Mapping frailty in people living with HIV: A nationwide study in Greece.

OBJECTIVES: Frailty is known to affect people living with HIV prematurely, compared to the ageing seronegative population. In this cross-sectional study, we aimed to assess frailty prevalence in people living with HIV in Greece and find associations of frailty criteria with clinical data. METHODS: Demographic and clinical data were collected from 477 participants in six HIV clinics. Fried's frailty phenotype was used to assess frailty prevalence, and participants were classified as frail, pre-frail or robust. Associations of several factors with overall frailty phenotype, as well as with frailty criteria, were explored. RESULTS: The median age was 43 years old (IQR = 51.5) and 444/477 (93%) were men. Most of the participants (429/477, 93.5%) had an undetectable HIV viral load, and a CD4 cell count over 500 cells/µl (366/477, 76.7%). Frailty assessment classified 285/477 (62.1%) as robust, 155/477 (33.8%) as pre-frail and 19/477 (4.1%) as frail. Weakness in grip strength was the most prevalent criterion (128/477, 26.8%), followed by exhaustion (46/477, 9.6%). Lower CD4 cell count, history of AIDS diagnosis, CNS disorders, psychiatric diagnoses, and polypharmacy were strongly associated with frailty. CONCLUSIONS: Although the prevalence of frailty in people living with HIV in Greece is uncommon, when combined with pre-frailty over a third of people are affected, which requires attention in clinical practice. The physical and psychological aspects of frailty highlight the need for a holistic approach to prevent or counteract it. The diverse associations of frailty criteria with HIV-related and non-HIV-related factors suggest a possible variation in people's different healthcare needs.

Climate change and human health in the Eastern Mediterranean and Middle East: Literature review, research priorities and policy suggestions.

Human health is linked to climatic factors in complex ways, and climate change can have profound direct and indirect impacts on the health status of any given region. Susceptibility to climate change is modulated by biological, ecological and socio-political factors such as age, gender, geographic location, socio-economic status, occupation, health status and housing conditions, among other. In the Eastern Mediterranean and Middle East (EMME), climatic factors known to affect human health include extreme heat, water shortages and air pollution. Furthermore, the epidemiology of vector-borne diseases (VBDs) and the health consequences of population displacement are also influenced by climate change in this region. To inform future policies for adaptation and mitigation measures, and based on an extensive review of the available knowledge, we recommend several research priorities for the region. These include the generation of more empirical evidence on exposure-response functions involving climate change and specific health outcomes, the development of appropriate methodologies to evaluate the physical and psychological effects of climate change on vulnerable populations, determining how climate change alters the ecological determinants of human health, improving our understanding of the effects of long-term exposure to heat stress and air pollution, and evaluating the interactions between adaptation and mitigation strategies. Because national boundaries do not limit most climate-related factors expected to impact human health, we propose that adaptation/mitigation policies must have a regional scope, and therefore require collaborative efforts among EMME nations. Policy suggestions include a decisive region-wide decarbonisation, the integration of environmentally driven morbidity and mortality data throughout the region, advancing the development and widespread use of affordable technologies for the production and management of drinking water by non-traditional means, the development of comprehensive strategies to improve the health status of displaced populations, and fostering regional networks for monitoring and controlling the spread of infectious diseases and disease vectors.

Elements of Th1/Th2 response and disease severity in COVID-19 patients: A short report.

The presence of a complex immune dysregulation syndrome has been established in COVID-19 patients. We aimed to assess Th1/Th2 response in COVID-19 patients and its association with disease severity by performing a prospective cohort study in a tertiary hospital COVID-19 referral center. We report no difference between Th1/Th2 responses between patients with severe and mild disease, except for levels of interleukin-6 (IL-6) and IL-10. Future larger studies should examine lung-specific versus systemic inflammatory responses, as well as, diverse immunotypes driving poor clinical outcomes.

Managing hospitalized patients with bacterial infections: the price-to-pay upon site of infection.

INTRODUCTION: Infections impose a significant burden on healthcare costs worldwide. We aimed to explore antibiotic- and hospital-related costs of infections needing admission in a tertiary university hospital in Greece. METHODS: We performed a prospective cohort study in the medical care unit of a tertiary university hospital in Greece, for the period May 2016 to May 2018. Patients admitted with respiratory, urinary, gastrointestinal tract, skin, soft tissue and bone infections or primary bacteremia were included in this study. Costs of hospitalization and unit cost of antibiotic regimen were retrieved from a database for Greek hospitals containing data for each International Classification of Diseases (ICD-10) code and the national formulary respectively, and manually calculated for each patient. RESULTS: Antibiotic costs represent approximately 14-40% of total hospital-related costs depending on infection studied. Skin, soft tissue and bone infections and primary bacteremia led hospital- and antibiotic-related costs, with median costs of €6370 (interquartile range (IQR) 3330.90-11 503.90), €2519.90 (IQR 431.50-8371.10), €4418.10 (IQR 2335-8281.90) and €1394.30 (IQR 519.12-6459.90), respectively. Antibiotic- and hospital-related costs significantly differs with site of infection (p<0.0001). Length of stay is strongly correlated with antibiotic- and hospital-related costs, while site of infection is moderately related to antibiotic cost (eta value 0.445), and hospital-related cost (eta value 0.387). CONCLUSION: Healthcare-related costs vary substantially depending on site of infection. Information about real-life costs can drive best decisions and help to reduce healthcare expenditures.

Assessment of HIV testing recommendations in Greek specialty guidelines: A missed opportunity and room for improvement for recommending testing.

HIV testing for individuals presenting with indicator conditions (ICs) including AIDS-defining conditions (ADCs) is explicitly recommended by European guidelines. We aimed to review specialty guidelines in Greece and assess if HIV was discussed and testing recommended. We reviewed European guidelines to produce a list of 25 ADCs and 48 ICs. We identified Greek guidelines for 11 of 25 (44%) ADCs and 30 of 48 (63%) ICs. In total, 47 guidelines were reviewed (range: 1-6 per condition); 11 (23%) for ADCs and 36 (77%) for ICs. Association with HIV was discussed in 7 of 11 (64%) ADC and 8 of 36 IC guidelines (22%), whereas HIV testing was appropriately recommended in two of 11 ADC (18%) and 10 of 36 IC guidelines (28%). Significant differences were found for the distribution of recommendations to test in both types of condition, with ICs having higher percentage of non-recommendation (50%, p < 0.05). No association was found between source of guideline or publication year and testing recommendation. Most guidelines for ICs and ADCs do not recommend testing. Specialists managing most ICs and ADCs may be unaware of the actual prevalence of undiagnosed HIV infection among their patients or the respective recommendations produced by HIV societies.

Patient-reported outcomes in HIV clinical trials evaluating antiretroviral treatment: a systematic review.

We aimed to assess patterns of patient-reported outcomes (PRO) instruments' utilization in HIV clinical trials in relation to antiretroviral therapy (ART). PubMed/MEDLINE, Scopus, and EMBASE were searched using the terms "Patient-Reported Outcomes" and "HIV/AIDS" or "Antiretroviral Treatment" or "ART" or "Antiretroviral Therapy" from 1 January 1990 until 1 December 2019. In total, 173 studies were identified and 26 were directly related to ART. Study population included treatment-naïve patients (n = 4), treatment-experienced (n = 20), or both (n = 2). Instruments were implemented to assess general experience with ART (n = 3), single-tablet regimens (STR) (n = 2), monotherapy (n = 4), regimen switch (n = 9), or regimen comparison (n = 8). The most commonly used instruments were Medical Outcomes Study-HIV Health Survey (MOS-HIV, n = 8), HIV Symptom Index (HIV-SI, n = 7) and unstructured self-reports (n = 5) followed by others. MOS-HIV was used mainly in comparative (n = 4) and monotherapy (n = 3) trials, HIV-SI in switch (n = 4) and STR (n = 2) trials, and self-reports in comparative trials (n = 3). Even though, the implementation of PRO tools is increasing with time, reporting of PRO in HIV clinical trials remains limited.

Patterns, price and predictors of successful empiric antibiotic therapy in a real-world setting.

WHAT IS KNOWN AND OBJECTIVE: Prompt and appropriate empiric antibiotic therapy (EAT) remains the cornerstone of successful outcomes, while the majority of blood cultures do not identify pathogen. We aimed to report patterns of EAT and its impact on outcomes and associated medical costs, while exploring predictors of its success in a real-world setting. METHODS: We retrospectively utilized the prospective registry of the medical unit of a tertiary university hospital, including patients admitted with diagnosis of infection between 1st May 2016 and 1st May 2018. Costs of hospitalization and unit of antibiotic regimen were retrieved from a database regarding Greek hospitals containing hospitalization-cost data for each ICD-10 code and the national formulary, respectively. RESULTS: A total of 489 patients were included in this study. Mean age was 61.3 years, 53% were males, while intra-abdominal infections predominated (55%). The most commonly administered EAT included quinolones (48%), followed by piperacillin/tazobactam (18%), or other regimens alone or in combination. EAT was successful in 67% and failed in 33% of cases. Fourteen patients died of the infection before EAT was switched, while among 55 patients that EAT had to be modified, mortality was 22%. Presence of urinary tract infection and use of quinolones, least predicted for failure of EAT [OR:0.15 (0.07-0.35), p < 0.0001, OR:0.53 (0.32-0.90), p = 0.019, respectively], in contrast to presence of sepsis [OR:3.11 (1.79-5.40), p < 0.0001]. Patients with failure had longer length of stay [7(5-11) versus 4 (3-6) days], higher antibiotic [201.9 (97.8-471.8) vs 104.6 (60.2-187.7) euros] and hospitalization costs [1409.3 (945.4-2311.6) vs 759.4 (516.5-1036.5) euros] (p < 0.0001). DISCUSSION: We observed significantly increased antibiotic-related, healthcare-related costs and length of stay in patients with failure of EAT. Moreover, in our cohort, absence of sepsis, presence of urinary tract infection and use of quinolones better predicted for success of EAT. WHAT IS NEW AND CONCLUSIONS: Appropriate selection of EAT is crucial to ensure better outcomes and minimize costs.

High flow nasal cannula oxygen therapy in adults with COVID-19 respiratory failure. A case report.

The novel corona virus (SARS-CoV-2) continuous to spread around the globe causing high mortality, tremendous stress on healthcare systems and an unprecedented disruption of everyday life with unpredictable socioeconomic ramifications. The diseaseis typically affecting the respiratory system and some patients will develop refractory hypoxemic respiratory insufficiency requiring mechanical ventilation. The role of non-invasive ventilation (NIV), high flow nasal cannula (HFNC) or continuous positive airway pressure devices (C-PAP) in the treatment of the 2019 corona virus disease (COVID-19) is not yet clear. We hereby report a case of a 44-year-old COVID-19 positive male patient suffering from hypoxic respiratory failure that was successfully treated with high flow nasal cannula oxygen therapy in a negative pressure intensive care room. Although specific criteria for the use of high flow nasal canula devices COVID-19 are not available at this time, clinicians could use this non-invasive modality as analternative method of respiratory support in selected patients presenting with respiratory failure.

Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas.

CONTEXT: Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. OBJECTIVE: To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. DESIGN: Retrospective cohort study. PATIENTS: Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. METHODS: Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). RESULTS: In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by -10 cm2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm2 decrease in mean total muscle mass (P = .002). CONCLUSIONS: The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas.

How well does qSOFA correspond to underlying systemic inflammatory response?

Need for prompt recognition and management of sepsis recently led to the introduction of qSOFA score. However, its association with underlying host inflammatory response remains unclear, while previous studies have challenged its performance in non - intensive care unit (ICU) patients comparing to previously used systemic inflammatory response syndrome (SIRS) criteria. Between June 2016 and April 2017, we performed a prospective observational study in the medical ward of a tertiary hospital to explore the relation of qSOFA ≥ 2 and <2 to underlying inflammatory response, as this is mirrored in levels of serum pro- and anti-inflammatory mediators i.e. IL-6, IL-10 and TNF-α. A total of 100 consecutive patients were finally included in this study. Comparable levels [(pg/ml) median (IQR)] of IL-6 [200 (53-200) vs 65.1 (17.3-200)], IL-10 [ 7 (2.3-170.6) vs 2.3 (2.3-27.7)], and TNF-α [4 (4-46.1) vs 46.06 (4-227.2)] were noted between group of patients with qSOFA ≥ 2 or <2. Nevertheless, prognosis was worse in patients with qSOFA ≥ 2 showing longer length of stay [10 (7-25) vs 5 (3-7) days, p = .03] and lower recovery rates (41 vs 93%, p < .0001). Our results underline the need for prompt management of critically ill patients in presence of systemic inflammatory response regardless of qSOFA score, partly reflecting its low sensitivity comparing to previously used SIRS criteria.

Gut-origin sepsis in the critically ill patient: pathophysiology and treatment.

INTRODUCTION: Gut permeability is increased in critically ill patients, and associated with the development of the systemic inflammatory response syndrome and multiple organ dysfunction syndrome (MODS). The pathogenetic link(s) and potential therapies are an area of intense research over the last decades. METHODS: We thoroughly reviewed the literature on gut-origin sepsis and MODS in critically ill patients, with emphasis on the implicated pathophysiological mechanisms and therapeutic interventions. FINDINGS: Intestinal barrier failure leading to systemic bacterial translocation associated with MODS was the predominant pathophysiological theory for several years. However, clinical studies with critically ill patients failed to provide the evidence of systemic spread of gut-derived bacteria and/or their products as a cause of MODS. Newer experimental data highlight the role of the mesenteric lymph as a carrier of gut-derived danger-associated molecular patterns (DAMPs) to the lung and the systemic circulation. These substances are recognized by pattern recognition receptor-bearing cells in diverse tissues and promote proinflammatory pathways and the development MODS. Therefore, the gut becomes a pivotal proinflammatory organ, driving the systemic inflammatory response through DAMPs release in mesenteric lymph, without the need for systemic bacterial translocation. CONCLUSIONS: There is an emerging need for application of sensitive non-invasive and easily measured biomarkers of early intestinal injury (e.g., citrulline, intestinal fatty acid protein, and zonulin) in our everyday clinical practice, guiding the early pharmacological intervention in critically ill patients to restore or prevent intestinal injury and improve their outcomes.

Sepsis favors high-on-clopidogrel platelet reactivity.

High-on-treatment platelet reactivity (HPR) is associated with ischemic events in patients on antiplatelet therapy with a history of cardiovascular disease. On the other hand, recent data have associated sepsis with adverse cardiovascular events in patients admitted with bacteremia or respiratory infection. We aimed to assess P2Y12-mediated platelet reactivity (PR) during sepsis and recovery in patients under clopidogrel. This was a prospective observational study. Incoming patients presenting with signs/symptoms of sepsis already on a maintenance dose of clopidogrel of 75 mg qd for cardiovascular events were included in this study. Patients were assessed for their PR on presentation and following septic syndrome, using the VerifyNow point-of-care P2Y12 assay. Patients were excluded in the presence of evidence of noncompliance to antiplatelet regimen or in need of discontinuation during this study. Twenty-two septic patients on clopidogrel were included in this study (Supplemental Figure S1). Clopidogrel was administered for previous stroke, coronary, and peripheral artery disease in 27.3, 40.9, and 31.8% of patients, respectively. The main site of infection was respiratory tract followed by urinary tract, while the same amounts of gram-negative and -positive pathogens were isolated. HPR was noted in 77% and 29% of patients during sepsis and recovery, respectively, presenting a significant decrease in P2Y12 reaction units values during follow-up [240.7 ± 58.3 versus 179.5 ± 58.4, 95% CI (-102.7, -39.76), p = 0.0002]. Five patients died of infection, while no adverse cardiovascular events were noted in our study. Our study shows that sepsis may favor HPR, which is reversed when recovery occurs. This finding may underlie the adverse cardiovascular events in patients admitted with sepsis, possibly requiring alteration of antiplatelet regimen during the inflammation period.

Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis.

BACKGROUND: A subanalysis of a randomized clinical trial indicated sepsis survival benefit from interleukin (IL)-1 blockade in patients with features of the macrophage activation-like syndrome (MALS). This study aimed to investigate the frequency of MALS and to develop a biomarker of diagnosis and prognosis. METHODS: Patients with infections and systemic inflammatory response syndrome were assigned to one test cohort (n = 3417) and a validation cohort (n = 1704). MALS was diagnosed for patients scoring positive either for the hemophagocytic syndrome score and/or having both hepatobiliary dysfunction and disseminated intravascular coagulation. Logistic regression analysis was used to estimate the predictive value of MALS for 10-day mortality in both cohorts. Ferritin, sCD163, IL-6, IL-10, IL-18, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were measured in the blood the first 24 h; ferritin measurements were repeated in 747 patients on day 3. RESULTS: The frequency of MALS was 3.7% and 4.3% in the test and the validation cohort, respectively. In both cohorts, MALS was an independent risk factor for 10-day mortality. A ferritin level above 4420 ng/ml was accompanied by 66.7% and 66% mortality after 28 days, respectively. Ferritin levels above 4420 ng/ml were associated with an increase of IL-6, IL-18, INF-γ, and sCD163 and a decreased IL-10/TNF-α ratio, indicating predominance of pro-inflammatory phenomena. Any less than 15% decrease of ferritin on day 3 was associated with more than 90% sensitivity for unfavorable outcome after 10 days. This high mortality risk was also validated in an independent Swedish cohort (n = 109). CONCLUSIONS: MALS is an independent life-threatening entity in sepsis. Ferritin measurements can provide early diagnosis of MALS and may allow for specific treatment.

Randomized, controlled, multicentre clinical trial of the antipyretic effect of intravenous paracetamol in patients admitted to hospital with infection.

AIM: No randomized study has been conducted to investigate the use of intravenous paracetamol (acetaminophen, APAP) for the management of fever due to infection. The present study evaluated a new ready-made infusion of paracetamol. METHODS: Eighty patients with a body temperature onset ≥38.5°C in the previous 24 h due to infection were randomized to a single administration of placebo (n = 39) or 1 g paracetamol (n = 41), and their temperature was recorded at standard intervals. Rescue medication with 1 g paracetamol was allowed. Serum samples were collected for the measurement of APAP and its metabolites. The primary endpoint was defervescence, defined as a core temperature ≤37.1°C. RESULTS: During the first 6 h, defervescence was achieved in 15 (38.5%) patients treated with placebo compared with 33 (80.5%) patients treated with paracetamol 1 g (P < 0.0001). The median time to defervescence with paracetamol 1 g was 3 h. Rescue medication was given to 15 (38.5%) and five (12.2%) patients allocated to placebo and paracetamol, respectively (P = 0.007); nine (60.0%) and two (40.0%) of these patients, respectively, experienced defervescence. No further antipyretic medication was needed for patients becoming afebrile with rescue medication. Serum glucuronide-APAP concentrations were significantly greater in the serum of patients who did not experience defervescence with paracetamol. The efficacy of paracetamol was not affected by serum creatinine. No drug-related adverse events were reported. CONCLUSIONS: The 1 g paracetamol formulation has a rapid and sustainable antipyretic effect on fever due to infection. Its efficacy is dependent on hepatic metabolism.

Platelet reactivity in sepsis syndrome: results from the PRESS study.

Platelet activation mediates systemic inflammatory response during infection. However, data on platelet reactivity (PR) varies among different settings. We assessed PR along different stages of sepsis and tried to predict for determinants of its variance. In parallel, we evaluated it as an early bedside diagnostic biomarker. This was an observational prospective cohort study. Incoming patients were assorted to distinct groups of uncomplicated infection, sepsis, and severe sepsis/septic shock. A control group of healthy volunteers was used as comparison. PR was assessed using the bedside point-of-care VerifyNow assay, in P2Y12 reaction units (PRU) alongside with levels of major inflammatory markers and whole blood parameters. A total of 101 patients and 27 healthy volunteers were enrolled. PR significantly and reversibly increases during sepsis compared to uncomplicated infection and healthy controls (244 ± 66.7 vs 187.33 ± 60.98, p < 0.001 and 192.17 ± 47.51, p < 0.001, respectively). In severe sepsis, PR did not significantly differ compared to other groups. Sepsis stage uniquely accounts for 15.5% of PR in a linear regression prediction model accounting for 30% of the variance of PR (F = 8.836, p < 0.001). PRU >253 had specificity of 91.2% and sensitivity of 40.8% in discriminating septic from non-septic patients. The addition of PRU to SOFA and qSOFA scores significantly increased their c-statistic (AUC SOFA + PRU, 0.867 vs SOFA, 0.824, p < 0.003 and AUC qSOFA + PRU, 0.842 vs qSOFA, 0.739, p < 0.001), making them comparable (AUC SOFA + PRU vs qSOFA + PRU, p = 0.4). PR significantly and reversibly increases early in sepsis, but seems to exhaust while disease progresses. Bedside assessment of PR can provide robust discriminative accuracy in the early diagnosis of septic patients.

Prognostic Models for Survival in Patients with Stable Cirrhosis: A Multicenter Cohort Study.

BACKGROUND: Two models are mostly used to predict survival in cirrhosis: the Child-Pugh score (CP score) and the model for end-stage liver disease score (MELD score). AIMS: The aim of this study is to evaluate the CP score and the MELD score for short- and long-term prognosis in cirrhosis, as well as CP-creatinine score, MELD-Na score, and UKELD score. METHODS: One thousand and forty-seven patients from five referral centers were included: men/women: 620/427, median age: 58 years (IQR 48-66), median follow-up: 33 months (IQR 12-74), CP (A/B/C): 493/357/147, CP score: 7 (IQR 5-9), MELD score: 12 (IQR 9-16). The performance of each score was evaluated by the Cox hazard model in terms of their: discrimination ability (C-index and Somer's D) and calibration (3, 12 months). Internal validation was done with bootstrapping (100 samples). RESULTS: Three hundred and fifty-two patients (33.6%) died. All scores were significantly associated with overall mortality, when assessed by univariate Cox analysis. CP-creatinine score performed significantly better than all other scores [bootstrap C-index 0.672, 95% CI 0.642-0.703, bootstrap Somer's D 0.344 (0.285-0.401)], apart from CP score, which showed similar performance. Inclusion in the multivariable Cox model of age together with CP-creatinine score improved the discriminative ability of the model [bootstrap C-index (95% CI) 0.700 (0.661-0.740)]. In terms of calibration, CP-creatinine score was the best for both 3- and 12-month survival in the total population. CONCLUSIONS: CP score and CP-creatinine score have better prognostic value compared to MELD score, MELD-Na score, and UKELD score for predicting short- and long-term mortality in patients with stable cirrhosis.