In the last 3 years, the global severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic has caused a high burden of mortality and morbidity worldwide. In December 2019, first cases of a SARS-CoV-2 infection were described in Wuhan, Hubei province, China [1, 2]. As of December 2022, more than 650 M confirmed infections and 6.6 M deaths—with a significant proportion of SARS-CoV-2 infections and deaths suggested not to be reported at all—have been registered officially [3,4,5]. Over the past 3 years, an astonishing global research effort has yielded a multitude of scientific insights scrutinizing the course of coronavirus disease 2019 (COVID-19) [6]. Deep immunological and molecular characterization of COVID-19 patients has generated crucial insight into the pathophysiology of SARS-CoV-2 infection. Despite these advances, treatment options still remain limited. Effective vaccination, however, has saved lives at an unprecedented scale [7,8,9,10].

COVID-19 disease severity ranges from asymptomatic and mild disease to critical illness as defined by WHO [11], and plentiful risk factors have been investigated and assigned to patient outcome [12]. In critical COVID-19 disease, SARS-CoV-2 infection leads to acute respiratory distress syndrome (ARDS) with the need of mechanical ventilation (MV) and sometimes extracorporeal membrane oxygenation (ECMO) [13, 14]. In severe COVID-19 and in mild disease, cardiovascular, neurologic, and further extra-pulmonary complications have been described [15, 16]. Persisting symptoms beyond the acute phase, particularly of the respiratory, cardio-circulatory and neuropsychiatric systems have been described, yet so far not sufficiently characterized.

A plethora of crucial questions remain unanswered and highlight the urgent need for well-characterized patient cohorts. To spark effective and high-impact research into COVID-19 in Germany, a network of medical universities (NUM), funded by the German Federal Ministry of Education and Research (BMBF), has been established (Fig. 1) in 2020. Within this consortium, a National Pandemic Cohort Network (NAPKON) was developed for three multicenter observational cohort studies including a deep phenotyping platform (high-resolution platform—HAP). Ten university hospitals within Germany participate in the NAPKON-HAP study (Fig. 1).

Fig. 1
figure 1

NUM members and NAPKON-HAP study centers in Germany. The following university clinics participate in NAPKON-HAP: Berlin, Cologne, Frankfurt, Freiburg, Gießen, Hannover, Heidelberg, Kiel/Lübeck, Munich (LMU). NUM members (as of November 2020) are Aachen, Augsburg, Berlin, Bielefeld (OWL), Bochum, Bonn, Cologne, Dresden, Düsseldorf, Erlangen, Essen, Frankfurt, Freiburg, Gießen/Marburg, Göttingen, Greifswald, Halle, Hamburg, Hannover, Heidelberg, Jena, Leipzig, Magdeburg, Mainz, Mannheim, Munich (LMU/TU), Münster, Oldenburg, Regensburg, Rostock, Saarland (UKS), Schleswig–Holstein (UKSH), Tübingen, Ulm, Würzburg

NAPKON-HAP implements a research infrastructure for high-resolution phenotyping of patients with SARS-CoV-2 infection of different disease severities. The primary objective is to provide a comprehensive and harmonized collection of data and biosamples for researchers and for participation in international research collaborations for the purpose of studying COVID-19 and future pandemics.

The deep phenotyping data and high-quality biospecimen collection provided by NAPKON-HAP enables research into the role of immunological, pulmonary, cardiovascular, neuropsychiatric, and endocrine events in COVID-19, among others. NAPKON-HAP serves to foster research into innate and adaptive immunity, to disseminate targets of SARS-CoV-2-induced innate and adaptive immune responses and its change over time to identify biomarkers for protective immunity and to develop therapeutic strategies and support development of vaccines. We also intend to provide data and biospecimen platform to identify biomarkers for early estimation of disease progression and provide prognostic markers acute and long-term outcome. NAPKON-HAP aims to correlate those findings within a collaborative research effort of immunological, microbiological, and virological expertise to clinical parameters to improve understanding of SARS-CoV-2-induced disease progression and to assess effects of specific COVID-19 treatments.


NAPKON ( provides a platform for harmonized collection and use of data and biospecimens, involving all health sectors within Germany. It ensures centrally coordinated time- and cost-efficient use of resources with high data and biomaterial quality. NAPKON aims to address scientific and health care-relevant questions comprehensively to provide representative, evidence-based information on COVID-19-specific risk factors, disease progression, and long-term sequelae.

NAPKON incorporates three different cohort platforms to represent the wide spectrum of COVID-19 severity and the associated characteristics of patients enrolled at different institutions. The cross-sector platform (NAPKON-SÜP) captures clinically ill patients with COVID-19 through a network of hospitals of all care levels and outpatient practices. The population-based platform (NAPKON-POP) recruits on the basis of public-health authority registries independent of disease severity and surveys representative long-term outcome over time. The high-resolution platform (NAPKON-HAP) comprehensively studies hospitalized patients with SARS-CoV-2 infection and evaluates their organ-specific sequelae after hospital discharge longitudinally and with high granularity.

Study design of NAPKON-HAP

NAPKON-HAP is a multi‐centered prospective observational study with a long‐term follow‐up phase of up to 36 months post-SARS-CoV-2 infection. The protocol was developed along the standards defined by the German Corona Consensus (GECCO) and evolved from the Berlin prospective COVID‑19 patient cohort (Pa‑COVID‑19) [17, 18]. The protocol was developed in accordance with the standardized protocol for the rapid, coordinated clinical investigation of severe acute infections by pathogens of public-health interest published by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) [19]. NAPKON-HAP is registered at (NCT04747366).

NAPKON-HAP constitutes a central platform of harmonized data for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. The first patient was enrolled in November 2020 in NAPKON-HAP at Charité Berlin, Germany. As of December 2022, 700 patients have been enrolled, and of those, 600 enrolled with COVID-19 until December 2021. Since then, patients were recruited into the amended NAPKON 2.0, aiming at the implementation of control cohorts (see “Control groups”). The preliminary end date of the study is the date of the last visit of the last patient undergoing the study.

Study inclusion criteria

Patients hospitalized at one of the participating study sites for COVID-19, confirmed by means of a positive SARS-CoV-2 PCR or initial positive rapid diagnostic test, in conjunction with characteristic radiological findings and infection of the respiratory tract, are eligible for inclusion. During hospital treatment, data are collected longitudinally from patients until discharge. After hospital discharge, structured follow-up visits over a period of up to 36 months after onset of first symptoms of COVID-19 will take place. Inclusion criteria are (i) age of 18 years or older; (ii) written consent to participate in the study by patient or appropriate legal representative; (iii) hospitalization at time of enrollment; (iv) positive SARS-CoV-2 PCR or initial positive rapid diagnostic test with positive PCR in due course, with typical clinical symptoms. Exclusion criteria are refusal to participate by patient or legal representative, or any condition that prohibits supplemental blood sampling.

Control groups

To distinguish between COVID-19 specific and non-specific findings, control groups of non-COVID-19 community acquired pneumonia (CAP) and non-COVID-19 ARDS were established. Further, to enable investigation into the mechanisms behind immunological failure to develop a protective immune response after SARS-CoV-2 vaccination, a separate group of vaccine break through infections was introduced.

Patient assessment and biosampling: in-hospital study visits and outpatient follow-up

Following hospital admission, the first study visit upon study inclusion surveys epidemiological and demographic parameters, medical history and potential risk factors, current medication, assessment of clinical status, disease symptoms, and patient-reported outcome measures (PROMIS) [20, 21]. In-hospital visits take place three times a week for up to 2 weeks in case of non-intensive care unit (ICU) treatment, and up to 5 weeks for ICU and intermediate care (IMC) unit treated patients. Blood sampling is performed during each visit, whereas sampling of urine, saliva, and oropharyngeal swabs are performed once a week. Data on disease severity as reflected by WHO ordinal scale for clinical improvement, concomitant medication, intercurrent diagnoses, and outcome are collected daily. At follow-up visits, laboratory blood testing and biosampling are continued (see Fig. 2, Table 1).

Fig. 2
figure 2

NAPKON-HAP study algorithm of data sampling and biosampling and deep phenotyping of the follow-up period: Upon hospital admission, participants are included, given SARS-CoV-2 infection and informed consent. Three study visits/week with biosampling are performed for 2 weeks for non-ICU and for 5 weeks for IMC/ICU patients during hospital admission. Biosampling starts at day of admission and will be continued at follow-up. Two deep phenotyping visits will take place at months 3 and 12 post-COVID-19 with a concise characterization of patients. Month 6 follow-up visits focus on pulmonary function testing. ICU intensive care unit, IMC intermediate care unit, V visit, FACS fluorescence activated cell sorting, EDTA ethylene diamine tetraacetic acid, BAL bronchoalveolar lavage, ENTA endotracheal aspirate, FU follow-up, ECG electrocardiogram, AGE advanced glycation end products, MRI magnetic resonance imaging, EEG electroencephalogram

Table 1 NAPKON-HAP study schedule for the acute and follow-up phase of patients with COVID-19: time points of clinical follow-up visits, biospecimen collection, and assessment of patient-reported outcome and quality of life measures

Harmonized collection of biospecimens in participating study sites was initially orchestrated by the NAPKON biosample core unit technically supported by the Laboratory Information Management System (LIMS) of German Center for Cardiovascular Research (DZHK), and has recently been transferred to the NAPKON NUKLEUS infrastructure [22]. The aim is to ensure consistent collection, processing, storage, and documentation of biospecimens and to enable usability of biospecimens collected within NAPKON-HAP. Regular monitoring visits will ensure high standards in biospecimen quality according to the Handbook for Quality Management in Biobanking [23].

Biosampling of the respiratory tract includes saliva and nasopharyngeal swabs per protocol from all patients as well as aliquots of bronchoalveolar lavage fluid (BAL) and endotracheal aspirate (ENTA) obtained within standard of care in case of invasively ventilated patients. Blood sampling includes serum, plasma, PBMCs, heparinized whole blood, and blood RNA for subsequent genotyping, transcriptomic and proteomic analyses, flow cytometry, and mass spectrometry as well as serum analysis of biomarkers and serological testing of antibodies and cytokines (see Fig. 2).

Deep phenotyping at months 3 and 12 include detailed pulmonary testing (including—but not restricted to—body plethysmography, pulmonary muscle strength testing, and spiroergometry), cardiological examination (cardiac magnetic resonance imaging (MRI), echocardiography, pulse wave analysis), neurological exploration (brain MRI, electroencephalogram (EEG), somatosensory testing), and endocrine investigation (14 days subcutaneous glucose monitoring). A comprehensive list of investigations is given in Table 1. Only in case of pathological findings, the latter examinations are performed at follow-up visits at months 24 and 36.

Harmonized data collection in electronic case report form (eCRF)

Data collection and biosampling are performed in accordance with the WHO supported case report form (CRF) proposed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) [24]. Items of the ISARIC-CRF were translated into German language using the standardized functional assessment of chronic illness therapy (FACIT) translation methodology [25]. The parameters were selected and adapted to local standards through a multidisciplinary expert review board [18]. All collected data at study sites including source documents and laboratory reports are being documented in eCRF. Medical and research records for this study are maintained in compliance with International Conference on Harmonization guideline for Good Clinical Practice (ICH-GCP) [26].

Data management and storage

The data management and study database are located at the Institute for Medical Informatics of the University Medical Center Göttingen. To capture data, the GCP-compliant software secuTrial® is used.

Patient identifying data are kept at the study sites and securely stored separately at the University Medical Center Greifswald (Zentrale Daten-Treuhandstelle,, where pseudonyms are generated and provided for data-, biomaterial- and image storage [27]. Integration of existing data and biospecimen of established clinical COVID-19 cohorts within Germany into the NAPKON-HAP platform was successfully performed and reviewed by an independent board.

Image data management and storage

Infrastructure for pseudonymized storage of image data is provided by the TrialComplete system. It enables pseudonymized DICOM data upload and transfer from the study centers to central imaging labs. eCRF data are automatically synchronized between the data management system and the image data storage system.

Data access and sharing

NAPKON established a core unit for overall coordination and interaction with scientists and partner sites. It implements and governs the use and access committee (UAC). The UAC steers user requests and decides upon the use of clinical data and biosamples for scientific projects. NAPKON-HAP aims to provide the research community with data and biosamples for their projects in a non-bureaucratic manner at the same time safeguarding patients’ rights. To date, 133 research projects are registered using NAPKON-HAP data.

Ethics and registration

The principles of Good Clinical Practice and other applicable regulations and guidelines are used to guide procedures and considerations. The study protocol and its amendments were reviewed and approved by the Charité Ethics Committee (EA2/066/20, EA2/226/21) as well as local ethics committees at each participating study center.


Within the first 2 years of the COVD-19 pandemic, academia has successfully demonstrated how to spark basic research on a novel pathogen and the host–pathogen interaction. In Germany, the network of medical universities was established in 2020 with the support of the German Federal Ministry of Education and Research, aiming to provide a research infrastructure for the COVID-19 and potential future pandemics. Clinical research was concerted within three observational cohort study platforms within the National Pandemic Cohort Network built on common core infrastructure units. Here, we describe the study protocol of the high-resolution platform, a multi-centered observational cohort study of patients hospitalized in one of the ten participating medical university centers with SARS-CoV-2 infection or non-COVID community acquired pneumonia or ARDS as controls. The study protocol expands from disease onset until 36 months follow-up and comprises a harmonized collection of clinical data as well as standardized biosampling procedures of blood and respiratory tract specimens. Data and biosamples are stored centrally and available for researchers through a use and access process after real-time verification of the status of consent documents. Exceptional clinical and biological data and specimen are especially designed for deep phenotyping projects including transcriptomics, proteomics, epigenomics, and metabolomics and will enhance translational research of COVID-19 and long COVID multi-omic approaches.

With this study, we will add significant scientific insights and provide high-quality data and biospecimen to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.