Patient-reported Outcomes and Lung Function After Hospitalization for COVID-19
Conditions: Covid19, Lung Function Decreased
Sponsor: University Hospital, Akershus

Protocol PROLIFE ver 2.1 220520 
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Patient-reported outcomes and lung function after hospitalization 
for COVID-19 (PROLUN) 
 
1. Background 
1.1 COVID-19 and its clinical course 
The first cases of Coronavirus Disease 2019 (COVID-19) emerged in early December 
2019 in Wuhan, Hubei, China [1]. The outbreak rapidly spread throughout the region and to 
other parts of the world [2,3]. COVID-19 is caused by the severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection. Since SARS-CoV-2 is a novel virus, none in the 
human population have established humoral immunological defense [4]. This contributes to 
the pandemic spread of the virus in the population. There is very limited evidence on 
immunity after infection with SARS-CoV-2 [4]. Currently, it is not known whether the 
immune reaction, including development of specific IgG-antibodies, in response to COVID-
19 is associated with long-term outcomes. 
Symptoms and disease severity of COVID-19 vary greatly, from asymptomatic 
infection to mild illness to severe or fatal illness. While most patients experience none or only 
minor upper respiratory symptoms, up to 15% may require hospital admissions, of whom 5% 
receive intensive care unit (ICU) treatment, and 3% develop disease similar to acute 
respiratory distress syndrome (ARDS), requiring mechanical ventilation [2]. 
In a recent report of hospitalized patients, dyspnea developed in 22 (55%) of 40 
patients, and all patients had pneumonia with abnormal findings on chest CT. Complications 
included ARDS (29%), RNAaemia (15%), acute cardiac injury (12%) and secondary 
infection (10%). In total, 32% of the patients with pneumonia were admitted to an ICU and 
15% died [1]. In those developing ARDS, mechanical ventilation using lower tidal volumes 
and lower inspiratory pressures are recommended, as is prone positioning for 12-16 h/day for 
those with severe ARDS [5].  
Norway rapidly became one of the earliest countries with a high number of infected 
individuals per capita [6]. As of March 2020, the Norwegian health authorities recognize that 
there is a high risk of a national COVID-19 epidemic, in which up to 2.2 million people may 
contract the virus and possibly 733.000 people may become ill [6]. As of 22 March 2020, 
2361 people have been verified with COVID-19 in Norway, with a mean age of 47.1 years; 
173 are hospitalized and 38 have or have had ICU care [7]. The National Institute of Public 
Health expects the number of affected people to increase rapidly [6].  
 
1.2 COVID-19 and interstitial lung disease 
Interstitial lung diseases (ILD) are a heterogeneous group of pulmonary diseases 
characterized by inflammation and fibrosis of the lung parenchyma [8]. While some patients 
with ILD only experience minor symptoms including cough and exercise dyspnea, others will 
progress to severe disease with substantially reduced lung function, severe dyspnea, 
hypoxemia, reduced health-related quality of life (HRQoL) and high rates of mortality [8]. 
ILD may produce a wide range of unspecific radiological features including patchy 
consolidations, bronchial wall thickening, honeycombing, traction bronchiectasis, nodules, 

Protocol PROLIFE ver 2.1 220520 
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cysts, as well as reticular and ground-glass opacities (GGO) [9]. Pulmonary function tests 
(PFT), including spirometry, plethysmography and diffusion tests, allow for the identification 
of restrictive ventilatory defects, a hallmark of ILD [10]. 
A study of 110 survivors of the SARS-CoV-1 outbreak in 2002–2003 found that after 
6 months 30% had abnormal chest radiographs, and various lung function parameters were 
reduced in up to 15% of patients [11]. Furthermore, SARS-CoV-1 survivors exhibited 
significant decrements in HRQoL and exercise capacity. Other studies reported organizing 
diffuse alveolar damage (DAD) with increased fibrosis, squamous metaplasia and 
multinucleated giant cells in SARS-CoV-1 patients with longer-standing disease (>10 days) 
[12–14]. 
The underlying mechanisms for the aforementioned lasting lung injuries have not been 
fully elucidated. However, studies on long-term lung injury after ARDS may shed some light 
on the pathophysiology. ARDS is a disease of multifactorial etiology characterized 
histologically by DAD, which can be differentiated into two major temporal phases [15]:  
1) An early exudative phase which is characterized by inflammatory edema in the 
airspaces, hyaline membrane formation and microvessel injury.  
2) A fibroproliferative phase, in which the tissue defense response attempts to resolve 
cellular debris and edema to restore the original lung parenchyma.  
Although histological, radiological and biochemical evidence suggest that both phases 
coexist from the onset of ARDS, the fibroproliferative phase appears to become the 
predominant feature after approximately 7 days [15–18]. In some individuals, this phase 
progresses to varying degrees of fibrosis with reduced HRQoL and persistent radiological 
changes in approximately 25% of the patients [16,19]. Moreover, about 25% of ARDS 
patients have reductions in PFT after 6 months with little change during 5 years of follow-up 
[20]. Additionally, the pulmonary stress of mechanical ventilation is a well-documented risk 
factor for developing unremitting fibrotic pulmonary changes [19]. 
 
1.3 COVID-19 and radiological findings 
According to a study by Shi et al. COVID-19 pneumonia manifests with chest CT imaging 
abnormalities, even in asymptomatic patients, with rapid evolution from focal unilateral to 
diffuse bilateral GGO that progressed to, or co-existed with, consolidations within 1–3 weeks 
[21]. Most patients showed bilateral lung involvement, with lesions mainly located 
peripherally and subpleurally with diffuse distribution. The predominant pattern was GGO 
with ill-defined margins, air bronchograms, smooth or irregular interlobular or septal 
thickening, and thickening of the adjacent pleura. These imaging characteristics are non-
specific and bear some resemblance to those of SARS-CoV-1 and MERS-CoV infections 
[21]. 
Among 21 patients in another study by Chung et al., GGO were observed in 12 
patients (57%) and consolidation was observed in six (29%) [22]. The extent of disease on CT 
scans shows a marked increase from the subclinical period through the first and second weeks 
after symptom onset, then decreases gradually during the third week [21]. 
Moreover, there is a high incidence of subclinical CT changes in cases with COVID-
19. Inui et al. have described more GGO over consolidation and milder extension of disease 
on CT in patients with asymptomatic SARS-CoV-2 infection compared to symptomatic cases 

Protocol PROLIFE ver 2.1 220520 
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[23]. The typical pattern of CT images in subclinical SARS-CoV-2 infected patients is 
unilateral, multifocal, predominantly GGOs [21].  
Shi et al. also found that serial CT imaging of patients can help to monitor disease 
changes by reflecting therapeutic effects that may be associated with COVID-19 outcomes 
[21]. The most common pattern of evolution throughout series of CT scans was initial 
progression to a peak level, followed by radiographic improvement [21]. None of the CT 
features of COVID-19 are specific or diagnostic, and COVID-19 pneumonia shares CT 
features with other non-infectious conditions that present as subpleural air-space disease [21].  
As COVID-19 is a new disease, there is little information about radiological changes 
over time and the association with clinical variables, and other outcomes, such as pulmonary 
function, physical functioning and patient-reported outcomes. More information about 
radiological patterns will be available as findings from larger series and follow-up studies are 
presented. As claimed in a recent comment, more research is needed into the correlation of 
CT findings with clinical severity and progression, the predictive value of baseline CT or 
temporal changes for disease outcome, and the sequelae of acute lung injury induced by 
COVID-19 [24]. 
 
1.4 COVID-19 and cardiac function 
Pre-existing cardiovascular disease (CVD) increases vulnerability to severe COVID-19 
infection [2,25]. In addition, COVID-19 can worsen underlying CVD and trigger new cardiac 
complications. In a study from Wuhan, China, a third of those hospitalized with COVID-19 in 
a study from Wuhan, China, had underlying CVD (hypertension, coronary heart disease, or 
cardiomyopathy), and 28% had acute myocardial injury [26]. 
In patients without previous history of CVD, SARS-CoV-2 may affect the 
cardiovascular (CV) system with short-term and potential long-term consequences for CV 
health [27,28]. Possible mechanisms of SARS-CoV-2 responsible for CV complications have 
been reported are for example the binding of SARS-CoV-2 to angiotensin-converting enzyme 
2 (ACE2) with alteration of ACE2 signaling pathways, systemic inflammation with high 
circulatory levels of proinflammatory cytokines and prothrombotic milieu, impaired 
myocardial oxygen demand-supply and electrolyte imbalance [27–29]. Further, adverse 
effects of antiviral drugs, corticosteroids and other therapies aimed at treating COVID-19 can 
also have harmful effects on the CV system. It is possible that patients with COVID-19 could 
suffer from cardiac injury, myocarditis, heart failure or arrhythmia. 
The clinical effects of hospitalization for pneumonia have been linked to a 50% higher 
risk of CVD than those not hospitalized for pneumonia with up to 10-year follow-up [30]. 
Heightened systemic inflammatory and pro-coagulant activity can persist in survivors of 
hospitalization for pneumonia long after resolution of the index infection. Therefore, 
pneumonia may be a risk factor for CVD. In survivors after SARS-CoV infection CV 
abnormalities, as well as altered lipid and glucose metabolism were present in 40%, 68% and 
60%, respectively, at 12-years follow-up [31]. Long-term follow-up data concerning the 
survivors of respiratory virus epidemics are in general scarce but suggest long-term CVD 
consequences. COVID-19 survivors could experience similar adverse CV outcomes.  
 
1.5 COVID-19 and patient-reported outcomes 

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The traditional goal for intensive care is to reduce acute mortality. However, acute life-
threatening illnesses may also cause severe sequela with great impact on patients’ quality of 
life. Therefore, attention has recently been directed to how acute, life threatening illness and 
treatment in ICU affects patients’ and their relatives’ health and HRQoL [32].   
It is well-known that age and disease severity are associated with the level of 
functioning after acute critical illness [33]. However, comparison of results between studies is 
difficult because of differences in case-mix, study designs and questionnaires, as well as 
different time of follow-up, and variations in treatment between countries [34]. There has also 
recently been growing interest in serious psychological sequela after ICU treatment, including 
posttraumatic stress disorder (PTSD) [35–38] PTSD is a chronic and debilitating mental 
condition that develops in response to catastrophic life events. Significant PTSD symptoms 
have been reported in 44% of critical illness survivors [39]. Furthermore, there is evidence 
that depressive symptoms may be prevalent after intensive care treatment, whereas studies on 
clinically significant anxiety symptoms are sparse [40]. Studying these symptoms after ICU 
treatment in patients with COVID-19 is crucial, since they may be modifiable contributors to 
decline in function and quality of life    
The COVID-19 epidemic leads to quarantine and social isolation in the general 
population, which may have important psychological impacts. About 5% of the general 
population of Wuhan, China suffered from symptoms of acute posttraumatic stress about 1 
month after the outbreak [41]. It is unknown how hospitalization for COVID-19 impacts long-
term HRQoL and psychological outcomes including PTSD, or whether this is dependent on 
whether ICU-treatment.  
Non-respiratory symptoms are frequently reported during COVID-19. Symptoms such 
as anosmia, headache, fatigue or sleepiness are reported in Norwegian patients with SARS-
CoV-2 (www.koronastudien.no, 16.05.2020). Currently, it is not known whether non-
respiratory symptoms may persist and influence HRQoL.  
  
2. Objectives 
2.1 General objectives 
The main objectives of this cohort study are to provide follow-up data on persistent lung or 
cardiac injury, self-reported pulmonary symptoms and symptoms of anxiety, depression and 
PTSD following hospitalization for COVID-19, and their association with clinical variables 
and biomarkers during hospitalization.  
 
2.2 Predetermined hypotheses 
 Only COVID-19 patients who were admitted to ICU have persistent clinical and 
radiological signs of pulmonary fibrosis after 12 months. 
 The proportion of COVID-19 patients with symptoms of anxiety, depression and PTSD is 
higher in patients admitted to ICU than in general wards. 
 Symptoms of anxiety, depression and PTSD and HRQoL improve from 3 to 12 months 
after hospitalization for COVID-19.  
 
2.3 Specific objectives 
Primary outcomes 

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1 a) The prevalence of restrictive lung function impairments and reduced gas diffusion after 
hospitalization for COVID-19. 
1 b) The prevalence of interstitial lung findings 3 months and 1 year after hospitalization for 
COVID-19; GGO, reticular and linear pulmonary findings, scaring and fibrosis, nodular 
changes, consolidations, peripheral or central zonal dominance, apical or basal zonal 
dominance. 
 
Secondary outcomes 
2 a) Explore the associations between baseline characteristics during COVID-19 
hospitalization and sustained reduced PFT and radiological signs of ILD. 
2 b) Assess the predictive value of surfactant protein A and D and antibody titer for sustained 
reduced PFT.  
2 c) Explore the associations between novel serum and plasma biomarker levels during 
hospitalization for COVID-19 and reduced PFT or radiological signs of pulmonary 
fibrosis.  
2 d) Assess the cardiopulmonary fitness, prevalence of cardiac dysfunction and arrhythmias 
following ICU- and non-ICU treatment for COVID-19, and their associations with 
baseline characteristics. 
2 e) The prevalence and time course of anxiety, depression, chronic insomnia and PTSD 
following hospitalization for COVID-19, according to ICU treatment. 
2 f) The prevalence and time course of upper respiratory symptoms, chronic sinusitis, 
anosmia and fatigue. 
2 g) Explore the associations between baseline characteristics and persistent symptoms of 
anxiety, depression and PTSD.  
2 h) Assess the HRQoL and changes in HRQoL following hospitalization for COVID-19, 
according to ICU treatment, age and gender. 
2 i) Assess the 10-year mortality and prevalence of pulmonary disease following 
hospitalization for COVID-19. 
 
3. Design, materials and methods:  
3.1 Study design and inclusion 
The proposed project is a prospective, multicenter cohort study from 2-6 weeks to 10 years 
after hospital discharge for COVID-19 infection. All patients ≥18 years of age discharged 
alive with a diagnosis code of  “U07.1”, U07.2”, “J12.X viral pneumonias” and living within 
the catchment areas of six large Norwegian university hospitals are eligible.  The hospitals are 
Akershus University Hospital (Ahus), Oslo University Hospital (OUH) Ullevål and 
Rikshospitalet, Østfold Hospital (SØ), Haukeland University Hospital (HUS) and St.Olav 
Hospital (St.Olav). Hospitalization is defined as time from hospital admission to discharge of 
≥8 hours. Participants in competing studies with the similar outcomes are not eligible.  
 
Eligible patients will be identified through the following sources:  
1) Patients to be discharged from one of the hospitals. 
2) Participants in the biomarker-study: “Mekanismer bak sykelighet og dødelighet ved Covid-
19” (REK 117589, Ahus) have consented to receive new invitations for follow-up studies.  

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3) Participants in the quality registry “Covid OUS” at OUS approved 13. March 2020 (20-
07119). The register contains all patients hospitalized with confirmed SARS-CoV-2 and 
contains prospectively collected clinical data and laboratory parameters from day of 
admission.   
4) Regular (weekly) extraction of diagnosis codes from the hospital information systems will 
provide the study group with a list of discharged patients with COVID-19 not covered by 
source 1-3 above.  
An invitation to participate in the project will be delivered directly to eligible persons 
identified from source 1 above, while eligible persons identified from sources 2-4 above will 
receive an invitation by mail within 6 weeks of discharge.  
  
We aim to use a digital consent form through the TSD-platform (University of Oslo). For 
patients who do not want to use a digital consent form, a paper consent form will be attached 
to the information letter. 
 
3.2 Patient flow and data collection: 
Completion of the digital or paper consent form will indicate the start of the follow-up period. 
This will enable the study group to obtain information from the electronic medical record file 
at the involved hospitals regarding the COVID-19-hospitalization, which will constitute the 
baseline data (Table 1). 
 
Table 1. Baseline variables obtained from the electronic medical record  
Clinical measures 
Medical history 
Treatment 
NEWS 
Charlson comorbidity index 
Medication 
qSOFA 
Cardiovascular/pulmonary 
Non-invasive ventilation 
CURB-65 
History of lung function  
ICU 
Vital parameters 
Clinical frailty scale 
COVID-19 symptoms 
Laboratory measures 
History of psychiatric 
disease 
Symptom type and initiation 
Clinical hematological and 
biochemical tests 
Radiological exams 
Travel history 
Arterial blood gas 
Chest radiograph 
 
Microbiological results 
History of chest CT-scans 
 
NEWS: National Early Warning Scale, qSOFA: quick Sequential Organ Failure Assessment; CT: 
Computer tomography.  
 
The first patient follow-up (T0) is questionnaire-based and will be provided digitally through 
Nettskjema in TSD following completion of the consent form. This package will include 
validated questionnaires for evaluation of pulmonary symptoms (Dyspnea-12 [42] and 
mMRC [43,44]), HRQoL (RAND-36 and EQ-5D-5L [45,46]), screening tools for anxiety 
(GAD-7 [47]), depression (PHQ-9 [48]) or PTSD (PCL-5 [49]). Participants may also opt to 
receive paper questionnaires by mail.  
The clinical follow-ups (T1 and T2) will be performed 2–4 months and 11-13 months 
after hospital discharge, respectively. The T1 visit will consist of a common set of 

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examinations related to the primary outcome for all centers: Low-dose chest CT scan, PFTs, 
pulse oximetry, blood samples (table 2) as well as information about smoking status, work 
status and current medication. Spirometry, gas diffusion test and whole-body 
plethysmography will be performed according to the European Respiratory Society 
recommendations. Antibody measurement against SARS-CoV-2 in serum or plasma samples 
will be tested using enzyme linked immunosorbent assays (ELISA) and/or 
chemiluminescence technology following the manufacturers’ (Roche) protocols and 
recommendations from the National reference laboratory on corona virus.   At the time of T1 
and T2, patients will also respond to the same questionnaire as at T0, with addition of fatigue 
(Chalder fatigue questionnaire, FQ). The collection of these questionnaires will be partly 
performed by the National COVID-19 pandemic registry, and partly by Nettskjema or mail. 
The T2-visit will consist of PFTs and a second low-dose CT-scan for those who had 
pathological findings on the CT-scan at T1. The patients will complete questionnaires as T1. 
The common set of examinations and patient-reported outcomes are summarized in Table 2.   
 
Table 2. Examinations and patient-reported outcomes/questionnaires administered in the 
study 
Data collection 
Numb
er of 
items 
T0 
T1 
T2 
Patient reported outcomes 
 
 
 
 
Dyspnea 
 
 
 
 
  Dyspnea-12 
12 
X 
X 
X 
  Modified MRC dyspnea scale 
1 
X 
X 
X 
Health-related quality of life 
 
 
 
 
  RAND 36 
36 
X 
X 
X 
  EQ-5D-5L 
6 
X 
X 
X 
Psychological symptoms or distress 
 
 
 
 
GAD-7 
7 
X 
X 
X 
PHQ-9 
9 
X 
X 
X 
PTSD Checklist for the DSM-5 
20 
X 
X 
X 
Chalder fatigue questionnaire 
12 
 
X 
X 
 
 
 
 
 
Case report forms 
 
 
 
 
Smoking habit 
 
 
X 
X 
Education and work status 
 
 
X 
X 
Current medication 
 
 
X 
X 
 
 
 
 
 
Clinical examinations 
 
 
 
 
Pulmonary function tests 
 
 
 
 
Spirometry 
 
 
X 
X 
Gas diffusion 
 
 
X 
X 
Oximetry 
 
 
X 
X 

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Whole-body plethysmography 
 
 
X 
X 
Chest CT scan 
 
 
X 
X1 
Blood samples2 
 
 
X 
X 
 
 
 
 
 
Additional substudy examinations3 
 
 
 
 
Echocardiography 
 
 
X 
X 
Cardiopulmonary exercise test 
 
 
X 
X 
Long-term ECG  
 
 
X 
X 
Nocturnal oximetry 
 
 
X 
 
Oscillometry 
 
 
X 
X 
CT paranasal sinus 
 
 
X 
 
Upper respiratory tract questions and 
diagnostic interview for chronic 
insomnia 
 
 
X 
X 
MRC: Medical Research Council; PTSD: Post-traumatic stress disorder  
1if clinically indication; 2Hemoglobin, leukocytes, thrombocytes, creatinine, lactat dehydrogenase, 
ferritin, D-dimer, N-terminal pro-B-type natriuretic peptide, troponin T, SARS-CoV-2 antibody titer. 3 
Ahus will perform all substudies; OUS, St.Olav and SØ will also perform cardiology substudies; HUS 
will perform oscillometry.  
 
In addition to the common set of examinations and patient-reported outcomes, the protocol 
enables substudies relating to biomarkers, additional PFT and cardiology;  Oscillometry, 
cardiopulmonary exercise test, long-term electrocardiography and echocardiography.  
The study group will follow the cohort for 10 years with respect to extract new 
incidents of pulmonary events and mortality.    
 
 
Figure 1. PROLUN study, flow-chart. 
 
3.4 Linkage to other databases 
The proposed project aims to link the database to information from the MSIS-database 
regarding the clinical information of the COVID-19 infection (time course of infection, etc.).  

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For participants who were included in baseline studies during the hospital admissions we can 
link our database to the biomarker results and the existing biobank. We will collaborate with 
the national COVID-19 pandemic registry, which will collect several of the same patient 
reported outcomes at similar time points as this study. To avoid that the participants need to 
complete the same questionnaires twice, we will obtain data of the following questionnaires 
from the national COVID-19 pandemic registry: EQ-5D, RAND-36, GAD-7, PHQ-9, Chalder 
fatigue questionnaire at 3 and 12 months. The pandemic registry will also collect 
questionnaires at 6 and 24 months, which we also will apply to link to our study.  
 
3.5 Sample size considerations 
To estimate whether the sample size is adequate for the primary outcomes are difficult to 
calculate, as the COVID-19 pandemic represents an unprecedented medical situation. The 
most important factor to evaluate the primary outcome is to ascertain that the included sample 
is similar to the general population. We believe that this will be the case in our study provided 
that the majority of patients from Norway’s major university hospitals are invited to 
participate. The catchment areas of these hospitals also cover the geographical areas with the 
most reported patients with COVID-19 so far. 
The Norwegian Health Institute of Public Health (NIPH) assumes that 42% of the 
population will contract the coronavirus, and that approximately 14% will develop COVID-19 
[6]. Furthermore, NIPH projects that 0.42% will need hospital admission and 0.11% will 
require treatment in intensive care units (ICU). The mortality rate for all infected patients is 
expected to be below 1%, but higher among hospitalized (5-10%). The hospitals have district 
hospital functions for approximately 1.580 000 individuals. Thus, based on the estimates from 
NIPH, the cumulative number of COVID19-associated admissions to the participating centers 
through first year of COVID-19 may measure up >5000, of which >1000 in the ICU. We 
estimate a participation rate of 50-60% of the invited patients, a total cohort size of 1000. To 
show a 15% improvement in quality of life during follow-up, a sample size of approximately 
200 is sufficient (=0.05, 1- =0.80).  
The COVID-19 pandemic represents an extraordinary medical situation and there is an 
urgent need for scientific data to help inform governments and health care providers who are 
trying to tackle the outbreak. We therefore propose to perform the study in two work-
packages (WP):  
In WP1 we will include only the first consecutive 100 participants, in an attempt to 
rapidly provide preliminary answers to the study´s primary outcomes (1a – 1b) while the 
pandemic is still active. Analyses in WP2 will include all included participants, and allow us 
to do more sophisticated statistics to answer both our primary and secondary outcomes (2a – 
2g). 
 
3.6 Statistical analyses: 
Descriptive statistics will be presented as mean and standard deviation, alternatively as 
median and interquartile range as appropriate. Relevant analyses for evaluation of secondary 
outcomes may be multiple linear regressions with outcome variables described in 2.3 as 
dependent variables. Continuous outcome variables will also be dichotomized according to 
clinically relevant cut-offs (restrictive lung function, established cut-offs of questionnaires) 

Protocol PROLIFE ver 2.1 220520 
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and multiple logistic regressions performed. Finally, Cox proportional hazards regression 
analyses may be used to examine the associations between baseline variables and long-term 
outcomes.  
 
4. Time schedule and dissemination of results:  
We will initiate the study immediately after approval from the ethical committee and data 
protection officer, estimated March 30th, 2020. Due to very low number of new admissions in 
May, the steering committee has decided in a protocol update of 22.05.2020 to end study 
inclusion at June 1 2020, at a timepoint where the necessary sample size as described in 3.5 
has been reached.  
 
5. Ethical and data protection considerations 
The project will seek approval by the regional ethical committee and the local data protection 
officer prior to study start. All participants must sign the consent based on written study 
information.  
A low dose CT protocol of approx. 2 mSv without the use of contrast enhancement 
will be applied. This dose corresponds to the annual background radiation exposure or 
equivalent to the radiation exposure during a flight over the Atlantic Ocean. An additional CT 
low-dosis of paranasal sinuses for participants at Ahus will involve additional 0.8-1 mSv. The 
protocol is safe and without any overexposure for the participants.  
If a patient presents radiological abnormalities, reduced lung function, alarm symptoms or 
hypoxemia at visit 1, the patient will be referred to the relevant outpatient clinic. In particular, 
pulmonary nodules may be detected on the chest CT scan. The Department of Radiology has 
established guidelines on how to follow-up such findings. All study visits will be in addition 
to any other clinical visits planned or performed during the study period.  
The TSD (Service for Sensitive Data) service is designed for storing and post-
processing sensitive data in compliance with the Norwegian “Personal Data Act” and “Health 
Reaserch Act”. TSD is developed and maintaned by USIT at the University of Oslo. Storage 
in TSD makes use of a dedicated portion of the storage facility “Astrastore” provided by 
NorSTore, the Norwegian data infrastructure provider. Furthermore, a PGP encrypted version 
of the UiO web-questionnaire (Nettskjema), interfaced with the governmental ID-portal for 
login, allows secure data harvesting, time-point studies and strong identification of the 
respondents. The TSD also provide secure and protected data storage of the images performed 
in the study. Transfer of images from the different sites will be by direct upload of encrypted 
image files to TSD or through a secure/encrypted PACS line (as used routinely for transfer of 
images between hospitals) to Ahus for subsequent upload to TSD. 
The 3-month control may start at the time of an ongoing large-scale COVID-19 
epidemic. We will seek to perform the visit 1 (at 3-4 months) at geographical sites not 
interfering with routine hospital work, including LHL-hospital Gardermoen.  
 
6. Personnel, partners and resources 
The study is initiated and led by the Pulmonary Research Group at Ahus, with Gunnar Einvik 
(MD, PhD) as the national primary investigator (PI). The conduction of the study will be 

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organized with a national steering group, as well as local study groups. Scientifically, the 
study will consist of three substudies in addition to the main study.  
The national steering committee consist of Einvik, associate professor Haseem Ashraf 
(MD, PhD), professor Knut Stavem (MD, MPH, PhD), professor Charlotte Ingul (MD, PhD) 
and the local PI’s from the other hospitals. The steering committee will be responsible for 
approving any further changes of the protocol, applications for funding and for the publication 
plan. 
Collaboration has been established with researchers in other institutions. Professor 
Toril Dammen leads the research group “Psychological aspects of somatic disease” at 
Department of Behavioural Science at University of Oslo, and will collaborate regarding 
psychological outcome data. Anne Edvardsen (BLS, PhD) leads the pulmonary research 
group in Landsforeningen for Hjerte- og Lungesyke (LHL)-Hospitals, and is responsible for 
the Norwegian translation of Dyspnea-12. Professor Charlotte Ingul (Nord University, 
NTNU), cardiologist (consultant LHL-hospital) and anesthesiologist, will collaborate 
regarding the cardiovascular sub-study. The Department of Microbiology at Ahus with 
researcher Anita Blomfeldt will collaborate regarding the antibody titer analyses. The 
department of ear-nose and throat disorders at Ahus with researcher Harald Hrubos-Strøm 
will collaborate regarding the upper respiratory tract symptoms and CT paranasal sinuses. 
John Solheim is a patient representative of LHL will participate which will contribute as the 
user representative in this project and has reviewed the revised protocol and patient 
information.  
Ass. professor Ashraf has received an unrestricted grant from Boehringer Ingelheim to 
support the conduction of the CT-scans. The sponsor will have no influence on the study 
conduction or publications. Personnel costs are covered by the departments of the researchers 
involved.  
 
7. Dissemination plan 
We will seek to publish results from the cohort study in open-access, peer-reviewed 
international medical journals and at national or international conferences. We have the 
following suggestions for papers from the cohort study:  
WP #1:  
 3-month descriptive analysis of radiological outcomes in COVID-19 patients.  
 3-month respiratory function and dyspnea in COVID-19 patients.  
 3-month cardiac function at rest and during exercise  in COVID-19 patients 
 
WP#2 
 1-year pulmonary radiological outcome in COVID-19 patients.  
 1-year clinical outcome in patients hospitalized with COVID-19 infection. 
 The clinical course of psychological symptoms and HRQoL during 2 years after 
hospitalization with COVID-19 infection.  
 The association between biomarkers during COVID-19 infection and persistent ILD after 
1 year  

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 Long-term mortality and respiratory morbidity after hospitalization with COVID-19 
infection.  
 1-year cardiac function at rest and during exercise in COVID-19 patients 
 
Additional papers may be suggested by collaborating partners during the study period and 
evaluated by the national steering committee before initiation of the analyses.  
For papers using patient-reported outcomes, a substudy scientific group of Stavem, Dammen, 
Edvardsen and Einvik are responsible. The substudy of radiological examinations is led by 
Ashraf, while the cardiology substudy is led by Ingul.    
In papers using data from other sources (section 3.4), those that have contributed considerably 
to the paper may be eligible for co-authorship according to the Vancouver protocol.   
 
8. Protocol changes 
8.1 Protocol version 1.1 29.03.2020 
Section 3.1 has been updated with a description of usage of the participant list of 
“Mekanismer bak sykelighet and dødelighet ved Covid-19” to identify eligible patients.  
Section 6 has been updated with information of an external sponsor, as well as minor text 
revisions.   
 
8.2 Protocol version 2.0 08.04.2020  
Multicenter 
The protocol has been updated with the inclusion of several study sites. In addition to Ahus, 
OUS Ullevål and Rikshospitalet, SØ, HUS and St.Olav are collaborating in inclusion of 
patients. Concurrently, section 3 has been revised to describe the change in number of 
participants, and section 6 has been revised to describe the changes in the organization of the 
project. 
 
Data collection 
Table 2 has been updated with a description of planned examinations. In particular, novel 
examinations that are not obligatory for all sites have been added; Whole-body 
plethysmography, oscillometry and cardiopulmonary exercise test for lung function 
evaluation, echocardiography and long-term electrocardiography for cardiac function 
evaluation. Finally, the protocol have been updated with blood samples analysed at T1 and T2 
regarding antibody against corona-virus. Accordingly, sections 1.1, 1.4, 2.1, 2.3 and 9 have 
been updated to describe the rationale and objectives for these new examinations.  
 
Dissemination plan 
We have added chapter 7 to describe the planned manuscripts from this project, as well as the 
procedure for later suggestions for new manuscripts.  
 
8.3 Protocol version 2.1 22.05.2020 
Title 
The acronym was changed to avoid association with other use of the acronym PROLIFE. 

Protocol PROLIFE ver 2.1 220520 
13 
 
 
Examinations 
We have added a paragraph in section 1.5, and accordingly a novel secondary aim 2f, to 
describe upper airway outcomes. The examinations related to this outcome are questions to 
the patients at T1 (anosmia, nasal symptoms, sleepiness/insomnia) and CT-scan of paranasal 
sinuses. These will only be applied at site Ahus.  
Whole-body plethysmography and blood samples have been made common for all sites. 
 
Linkage to the national pandemic registry 
In section 3.4 and table 2, the rationale for linkage to the novel national pandemic registry has 
been added. This registry was not initiated when the initial protocol was submitted. 
Accordingly, some of the questionnaires previously administered in this study will be 
obtained from the national pandemic registry.  
 
End of inclusion 
The end of inclusion date has been changed to June 1 2020 (section 3.4) 
 
Inclusion/exclusion criteria 
The ICD-codes described in the initial protocol were erroneous, the correct codes is described 
in section 3.1. After the initial protocol was drafted it has been evident that another ongoing 
study on the same sites also will perform PFT and pulmonary CT scans. We will not include 
the same participants in both studies, thus an additional exclusion criterion has been added in 
3.1.   
 
Data management 
Section 5 is updated with a description on how images from CT-scans and echocardiography 
will be uploaded into TSD.  
 
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