Activation of Vasopressin System During COVID-19 is Associated With Adverse Clinical Outcomes: An Observational Study.

BACKGROUND: Activation of the vasopressin system plays a key role for the maintenance of osmotic, cardiovascular, and stress hormone homeostasis during disease. We investigated levels of copeptin, the C-terminal segment of the vasopressin prohormone, that mirrors the production rate of vasopressin in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We measured levels of copeptin on admission and after days 3/4, 5/6, and 7/8 in 74 consecutive hospitalized adult COVID-19 patients and compared its prognostic accuracy to that of patients with community-acquired pneumonia (n = 876) and acute or chronic bronchitis (n = 371) from a previous study by means of logistic regression analysis. The primary endpoint was all-cause 30-day mortality. RESULTS: Median admission copeptin levels in COVID-19 patients were almost 4-fold higher in nonsurvivors compared with survivors (49.4 pmol/L [iterquartile range (IQR) 24.9-68.9 pmol/L] vs 13.5 pmol/L [IQR 7.0-26.7 pmol/L]), resulting in an age- and gender-adjusted odds ratio of 7.0 (95% confidence interval [CI] 1.2-40.3), p < 0.03 for mortality. Higher copeptin levels in nonsurvivors persisted during the short-term follow-up. Compared with the control group patients with acute/chronic bronchitis and pneumonia, COVID-19 patients did not have higher admission copeptin levels. CONCLUSIONS: A pronounced activation of the vasopressin system in COVID-19 patients is associated with an adverse clinical course in COVID-19 patients. This finding, however, is not unique to COVID-19 but similar to other types of respiratory infections.

Does mid-regional pro-adrenomedullin (MR-proADM) improve the sequential organ failure assessment-score (SOFA score) for mortality-prediction in patients with acute infections? Results of a prospective observational study.

OBJECTIVES: Risk stratification in patients with infection is usually based on the Sequential Organ Failure Assessment-Score (SOFA score). Our aim was to investigate whether the vasoactive peptide mid-regional pro-adrenomedullin (MR-proADM) improves the predictive value of the SOFA score for 30-day mortality in patients with acute infection presenting to the emergency department (ED). METHODS: This secondary analysis of the prospective observational TRIAGE study included 657 patients with infection. The SOFA score, MR-proADM, and traditional inflammation markers were all measured at time of admission. Associations of admission parameters and 30-day mortality were investigated by measures of logistic regression, discrimination analyses, net reclassification index (NRI), and integrated discrimination index (IDI). RESULTS: MR-proADM values were higher in non-survivors compared with survivors (4.5±3.5 nmol/L vs. 1.7 ± 1.8 nmol/L) with an adjusted odds ratio of 26.6 (95% CI 3.92 to 180.61, p=0.001) per 1 nmol/L increase in admission MR-proADM levels and an area under the receiver operator curve (AUC) of 0.86. While the SOFA score alone revealed an AUC of 0.81, adding MR-proADM further improved discrimination (AUC 0.87) and classification within predefined risk categories (NRI 0.075, p-value <0.05). An admission MR-proADM threshold of 1.75 nmol/L provided the best prognostic accuracy for 30-day mortality; with a sensitivity of 81% and a specificity of 75%, and a negative predictive value of 98%. CONCLUSIONS: MR-proADM improved the mortality risk stratification in patients with infection presenting to the ED beyond SOFA score alone and may further improve initial therapeutic site-of-care decisions. TRIAL REGISTRATION: ClinicalTrials.gov NCT01768494. Registered January 15, 2013.

The value of biomarker-guided antibiotic therapy.

INTRODUCTION: There is an increasing interest to individualize patient management and decisions regarding antibiotic treatment. Biomarkers may provide relevant information for this purpose. AREAS COVERED: Despite a growing number of clinical trials investigating several biomarkers, there remain open questions regarding the best type of biomarker, timing or frequency of testing, and optimal cutoffs among others. The most promising results in regard to diagnosis of bacterial infection and therapy monitoring are found for procalcitonin (PCT), although some recent trials were not able to validate the promising earlier findings. Furthermore, less specific markers like C-reactive protein (CRP) and new prognostic biomarkers such as proadrenomedullin (MR-proADM) may improve the prognostic assessment of patients and proteomics may help shorten time to microbiological results. The aim of this review is to summarize the current concept of biomarker-guided management and provide an outlook of promising ongoing investigations. EXPERT OPINION: 'Antibiotic stewardship' is complex and needs more than just the measurement of one single biomarker. However, when integrated into the context of a thorough clinical examination, standard blood parameters and a well done risk stratification by clinical scores such as the SOFA-score, biomarkers have great potential to improve the diagnostic and prognostic assessment of patients.

Role of procalcitonin use in the management of sepsis.

Important aspects of sepsis management include early diagnosis as well as timely and specific treatment in the first few hours of triage. However, diagnosis and differentiation from non-infectious causes often cause uncertainties and potential time delays. Correct use of antibiotics still represents a major challenge, leading to increased risk for opportunistic infections, resistances to multiple antimicrobial agents and toxic side effects, which in turn increase mortality and healthcare costs. Optimized procedures for reliable diagnosis and management of antibiotic therapy has great potential to improve patient care. Herein, biomarkers have been shown to improve infection diagnosis, help in early risk stratification and provide prognostic information which helps optimizing therapeutic decisions ("antibiotic stewardship"). In this context, the use of the blood infection marker procalcitonin (PCT) has gained much attention. There is still no gold standard for the detection of sepsis and use of conventional diagnostic approaches are restricted by some limitations. Therefore, additional tests are necessary to enable early and reliable diagnosis. PCT has good discriminatory properties to differentiate between bacterial and viral inflammations with rapidly available results. Further, PCT adds to risk stratification and prognostication, which may influence appropriate use of health-care resources and therapeutic options. PCT kinetics over time also improves the monitoring of critically ill patients with sepsis and thus influences decisions regarding de-escalation of antibiotics. Most importantly, PCT helps in guiding antibiotic use in patients with respiratory infection and sepsis by limiting initiation and by shortening treatment duration. To date, PCT is the best studied biomarker regarding antibiotic stewardship. Still, further research is needed to understand optimal use of PCT, also in combination with other remerging diagnostic tests for most efficient sepsis care.

Ethylene supports colonization of plant roots by the mutualistic fungus Piriformospora indica.

The mutualistic basidiomycete Piriformospora indica colonizes roots of mono- and dicotyledonous plants, and thereby improves plant health and yield. Given the capability of P. indica to colonize a broad range of hosts, it must be anticipated that the fungus has evolved efficient strategies to overcome plant immunity and to establish a proper environment for nutrient acquisition and reproduction. Global gene expression studies in barley identified various ethylene synthesis and signaling components that were differentially regulated in P. indica-colonized roots. Based on these findings we examined the impact of ethylene in the symbiotic association. The data presented here suggest that P. indica induces ethylene synthesis in barley and Arabidopsis roots during colonization. Moreover, impaired ethylene signaling resulted in reduced root colonization, Arabidopsis mutants exhibiting constitutive ethylene signaling, -synthesis or ethylene-related defense were hyper-susceptible to P. indica. Our data suggest that ethylene signaling is required for symbiotic root colonization by P. indica.

N-acyl-homoserine lactone confers resistance toward biotrophic and hemibiotrophic pathogens via altered activation of AtMPK6.

Pathogenic and symbiotic bacteria rely on quorum sensing to coordinate the collective behavior during the interactions with their eukaryotic hosts. Many Gram-negative bacteria use N-acyl-homoserine lactones (AHLs) as signals in such communication. Here we show that plants have evolved means to perceive AHLs and that the length of acyl moiety and the functional group at the γ position specify the plant's response. Root treatment with the N-3-oxo-tetradecanoyl-L-homoserine lactone (oxo-C14-HSL) reinforced the systemic resistance to the obligate biotrophic fungi Golovinomyces orontii in Arabidopsis (Arabidopsis thaliana) and Blumeria graminis f. sp. hordei in barley (Hordeum vulgare) plants. In addition, oxo-C14-HSL-treated Arabidopsis plants were more resistant toward the hemibiotrophic bacterial pathogen Pseudomonas syringae pv tomato DC3000. Oxo-C14-HSL promoted a stronger activation of mitogen-activated protein kinases AtMPK3 and AtMPK6 when challenged with flg22, followed by a higher expression of the defense-related transcription factors WRKY22 and WRKY29, as well as the PATHOGENESIS-RELATED1 gene. In contrast to wild-type Arabidopsis and mpk3 mutant, the mpk6 mutant is compromised in the AHL effect, suggesting that AtMPK6 is required for AHL-induced resistance. Results of this study show that AHLs commonly produced in the rhizosphere are crucial factors in plant pathology and could be an agronomic issue whose full impact has to be elucidated in future analyses.

Barley leaf transcriptome and metabolite analysis reveals new aspects of compatibility and Piriformospora indica-mediated systemic induced resistance to powdery mildew.

Colonization of barley roots with the basidiomycete fungus Piriformospora indica (Sebacinales) induces systemic resistance against the biotrophic leaf pathogen Blumeria graminis f. sp. hordei (B. graminis). To identify genes involved in this mycorrhiza-induced systemic resistance, we compared the leaf transcriptome of P. indica-colonized and noncolonized barley plants 12, 24, and 96 h after challenge with a virulent race of B. graminis. The leaf pathogen induced specific gene sets (e.g., LRR receptor kinases and WRKY transcription factors) at 12 h postinoculation (hpi) (prepenetration phase) and vesicle-localized gene products 24 hpi (haustorium establishment). Metabolic analysis revealed a progressing shift of steady state contents of the intermediates glucose-1-phosphate, uridinediphosphate-glucose, and phosphoenolpyruvate 24 and 96 hpi, indicating that B. graminis shifts central carbohydrate metabolism in favor of sucrose biosynthesis. Both B. graminis and P. indica increased glutamine and alanine contents, whereas substrates for starch and nitrogen assimilation (adenosinediphosphate- glucose and oxoglutarate) decreased. In plants that were more B. graminis resistant due to P. indica root colonization, 22 transcripts, including those of pathogenesis-related genes and genes encoding heat-shock proteins, were differentially expressed ?twofold in leaves after B. graminis inoculation compared with non-mycorrhized plants. Detailed expression analysis revealed a faster induction after B. graminis inoculation between 8 and 16 hpi, suggesting that priming of these genes is an important mechanism of P. indica-induced systemic disease resistance.

Broad-spectrum suppression of innate immunity is required for colonization of Arabidopsis roots by the fungus Piriformospora indica.

Piriformospora indica is a root-colonizing basidiomycete that confers a wide range of beneficial traits to its host. The fungus shows a biotrophic growth phase in Arabidopsis (Arabidopsis thaliana) roots followed by a cell death-associated colonization phase, a colonization strategy that, to our knowledge, has not yet been reported for this plant. P. indica has evolved an extraordinary capacity for plant root colonization. Its broad host spectrum encompasses gymnosperms and monocotyledonous as well as dicotyledonous angiosperms, which suggests that it has an effective mechanism(s) for bypassing or suppressing host immunity. The results of our work argue that P. indica is confronted with a functional root immune system. Moreover, the fungus does not evade detection but rather suppresses immunity triggered by various microbe-associated molecular patterns. This ability to suppress host immunity is compromised in the jasmonate mutants jasmonate insensitive1-1 and jasmonate resistant1-1. A quintuple-DELLA mutant displaying constitutive gibberellin (GA) responses and the GA biosynthesis mutant ga1-6 (for GA requiring 1) showed higher and lower degrees of colonization, respectively, in the cell death-associated stage, suggesting that P. indica recruits GA signaling to help establish proapoptotic root cell colonization. Our study demonstrates that mutualists, like pathogens, are confronted with an effective innate immune system in roots and that colonization success essentially depends on the evolution of strategies for immunosuppression.

Common Motifs in the Response of Cereal Primary Metabolism to Fungal Pathogens are not Based on Similar Transcriptional Reprogramming.

During compatible interactions with their host plants, biotrophic plant-pathogens subvert host metabolism to ensure the sustained provision of nutrient assimilates by the colonized host cells. To investigate, whether common motifs can be revealed in the response of primary carbon and nitrogen metabolism toward colonization with biotrophic fungi in cereal leaves, we have conducted a combined metabolome and transcriptome study of three quite divergent pathosystems, the barley powdery mildew fungus (Blumeria graminis f.sp. hordei), the corn smut fungus Ustilago maydis, and the maize anthracnose fungus Colletotrichum graminicola, the latter being a hemibiotroph that only exhibits an initial biotrophic phase during its establishment. Based on the analysis of 42 water-soluble metabolites, we were able to separate early biotrophic from late biotrophic interactions by hierarchical cluster analysis and principal component analysis, irrespective of the plant host. Interestingly, the corresponding transcriptome dataset could not discriminate between these stages of biotrophy, irrespective, of whether transcript data for genes of central metabolism or the entire transcriptome dataset was used. Strong differences in the transcriptional regulation of photosynthesis, glycolysis, the TCA cycle, lipid biosynthesis, and cell wall metabolism were observed between the pathosystems. However, increased contents of Gln, Asn, and glucose as well as diminished contents of PEP and 3-PGA were common to early post-penetration stages of all interactions. On the transcriptional level, genes of the TCA cycle, nucleotide energy metabolism and amino acid biosynthesis exhibited consistent trends among the compared biotrophic interactions, identifying the requirement for metabolic energy and the rearrangement of amino acid pools as common transcriptional motifs during early biotrophy. Both metabolome and transcript data were employed to generate models of leaf primary metabolism during early biotrophy for the three investigated interactions.

The mycorrhiza fungus Piriformospora indica induces fast root-surface pH signaling and primes systemic alkalinization of the leaf apoplast upon powdery mildew infection.

We analyze here, by noninvasive electrophysiology, local and systemic plant responses in the interaction of barley (Hordeum vulgare L.) with the root-colonizing basidiomycete Piriformospora indica. In the short term (seconds, minutes), a constant flow of P. indica chlamydospores along primary roots altered surface pH characteristics; whereas the root-hair zone transiently alkalized-a typical elicitor response-the elongation zone acidified, indicative of enhanced H(+) extrusion and plasma membrane H(+) ATPase stimulation. Eight to 10 min after treating roots with chlamydospores, the apoplastic pH of leaves began to acidify, which contrasts with observations of an alkalinization response to various stressors and microbe-associated molecular patterns (MAMPs). In the long term (days), plants with P. indica-colonized roots responded to inoculation with the leaf-pathogenic powdery mildew fungus Blumeria graminis f. sp. hordei with a leaf apoplastic pH increase of about 2, while the leaf apoplast of noncolonized barley responded to B. graminis f. sp. hordei merely with a pH increase of 0.8. The strong apoplastic pH response is reminiscent of B. graminis f. sp. hordei-triggered pH shifts in resistance gene-mediated resistant barley leaves or upon treatment with a chemical resistance inducer. In contrast, the MAMP N-acetylchito-octaose did not induce resistance to B. graminis f. sp. hordei and did not trigger the primed apoplastic pH shift. We speculate that the primed pH increase is indicative of and supports the potentiated systemic response to B. graminis f. sp. hordei-induced by P. indica in barley.

Systemic resistance in Arabidopsis conferred by the mycorrhizal fungus Piriformospora indica requires jasmonic acid signaling and the cytoplasmic function of NPR1.

We analyzed the requirement of specific defense pathways for powdery mildew (Golovinomyces orontii) resistance induced by the basidiomycete Piriformospora indica in Arabidopsis. Piriformospora indica root colonization reduced G. orontii conidia in wild-type (Col-0), npr1-3 (nonexpressor of PR genes 1-3) and NahG plants, but not in the npr1-1 null mutant. Therefore, cytoplasmic but not nuclear localization of NPR1 is required for P. indica-induced resistance. Two jasmonate signaling mutants were non-responsive to P. indica, and jasmonic acid-responsive vegetative storage protein expression was primed and thus elevated in response to powdery mildew, suggesting that P. indica confers resistance reminiscent of induced systemic resistance (ISR).