Post-acute COVID syndrome (PACS) /post-acute sequale of COVID-19 (PASC) / post-COVID is anovel clinical syndrome with unknown biological mechanisms, and to date nostandard-of-care, routines for follow-up, or evidence-based treatments have beenestablished. In this project, we will employ a systems medicine approach to identifypathways and networks of genes, proteins and metabolites that are critical in diseaseonset and progression, towards the goal of understanding specific mechanisms in theetiology of PASC.The objective of the project is to perform clinical and molecular characterization andsub-phenotyping of patients with PASC, (a.k.a. PACS, or post-COVID), into mechanisticallyrelevant groups, with focus on sex differences in patients with lung involvement.Molecular pathways involved in disease etiology will be identified by correlatingrigorous clinical phenotyping and longitudinal eHealth data (home-monitoring via App,home spirometer etc), with multi-molecular level omics profiling of samples collectedfrom the lung, integrated with our systems medicine framework. Aim I involveslongitudinal home-monitoring at baseline to investigate fluctuations in generalwellbeing, and causes thereof, in PASC patients with lung involvement compared to healthycontrols. In Aim II, a set of omics technologies will be employed to provide in-depthmolecular characterization of samples from the lung, exhaled particles (PExA), blood andurine. In depth clinical characterizations including photon-counting CT will beperformed. In Aim III, integrative statistical- and network modeling approaches will beutilized to: i) identify molecularly distinct sub-groups of obstructive lung diseasesbased on multi-molecular level network-integration, and ii) identify individual mediatorsand molecular pathways related to clinical phenotype including longitudinalhome-monitoring data, prognosis, diagnosis, and disease etiology of the identifiedsub-groups.
The core of the home monitoring study is a mobile Application recently developed by our
research group. The App, termed HemCOV, is developed on the MyCap/REDCap platformed that
is GDPR approved, and is installed on the research subjects (RS) own mobile phone during
Visit 1 (virtual visit). The RS will also be assisted in initiate a wearable activity
monitor. The RS is then triggered by the App first to answer a set of questionnaires
related to health both prior to COVID infection, and currently. Given frequent fatigue
among PASC patients, the RS is given 3 days to complete this first task. Thereafter the
RS is triggered by the App to answer a brief set of questions daily for 1 weeks to
establish a baseline of wellbeing. The RS is then called to Visit 2 which entails
spirometry, as well as initiation of a 2 week evaluation using AsthmaTuner (AT). AT
triggers the RS to perform spirometry with a portable home spirometer daily. The HemCOV
and AsthmaTuner Apps are run daily in parallel for a week. The HemCOV App is the reduced
to once every 3 days during the rest of the study to avoid cognitive overload. Initiated
and developed by B. Nordlund research group at the Karolinska Institute and Astrid
Lindgren Children's Hospital, with support from Swedish innovation programs, AsthmaTuner
facilitate asthma diagnosis 7. Given that a number of PASC patients report having been
diagnosed with asthma after their initial COVID diagnosis without having been properly
investigated, this particular aspect of the AsthmaTuner system is of great interest. In
addition, it allows us to follow and identify any alterations in lung function associated
with reported alterations in wellbeing, energy levels, or worsening of any
PASC-associated symptoms such as fatigue, brain fog, shortness of breath etc. The
spirometry registers forced expiratory volume in 1 s (FEV1) and FEV6 (an approximation of
forced vital capacity [FVC], to enable the calculation of the ratio that is the basis for
measuring lung obstruction (FEV1 / FVC). Visit 3 includes a physical exam by physician to
assure the RS is fit to undergo bronchoscopy. If CT has not yet been performed, the RS
will also undergo a chest X-ray at this point. In week 4, non-invasive sampling of PExA,
blood and urine is performed during Visit 4, and finally in Visit 5 two days later the RS
will undergo bronchoscopy, which includes sampling of bronchial epithelial cells (BEC),
and immune cells and airway exudates through bronchoalveolar lavage (BAL). Blood hormone
profiles to allow investigation of hormone related gender differences in PASC are also
performed (lead by endocrinologist prof. Angelica Lindén Hirschberg). Finally at Visit 6,
the diffusion capacity is determined. All sample workup and storage of biospecimens will
be performed in-house under direct supervision of the PI, utilizing standardized
operating procedures (SOP) identical to those utilized in our previous studies, where
sample integrity and quality has been confirmed for all omics platforms. Following
completion of the base study, participants will be invited for follow-ups after 1, 2, 5
and 10 years. The followup visits include the App questions and questionnaires included
in the base study, as well as sampling of blood, urine and PExA.
Inclusion Criteria:
PASC group (n=50): Verified SARS-CoV-2 infections (PCR or serology prior to vaccination)
during wave 1 and 2 (prior to 2021-02-28). Symptoms >12 weeks after initial illness but
with mild-to-moderate disease that did not require hospitalization during the initial
infection, disabling persistent symptoms that at some point has affect work capacity 50%.
Focus in this study will be placed on subject with some level of lung involvement,
including but not limited to Air-trapping on HRCT images, ground glass alterations in
radiology, airway obstruction, or shortness of breath as defined by CAT. Experience of
dyspnea (mMRC>3 within past 2 weeks) is a required inclusion criteria, with the addition
of one of the following: lung obstruction (FEv1/FVC>70 or Z-score < -1.64), lung
restriction (FEV1<80% or FVC < 80%, air-trapping, ground glass- or mosaic attenuation
observed by HRCT.
Health control group (n=50): Confirmed SARS-CoV-2 infection during wave 1 or 2. Fully
recovered within 12 weeks of primary infection.
Exclusion Criteria:
Chronic disease other than asthma. Asthma diagnosis after 2020 allowed in the PASC group.
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Karolinska Institutet/Karolinska University Hospital Solna
Stockholm, Sverige, Sweden
Investigator: Asa Wheelock, PhD
Contact: +46702200308
asa.wheelock@ki.se
Investigator: Asa M Wheelock, PhD
Asa M. Wheelock, PhD
+46702200308
asa.wheelock@ki.se
Asa M. Wheelock, PhD, Principal Investigator
Karolinska Institutet