews supported by a card-sorting technique to examine HCPs' mental models of the patient zone and compared these to IPC expert models. Ten participants (five nurses, five physicians) without IPC specialization and two IPC experts provided definitions of the patient zone and allocated 32 items to "inside" or "outside" the patient zone while verbalizing their thought processes. We calculated similarity as percent agreement among participants and accuracy as percent allocated consistently with expert consensus. A content analysis of interview recordings served to identify mental models underlying the allocation decisions. Results: Our study revealed limited similarity among participants, with seven of 32 items allocated consistently among all participants. Overall, 68% of items were sorted accurately according to expert consensus. Identified mental models were categorized as follows: "Patient contact", the patient zone defined according to objects having patient contact; "Sectors", the patient zone as a defined physical space; "Disinfection", the patient zone deduced based on need to disinfect hands and objects; and "Context-dependency", the patient zone defined depending on the context of an object's use. Conclusions: Our study revealed ambiguity surrounding the patient zone concept as evidenced by low similarity between participants and important discrepancies between participant and expert mental models. Such ambiguity may lead to inconsistent application of the patient zone concept and represents a patient safety risk. Initiatives to improve understanding and application of the patient zone concept should focus on establishing consistent, theoretically founded mental models.

Likelihood of Infectious Outcomes Following Infectious Risk Moments During Patient Care-An International Expert Consensus Study and Quantitative Risk Index.

OBJECTIVE To elicit expert consensus on the likelihood of infectious outcomes (patient colonization or infection) following a broad range of infectious risk moments (IRMs) from observations in acute care. DESIGN Expert consensus study using modified Delphi technique. PARTICIPANTS Panel of 40 international experts including nurses, physicians and microbiologists specialized in infectious diseases and infection prevention and control (IPC). METHODS The modified Delphi process consisted of 3 online survey rounds, with feedback of mean ratings and expert comments between rounds. The Delphi survey comprised 52 care scenarios representing observed IRMs organized into 6 sections: hands, gloves, medical devices, mobile objects, invasive procedures, and additional moments. For each scenario, experts indicated the likelihood of both patient colonization and infection on a scale from 0 to 5 (high). Expert ratings were plotted against frequencies of IRMs observed during actual patient care resulting in a risk index. RESULTS Following 3 rounds, consensus was achieved for 92 of 104 items (88.5%). The mean ratings across all scenarios for likelihood of colonization and infection were 2.68 and 2.02, respectively. The likelihood of colonization was rated higher than infection for 48 of 52 scenarios. Ratings were significantly higher for colonization (P=.001) and infection (P<.0005) when the scenario involved transfer of pathogens to critical patient sites. CONCLUSIONS The design of effective IPC strategies requires the selection of behaviors according to their impact on patient outcomes. The IRM index reported here provides a basis for standardizing and prioritizing targets for quality improvement initiatives, training, and future research in acute health care. Infect Control Hosp Epidemiol 2018;39:280-289.

Frequency and Nature of Infectious Risk Moments During Acute Care Based on the INFORM Structured Classification Taxonomy.

OBJECTIVE In this study, we sought to establish a comprehensive inventory of infectious risk moments (IRMs), defined as seemingly innocuous yet frequently occurring care manipulations potentially resulting in transfer of pathogens to patients. We also aimed to develop and employ an observational taxonomy to quantify the frequency and nature of IRMs in acute-care settings. DESIGN Prospective observational study and establishment of observational taxonomy. SETTING Intensive care unit, general medical ward, and emergency ward of a university-affiliated hospital. PARTICIPANTS Healthcare workers (HCWs) METHODS Exploratory observations were conducted to identify IRMs, which were coded based on the surfaces involved in the transmission pathway to establish a structured taxonomy. Structured observations were performed using this taxonomy to quantify IRMs in all 3 settings. RESULTS Following 129.17 hours of exploratory observations, identified IRMs involved HCW hands, gloves, care devices, mobile objects, and HCW clothing and accessories. A structured taxonomy called INFORM (INFectiOus Risk Moment) was established to classify each IRM according to the source, vector, and endpoint of potential pathogen transfer. We observed 1,138 IRMs during 53.77 hours of structured observations (31.25 active care hours) for an average foundation of 42.8 IRMs per active care hour overall, and average densities of 34.9, 36.8, and 56.3 IRMs in the intensive care, medical, and emergency wards, respectively. CONCLUSIONS Hands and gloves remain among the most important contributors to the transfer of pathogens within the healthcare setting, but medical devices, mobile objects, invasive devices, and HCW clothing and accessories may also contribute to patient colonization and/or infection. The INFORM observational taxonomy and IRM inventory presented may benefit clinical risk assessment, training and education, and future research. Infect Control Hosp Epidemiol 2018;39:272-279.

Transfer of pathogens to and from patients, healthcare providers, and medical devices during care activity-a systematic review and meta-analysis.

OBJECTIVE: The transfer of pathogens may spread antimicrobial resistance and lead to healthcare-acquired infections. We performed a systematic literature review to generate estimates of pathogen transfer in relation to healthcare provider (HCP) activities. METHODS: For this systematic review and meta-analysis, Medline/Ovid, EMBASE, and the Cochrane Library were searched for studies published before July 7, 2017. We reviewed the literature, examining transfer of pathogens associated with HCP activities. We included studies that (1) quantified transfer of pathogens from a defined origin to a defined destination surface; (2) reported a microbiological sampling technique; and (3) described the associated activity leading to transfer. For studies reporting transfer frequencies, we extracted data and calculated the estimated proportion using Freeman-Tukey double arcsine transformation and the DerSimonian-Laird random-effects model. RESULTS: Of 13,121 identified articles, 32 were included. Most articles (n=27, 84%) examined transfer from patients and their environment to HCP hands, gloves, and gowns, with an estimated proportion for transfer frequency of 33% (95% confidence interval [CI], 12%-57%), 30% (95% CI, 23%-38%) and 10% (95% CI, 6%-14%), respectively. Other articles addressed transfer involving the hospital environment and medical devices. Risk factor analyses in 12 studies suggested higher transfer frequencies after contact with moist body sites (n=7), longer duration of care (n=5), and care of patients with an invasive device (n=3). CONCLUSIONS: Recognizing the heterogeneity in study designs, the available evidence suggests that pathogen transfer to HCPs occurs frequently. More systematic research is urgently warranted to support targeted and economic prevention policies and interventions.

Are direct-acting antivirals safe and effective in hepatitis C virus-cryoglobulinemia? virological, immunological, and clinical data from a real-life experience.

OBJECTIVES: Hepatitis C virus (HCV) is the major cause of cryoglobulinemia. Direct-acting antivirals (DAAs) have markedly changed the therapeutic outcomes in the treatment of patients with HCV. We evaluate the efficacy, safety, immunological, and clinical response of different DAA regimens in HCV-cryoglobulinemia. PATIENTS AND METHODS: Ninety-three cryoglobulinemic patients, divided into symptomatic [symptomatic cryoglobulinemic patients (SCP; n=35)] and asymptomatic [nonsymptomatic cryoglobulinemic patients (NSCP; n=60)], underwent DAAs. Eighty-nine comparable noncryoglobulinemic patients were selected as a control group. We evaluated the sustained virological response (SVR), the adverse effects, and the immune and symptomatic response. RESULTS: Percentages of patients who achieved SVR and experienced adverse effects were not statistically different between the three groups (100, 95, 93.3% and 57.1, 53.3, 48.3%). In 68.5% of SCP and in 76.7% of NSCP, cryoglobulins disappeared at SVR. No risk factor was associated with the persistence of cryoglobulins. An increase was observed both in C4 (P=0.002; P=0.018) and in C3 (P=0.0037; P=0.031) in SCP and NSCP. About 70% of symptomatic patients showed a complete or partial symptomatic remission: persistence of symptoms is correlated to the type of clinical picture. CONCLUSION: DAA regimens are safe and effective in patients with HCV-cryoglobulinemia. The achievement of SVR is necessary, but not sufficient, to achieve a complete immunological and clinical response.

Weight Gain: A Possible Side Effect of All Antiretrovirals.

Weight gain and body mass index (BMI) increase are central issues in patients living with HIV who need to minimize the risk of metabolic disease. Information collected through the SCOLTA cohort revealed significant 1-year BMI increase in patients treated with dolutegravir (P = .004), raltegravir (P = .0004), elvitegravir (P = .004), darunavir (P = .0006), and rilpivirine (P = .029). BMI gain correlated with low baseline BMI (P = .002) and older age (P = .0007) in Centers for Disease Control and Prevention stages A/B, with lower BMI (P = .005) and CD4+ T-cell count (P = .007) at enrollment in stage C.

Atherosclerosis is associated with multiple pathogenic mechanisms in HIV-infected antiretroviral-naive or treated individuals.

OBJECTIVES: HIV-infected patients have a greater burden of sub-clinical and clinical atherosclerotic disease compared to the general population. The primary objective of this study was to compare the relative roles of inflammation, endothelial alterations, and metabolic factors in the induction and maintenance of atherosclerosis in antiretroviral therapy (ART)-treated or ART-naive patients. DESIGN: Cross-sectional study; 79 HIV-infected patients (55 ART-treated and 24 naive individuals) were consecutively enrolled. In both groups, nearly 50% of the individuals had a high cardiovascular risk (Framingham value >20%). METHODS: Echo-Doppler [intima-media thickness (IMT)], inflammatory, thrombophilic, endothelial, metabolic indexes, and cholesterol efflux molecules were evaluated. Multivariate analysis adjusted for age, CD4 nadir, BMI, and Framingham's score were used to analyze the results. RESULTS: A complex pathogenesis drives atherogenesis in HIV infection. Thus, whereas inflammation could be responsible for this process in ART-naive individuals, metabolic factors [low-density lipoprotein (LDL), apolipoprotein B (ApoB), lipoprotein A] seem to play a more prevalent role in ART-treated patients. Notably, ABCA-1, an ATP-binding transporter cassette protein involved in cholesterol efflux, which is inhibited by Nef, is up-regulated in ART-treated individuals. CONCLUSION: Atherosclerosis in HIV infection results from the interaction of multiple factors: an inflammatory and HIV-driven disease could prevail in the absence of therapy; metabolic, non-inflammatory causes may be more important in patients undergoing therapy. Approaches to atherosclerotic disease in HIV infection should consider these differences.

Lipid Metabolism and Cardiovascular Risk in HIV-1 Infection and HAART: Present and Future Problems.

Many infections favor or are directly implicated with lipid metabolism perturbations and/or increased risk of coronary heart disease (CHD). HIV itself has been shown to increase lipogenesis in the liver and to alter the lipid profile, while the presence of unsafe habits, addiction, comorbidities, and AIDS-related diseases increases substantially the risk of cardiovascular disease (CVD) in the HIV-infected population. Antiretroviral therapy reduces such stimuli but many drugs have intrinsic toxicity profiles impacting on metabolism or potential direct cardiotoxicity. In a moment when the main guidelines of HIV therapy are predating the point when to start treating, we mean to highlight the contribution of HIV-1 to lipid alteration and inflammation, the impact of antiretroviral therapy, the decisions on what drugs to use to reduce the probability of having a cardiovascular event, the increasing use of statins and fibrates in HIV-1 infected subjects, and finally the switch strategies, that balance effectiveness and toxicity to move the decision to change HIV drugs. Early treatment might reduce the negative effect of HIV on overall cardiovascular risk but may also evidence the impact of drugs, and the final balance (reduction or increase in CHD and lipid abnormalities) is not known up to date.