Counter-Regulatory Hormonal and Stress Systems in Patients With COVID-19 (CROSS-CO19)

The COVID-19 pandemic is associated with a highly variable presentation, ranging from patients who are asymptomatic or experience only mild symptoms to others with acute respiratory syndrome (ARDS) who require ventilatory support and carry a high risk of severe adverse outcomes and mortality. The most vulnerable population are older adults, usually people with chronic medical conditions and more often men than women.. Nevertheless, infection with SARS-CoV-2 can have deadly consequences even among those without any clear pre-existing medical conditions. Differences in adaptive immune responses and ensuing inflammatory reactions are proposed to contribute to the variable vulnerability to severe disease among patients infected with SARS-CoV-19. It is also possible that inter-individual differences in responsiveness of counter-regulatory hormonal and stress systems may further contribute to variable outcomes in infected patients, and that this may involve modulation of inflammatory responses. The hypothalamo-pituitary adrenal (HPA) axis in particular is a critical regulator of adaptive responses of metabolic and immune systems to various stressors, including. Sex-differences and age-related declines in adrenal cortical production of glucocorticoids and androgens as well as responsiveness of the HPA axis and immune function to stressors are particularly in older men. Such factors may contribute to the high morbidity associated with SARS-CoV-2 infection in elderly males.Among other important hormonal counter-regulatory systems, the renin angiotensin aldosterone system (RAAS) is prominently and directly impacted by SARS-CoV-2. Specifically both SARS-CoV-2 and SARS-CoV angiotensin-converting enzyme 2 (ACE2) to gain entry into cells. Tissue distrubtions of ACE2 match to viral distributions and systemic-wide impacts of SARS-CoV-2 or SARS-CoV beyond the lungs to kidneys, pancreas heart and other tissues. Studies in rats have shown that ACE2 is expressed in substantially higher amounts in alveolar epithelium, bronchiolar epithelium, endothelium and smooth muscle cells of pulmonary vessels of younger than older animals and among the latter group in higher amounts in females than males. Should the same apply to humans such differences may underly the predominance of symptomatic and more severe infections with both SARS-CoV-2 and SARS-CoV in older than younger patients, particularly male

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Diagnostic test: Blood sampling

Detailed Description

The evidence outlined above altogether favors the possibility that inbalance of the RAAS involving upregulated ACE and and angiotensin II and downregulated ACE2 and angiotensin 1-7 might be involved in the susceptibility of SARS-CoV-2 infected patients to more severe outcomes. Given links between the RAAS and the HPA axis with inflammatory processes [38-40], it is also possible that alterations in adrenal steroidal systems might further contribute to the highly variable responses to SARS-CoV-2 infection. This clinical protocol will therefore examine RAAS and the HPA stress system in SARS-CoV-2 infected patients with the objective of identifying differences in these counter-regulatory hormonal and stress systems that might explain progression to more severe disease in infected patients. With this and associated patient data (e.g., age, sex, comorbidities, medications) the plan is to also include application of artificial intelligence-based machine learning approaches to develop algorithms for prognostic prediction of disease outcomes. Given the forecasted numbers of deaths and secondary impacts on health even amongst those not infected, as well as the estimated more than one trillion dollar hit to the world economy, it is clearly important to identify effective treatments that may also be relevant to possible future outbreaks resistant to vacines developed based on the current pandemic. With this in mind the associated data should better facilitate identification of disease mechanisms that underly the more severe clinical phenotypes, thereby enabling educated identification of most appropriate therapeutic approaches for successful management of infected patients. Finally there is some evidence from the earlier SARS-CoV epidemic that infection with these coronaviruses may have health consequences well beyond the acute infection stage. By long-term follow-up, that also allows for inclusion of additional patients at follow-up, this protocol will further address concerns about chronic impacts on health among patients infected with the virus.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Roma, Italy, 00188
    • Mingrone Geltrude

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult (age > 18 years)
• Patients who meet on one or more of the following criteria for the screening test according to the CDC guidelines:
• Have fever or lower respiratory symptoms (cough, shortness of breath) and close contact with a confirmed COVID-19 case within the past 14 days; OR Have fever and lower respiratory symptoms (cough, shortness of breath) and a negative rapid flu test
• Patients with previous documented history of SARS-CoV-2 infection withn appropriate retrospectively collected andv available data.

Exclusion Criteria:

• Patients with impaired mental capacity that precludes informed consent
• Subjects who need medications that may interfere with or invalidate outcome parameters and that can not be stopped without significant risk (e.g., steroids, oral contraceptives)
• Severe or terminal co-morbidity which seriously interferes with possible treatment or health related quality of life
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients with COVID-19; Patients admitted as in-patients with SARS-CoV-2 Infection	Diagnostic test: Blood sampling; One samples of 5 mL blood is taken into a Serum tube for measurement of the RAAS-Biomarkers. After allowing to coagulate between 30 min and 60 min at room temperature, samples are centrifuged at 3000g for 10 min at room temperature.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
measure of the clinical status of patients at long-term follow up	This will be based on a composite cardiovascular and metabolic score that takes into account multiple clinical conditions known to be associated with SARS-CoV2 and SARS-CoV infections and hypothesized to be further worsened be infections. We will evaluate these scores using an established and widely implemented metabolic syndrome (MetS) severity Z-score (http://mets.health-outcomes-policy.ufl.edu). Clinical conditions will include diabetes mellitus, hypertension, ischemic heart disease, pulmonary disorders and any associated clinical complications that develop after infection (e.g., stroke, cardiac failure, death).	1 year

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Investigators: Principal Investigator: geltrude mingrone, Policlinico A. Gemelli IRCCS

Publications and helpful links

General Publications

• Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum In: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038.
• Bornstein SR, Dalan R, Hopkins D, Mingrone G, Boehm BO. Endocrine and metabolic link to coronavirus infection. Nat Rev Endocrinol. 2020 Jun;16(6):297-298. doi: 10.1038/s41574-020-0353-9.
• Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, Pan P, Wang W, Hu D, Liu X, Zhang Q, Wu J. Coronavirus infections and immune responses. J Med Virol. 2020 Apr;92(4):424-432. doi: 10.1002/jmv.25685. Epub 2020 Feb 7.
• Sternberg EM, Chrousos GP, Wilder RL, Gold PW. The stress response and the regulation of inflammatory disease. Ann Intern Med. 1992 Nov 15;117(10):854-66. doi: 10.7326/0003-4819-117-10-854.

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2020
• Primary Completion (Actual): February 9, 2021
• Study Completion (Actual): June 12, 2021

Study Registration Dates

• First Submitted: February 20, 2023
• First Submitted That Met QC Criteria: February 20, 2023
• First Posted (Actual): February 21, 2023

Study Record Updates

• Last Update Posted (Actual): March 14, 2023
• Last Update Submitted That Met QC Criteria: March 13, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 3223 (VABHS)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No