Latest developments in early diagnosis and specific treatment of severe influenza infection.

Influenza pandemics are unpredictable recurrent events with global health, economic, and social consequences. The objective of this review is to provide an update on the latest developments in early diagnosis and specific treatment of the disease and its complications, particularly with regard to respiratory organ failure. Despite advances in treatment, the rate of mortality in the intensive care unit remains approximately 30%. Therefore, early identification of potentially severe viral pneumonia is extremely important to optimize treatment in these patients. The pathogenesis of influenza virus infection depends on viral virulence and host response. Thus, in some patients, it is associated with an excessive systemic response mediated by an authentic cytokine storm. This process leads to severe primary pneumonia and acute respiratory distress syndrome. Initial prognostication in the emergency department based on comorbidities, vital signs, and biomarkers (e.g., procalcitonin, ferritin, human leukocyte antigen-DR, mid-regional proadrenomedullin, and lactate) is important. Identification of these biomarkers on admission may facilitate clinical decision-making to determine early admission to the hospital or the intensive care unit. These decisions are reached considering pathophysiological circumstances that are associated with a poor prognosis (e.g., bacterial co-infection, hyperinflammation, immune paralysis, severe endothelial damage, organ dysfunction, and septic shock). Moreover, early implementation is important to increase treatment efficacy. Based on a limited level of evidence, all current guidelines recommend using oseltamivir in this setting. The possibility of drug resistance should also be considered. Alternative options include other antiviral drugs and combination therapies with monoclonal antibodies. Importantly, it is not recommended to use corticosteroids in the initial treatment of these patients. Furthermore, the implementation of supportive measures for respiratory failure is essential. Current recommendations are limited, heterogeneous, and not regularly updated. Early intubation and mechanical ventilation is the basic treatment for patients with severe respiratory failure. Prone ventilation should be promptly performed in patients with acute respiratory distress syndrome, while early tracheostomy should be considered in case of planned prolonged mechanical ventilation. Clinical trials on antiviral treatment and respiratory support measures specifically for these patients, as well as specific recommendations for different at-risk populations, are necessary to improve outcomes.

Host response dysregulations amongst adults hospitalized by influenza A H1N1 virus pneumonia: A prospective multicenter cohort study.

BACKGROUND: Limited knowledge exists on how early host response impacts outcomes in influenza pneumonia. METHODS: This study assessed what was the contribution of host immune response at the emergency department on hospital mortality amongst adults with influenza A H1N1pdm09 pneumonia and whether early stratification by immune host response anticipates the risk of death. This is a secondary analysis from a prospective, observational, multicenter cohort comparing 75 adults requiring intensive care with 38 hospitalized in medical wards. Different immune response biomarkers within 24 h of hospitalization and their association with hospital mortality were assessed. RESULTS: Fifty-three were discharged alive. Non-survivors were associated (p<0.05) with lower lymphocytes (751 vs. 387), monocytes (450 vs. 220) expression of HLA-DR (1,662 vs. 962) and higher IgM levels (178 vs. 152;p<0.01). Lymphocyte subpopulations amongst non-survivors showed a significantly (p<0.05) lower number of TCD3+ (247.2 vs. 520.8), TCD4+ (150.3 vs. 323.6), TCD8+ (95.3 vs. 151.4) and NKCD56+ (21.9 vs. 91.4). Number of lymphocytes, monocytes and NKCD56+ predicted hospital mortality (AUC 0.854). Hospital mortality was independently associated with low HLA-DR values, low number of NKCD56+ cells, and high IgM levels, in a Cox-proportional hazard analysis. A second model, documented that hospital mortality was independently associated with a phenotype combining immunoparalysis with hyperinflammation (HR 5.53; 95%CI 2.16-14.14), after adjusting by predicted mortality. CONCLUSIONS: We conclude that amongst influenza pneumonia, presence of immunoparalysis was a major mortality driver. Influenza heterogeneity was partly explained by early specific host response dysregulations which should be considered to design personalized approaches of adjunctive therapy.

Plasma Levels of Mid-Regional Proadrenomedullin Accurately Identify H1N1pdm09 Influenza Virus Patients with Risk of Intensive Care Admission and Mortality in the Emergency Department.

Early identification of severe viral pneumonia in influenza virus A (H1N1pdm09) patients is extremely important for prompt admission to the ICU. The objective is to evaluate the usefulness of MR-proadrenomedullin (MR-proADM) compared to C reactive protein (CRP), procalcitonin (PCT), and ferritin in the prognosis of influenza A pneumonia. This prospective, observational, multicenter study included one hundred thirteen patients with confirmed influenza virus A (H1N1pdm09) admitted to an Emergency Department and ICUs of six hospitals in Spain. Measurements and Main Results: one-hundred thirteen patients with confirmed influenza virus A (H1N1pdm09) were enrolled. Seventy-five subjects (mortality 29.3%) with severe pneumonia caused by influenza A H1N1pdm09 virus (H1N1vIPN) were compared with 38 controls (CG).The median MR-proADM levels at hospital admission were 1.2 nmol/L (IQR (0.8-2.6) vs. 0.5 nmol/L (IQR 0.2-0.9) in the CG (p = 0.01), and PCT levels were 0.43 µg/L (IQR 0.2-1.2) in the H1N1vIPN group and 0.1 µg/L (IQR 0.1-0.2) in the CG (p < 0.01). CRP levels at admission were 15.5 mg/dL(IQR 9.2-24.9) in H1N1vIPN and 8.6 mg/dL(IQR 3-17.3) in the CG (p < 0.01). Ferritin levels at admission were 558.1 ng/mL(IQR 180-1880) in H1N1vIPN and 167.7 ng/mL(IQR 34.8-292.9) in the CG (p < 0.01). A breakpoint for hospital admission of MR-proADM of 1.1 nmol/L showed a sensitivity of 55% and a specificity of 90% (AUC-ROC0.822). Non-survivors showed higher MR-proADM levels: median of 2.5 nmol/L vs. 0.9 nmol/L among survivors (p < 0.01). PCT, CRP, and ferritin levels also showed significant differences in predicting mortality. The MR-proADM AUC-ROC for mortality was 0.853 (p < 0.01). In a Cox proportional hazards model, MR-proADM levels > 1.2 nmol/L at hospital admission were significant predictive factors for ICU and 90-day mortality (HR: 1.3). Conclusions: the initial MR-proADM, ferritin, CRP, and PCT levels effectively determine adverse outcomes and risk of ICU admission and mortality in patients with influenza virus pneumonia. MR-proADM has the highest potency for survival prediction.

Evaluation of the quality of evidence supporting guideline recommendations for the nutritional management of critically ill adults.

AIMS: The primary aim of this study was to evaluate the quality of evidence supporting the 2019 European Society for Clinical Nutrition and Metabolism (ESPEN) and 2016 American Society for Parenteral and Enteral Nutrition (ASPEN) recommendations for medical nutrition therapy in critically ill patients. Secondary objectives are to assess the differences between 2019 ESPEN and 2016 ASPEN recommendations and to inform relevant stakeholders of areas requiring improvement in the research. METHODS: The 2019 ESPEN and 2016 ASPEN guidelines were identified and downloaded from the official websites. The level of evidence and strength of recommendations from the guidelines were standardised to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Level of evidence was classified as high-quality (randomised controlled trials (RCTs) without important limitations), moderate-quality (downgraded RCTs or upgraded observational studies) or low-quality (observational studies without specific strengths or important limitations, case series, case reports). In addition, good practice points (GPP; recommendations based on the clinical experience of the guideline development group) were considered. Strength of recommendation was reported as strong or weak. RESULTS: From 152 total recommendations, only five (3.3%) were supported by high-quality evidence, with 14 being strong recommendations. A total of 79 (52.0%) recommendations were GPPs. Overall, the proportion of recommendations supported by high-quality (7% [ESPEN] vs. 1.1% [ASPEN], p < 0.05) and moderate-quality evidence (33.3% [ESPEN] vs. 8.4% [ASPEN], p < 0.01) was significantly higher in ESPEN guidelines. On the other hand, ASPEN guidelines reported a greater proportion of recommendations supported by GPPs (58.9% [ASPEN] vs. 40.4% [ESPEN], p = 0.03). In enteral and parenteral nutrition, the proportion of recommendations supported by moderate-quality evidence (50% [ESPEN] vs. 15.8% [ASPEN], p < 0.01) was significantly higher in ESPEN guidelines. CONCLUSION: Published guideline recommendations for the nutritional management of critically ill adults remain largely supported by expert opinion and only a minority by high-quality evidence. An urgent unmet clinical need for high-quality clinical trials is warranted.

Plasma levels of mid-regional pro-adrenomedullin in sepsis are associated with risk of death.

BACKGROUND: Identifying Intensive Care Unit (ICU) patients with sepsis and predicting the risk of death are unmet clinical needs. METHODS: Prospective observational single-center study of 120 consecutive ICU patients with suspected severe sepsis at Jerez Hospital. Epidemiological, clinical, laboratory data and MR-proADM, Procalcitonin (PCT) and C-reactive protein (CRP) levels were recorded at ICU admission and follow-up. RESULTS: At ICU discharge, 104 patients were diagnosed with severe sepsis and 39 died. Plasma MR-proADM was highly indicative of sepsis: 4.05 nmol/L vs. of 0.309 nmol/L (P<0.001), with area under the ROC curve (AUC-ROC) was 0.947. At 48 hours following admission, the median MR-proADM levels in surviving sepsis patients fell to 1.65 nmol/L but remained higher in the non-survivors (2.475 nmol/L) (P=0.04). On day 5 the levels fell to 1.36 nmol/L in surviving sepsis patients vs. 3.42 nmol/L in the non-survivors (P<0.001). On day 5 the survivors showed greater MR-proADM clearance (62.7% vs. 21.2%). The AUC-ROC on day 5 was 0.825, PCT 0.725 and CRP 0.700. The AUC-ROC to MR-proADM clearance on day 5 was 0.734. In a multivariable model, MR-proADM levels at 48 hours and on day 5 and clearance on day 5 following admission were statistically significant predictive factors of mortality. CONCLUSIONS: In clinical practice, in ICU patients admitted with SIRS and organ dysfunction, an MR-proADM cut-off point of 1.425 nmol/L helps to identify those with sepsis. An MR-proADM value above 5.626 nmol/L 48 hours after admission was associated with a high risk of death.

Mid-Regional Pro-Adrenomedullin (MR-proADM) as a Biomarker for Sepsis and Septic Shock: Narrative Review.

Early identification and diagnosis of sepsis and septic shock is vitally important; despite appropriate management, mortality and morbidity rates remain high. For this reason, many biomarkers and screening systems have been investigated in accordance with the precision medicine concept. A narrative review was conducted to assess the role of mid-regional pro-adrenomedullin (MR-proADM) as a biomarker for sepsis and septic shock. Relevant studies were collected via an electronic PubMed, Web of Science, and The Cochrane Library search. The review focused on both diagnosis and prognosis in patients with sepsis and septic shock and specifically in subpopulations of patients with sepsis and septic shock with burns or malignant tumors. No exclusion criteria regarding age, sex, intensive care unit admission, follow-up duration, or co morbidities were used so as to maximize sensitivity and due to lack of randomized controlled trials, opinion paper and reviews were also included in this review. A total of 22 studies, one opinion paper, and one review paper were investigated. MR-proADM levels were found to be useful in assessing patients' initial evolution and become even more useful during follow-up with increased area under curve values in the mortality prognosis by exceeding values of 0.8 in the data shown in several studies. These results also improve along with other biomarkers or severity scores and especially correlate with the organ failure degree. The results of this study indicate that MR-proADM is a good biomarker for the diagnosis and prognosis of sepsis and septic shock patients as well as for organ failure. Although several publications have discussed its role as a biomarker for pneumonia, its value as a biomarker for sepsis and septic shock should now be assessed in randomized controlled trials and more collaborative prospective studies with larger patient samples.

Sepsis: A Review of Advances in Management.

Infections represent a common health problem in people of all ages. Usually, the response given to them is appropriate and so little treatment is needed. Sometimes, however, the response to the infection is inadequate and may lead to organ dysfunction; this is the condition known as sepsis. Sepsis can be caused by bacteria, fungi or viruses and at present there is no specific treatment; its management basically focuses on containing the infection through source control and antibiotics plus organ function support. This article reviews key elements of sepsis management, focusing on diagnosis, biomarkers and therapy. The main recent advance in therapy is the strategy of personalized medicine, based on a precise approach using biomarkers to identify specific individuals who are likely to benefit from more personalized attention.

New role of biomarkers: mid-regional pro-adrenomedullin, the biomarker of organ failure.

Mid-regional pro-adrenomedullin (MR-proADM) has a good biomarker profile: its half-life is several hours, and its plasma concentrations can be determined in clinical practice, it is essentially irrelevant, but proportionally represents the levels and activity of adrenomedullin (ADM). ADM synthesis is widely distributed in tissues, including bone, adrenal cortex, kidney, lung, blood vessels and heart. Its fundamental biological effects include vasodilator, positive inotropic, diuretic, natriuretic and bronchodilator. It has been described high levels in septic patients, interacting directly with the relaxation of vascular tone, triggering hypotension of these patients. It is also found high levels in other diseases such as hypertension, heart failure, respiratory failure, renal failure, cirrhosis and cancer. MR-proADM has been identified as a prognostic marker, stratifying the mortality risk in patients with sepsis in emergency department (ED) and ICU. Evolutionary MR-proADM levels and clearance marker to the 2nd-5th days of admission help to determine the poor performance and the risk of mortality in patients with severe sepsis admitted to the ICU. The MR-proADM levels are more effective than procalcitonin (PCT) and C-reactive protein (CRP) levels to determine an unfavorable outcome and the risk of mortality in patients with sepsis admitted to the ICU. It has also proved useful in patients diagnosed with organ dysfunction of infectious etiology. MR-proADM levels are independent of the germ conversely it is related to the magnitude of organ failure and therefore severity. We consider advisable incorporating the MR-proADM the panel of biomarkers necessary for the diagnosis and treatment of critically ill patients admitted to the ICU with severe sepsis. The combined PCT and MR-proADM levels could represent a valid tool in the clinical practice to timely identify patients with bacterial infections and guide the diagnosis and treatment of sepsis and septic shock.