The CAPNETZ Study – at the heart of the foundation CAPNETZ STIFTUNG
20 years ago CAPNETZ – the NETwork of competence on Community-Acquired Pneumonia – was funded with the goal of increasing our understanding of the disease and decreasing the mortality of CAP patients. The initiation of the CAPNETZ study also laid the cornerstone of what is now the world’s largest data- and biomaterial bank on CAP and with this the cadre for many avenues of CAP research. To avail research funding, the trust CAPETZ STIFTUNG procures and provides materials and data to clinical centers and researchers within the growing network.
CAP is a disease of high medical and health-economical importance globally – also in Germany¹. Of all common infectious diseases it has the highest mortality rate and hospitalises around a quarter of a million people annually in Germany. Of these, around 13 % die, which accounted for up to 32 800 deaths in the year 2019.
The high mortality of infectious diseases can only be reduced by dedicated research, which has been the ascribed goal of CAPNETZ for over 20 years.
2001: The starting signal for the network of competence on community-acquired pneumonia
The CAPNETZ network of competence was established in 2001 in order to improve the state of knowledge, the diagnostic standards, and available therapies of CAP. It has since grown in popularity in the medical field throughout Europe. The concept of CAPNETZ was compiled by renowned professors R. Marre (University Clinic of Ulm), T. Welte (Medical School Hannover), and N. Suttorp (Charité-University Clinic Berlin) who secured the necessary funding from the German Ministry of Research and Education and took the lead in initial research efforts. In 2007 the foundation CAPNETZ STIFTUNG was established as an independent body that still promotes and implements clinical research on CAP.
2002: Initiation of the CAPNETZ study
CAPNETZ study recruitment started in 2002. By 2022, over 14 000 CAP patients have been documented. The result is a comprehensive database on CAP-data and an associated biomaterial collection – currently the largest CAP repository in the world. These data and biomaterials are available to researchers and clinicians all over the world which has lead to a considerable contribution of CAPNETZ to our current state of knowledge on CAP through clinical, microbiological and molecular biology research. Insights have been gained on pathogenesis, underlying genetics, and pathogen-host interactions. The development and improvement of diagnostic and treatment standards are a further focus of CAPNETZ-associated research. The findings directly benefit primary care in the form of national guidelines ² which are issued in collaboration with CAPNETZ. In addition, results from the CAPNETZ study have lead to various “spin-off” projects.
„The CAPNETZ spin-off study “PROGRESS” has lead to significant advances such as the discovery of a 5-gene signature which can reliably predict a requirement for intensive care medicine and increased CAP mortality.”
New goals of CAPNETZ
The network of competence has set the goal to close all gaps in our understanding and handling of CAP. These goals are:
- The development of a predictable and reliable standardised procedure for the detection of respiratory pathogens
- The detailed investigation of the reciprocal relationship between pneumonia and chronic diseases
- The definition of increased-risk CAP patients who require emergency care
- The development of strategies for treatment of CAP patients with HIV or immunosuppression
Unmet needs in CAP: The challenges of the future
In a recent workshop between leading experts on CAP a CAPNETZ initiative devised on the current unmeet needs around CAP:
Diagnostics The therapy depends on the pathogen. Accordingly, accurate diagnostics are paramount. However, a diagnostic standard for pathogen detection is missing. In the future, Next-Generation Sequencing might become a barrier-breaking tool to be used in diagnostics as well as for observation of the clinical course of the disease. Nanopore-sequencing in particular has been in the focus of research on pathogen detection. Furthermore, imaging techniques, such as computer tomography (CT), are already being used in the clinic to diagnose CAP and show potential as future tool to distinguish between infectious and non-infectious pneumonia. To date, the distinction of these two forms of pneumonia is difficult. It further needs to be validated and defined which patients would most benefit from use of expensive imaging technologies.
„With the help of new technologies we will be able to further decipher the interaction of bacterial and viral pathogens in the lung. Our increased understanding of etiological processes will contribute to advancements in diagnosis and therapy of CAP.“
Biomarker For the identification and monitoring of severe airway infection biomarkers such as C-reactive protein and procalcitonin can be used. However, these proteins are pathogen-unspecific. Advances in metabolomics, genomics and epigenomics might allow to find pathogen-specific markers, as well as markers to predict disease progression such as coronary artery calcium, which was found in patients with increased cardiovascular risk, but has been characterized by high heterogeneity.
Risk stratification The clinical score CRB-65 aids the identification of low-risk patients. It is combined with measurement of blood oxygen saturation and consideration of potential instable comorbidities. For the identification of high-risk patients which qualify for intensified surveillance and care, the IDSA/ATS minor criteria are considered. However, early risk stratification for CAP patients is not fully implemented yet and more research is required in this direction to guide decision making concerning treatment and hospital admission with CAP.
Therapy Currently, antibiotic therapy is mainly guided by empirical choices, as bacterial pathogens are generally more common causes of CAP than respiratory viruses. However, the epidemiological circumstances change, and the importance of bacterial-viral mix infections might be underestimated. For severe CAP cases, a combination therapy of beta-lactam and macrolide antibiotics is recommended to cover a broad spectrum of potential bacterial pathogens: Beta-lactam antibiotics are effective against the most typical and macrolides against atypical bacteria. However, macrolides are known to interact with a range of other medications and can lead to serious side effects – especially in older patients with cardiac comorbidities and pre-existing medication regimen.
An interesting tool for decision making around macrolide application was developed based on machine-learning in a CAPNETZ-supported research project. Also aerosolised antibiotics are being developed and might constitute a treatment option in the future. However, viral pathogens are gaining importance in pneumonia – especially in immunocompromised patients – and their detection and treatment are under-researched.
Excessive inflammation The result of therapy failure – e.g. due to use of the wrong antimicrobial – can be excessive inflammation caused by the interaction of the pathogen and the immune system. Therefore, the potential of immunomodulatory therapeutics, such as steroids, or IL-6 inhibitors is under discussion. Immunomodulation is controversial, as the immune system is required to fight infection – but it can overshoot and cause harm. Different small molecule substances and biologica to stimulate improved fine tuning and regulation of inflammatory processes in the body are under research.
Prevention by vaccination A vaccination exists against several pneumonia pathogens. Particularly, pneumococcal vaccines have been used for many years and to date, various forms of pneumococcal vaccines exist with different modes of action, and which contain varying ranges of pneumococcal serotypes.
„The burden of disease of CAP is high, especially considering the increased risk for cardiovascular complications that can persist for many years after surviving CAP. Therefore, vaccination can help to prevent a lot of suffering. It is important to have clear data on the prevalence and burden of individual pathogens – and in the case of pneumococci serotypes - to guide vaccine development and assessment. CAPNETZ has made a significant contribution to this in Germany. “
A strong immune reaction during the CAP event can cause lasting lung damage. Parenchymal changes caused by inflammation increase the risk of chronic non-infective lung conditions such as chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). But this does not mean that anti-inflammatory treatment is the right strategy to ensure survival. When interfering with inflammatory processes, the right approach and the right timing are crucial. Also genetic differences between patients affect the immune response. More research needs to be done to facilitate a personalized treatment with immune modulators.
Underestimated: Immunosuppression Immunosuppression can come with age (immunosenescence), be the side effect of certain medications, or can be a hereditary or acquired disease. Immunocompromised CAP patients are at higher risk for severe complications. Guidelines on treating CAP with immunosuppression have not yet been established, but are necessary considering around 29% of hospitalized CAP-patients are immunocompromised.
„The immune system can overreact in the CAP event. We are not yet able to predict a patient’s immune reaction. To investigate this is subject of the CAPNETZ study and research projects. “
Keeping an eye on cardiovascular complications Hospitalised CAP patients are at increased risk for cardiovascular complications both in the short term, but also in the long term. Conditions such as heart insufficiency, cardiac arrhythmia, myocardial infarction, and stroke have been associated to surviving CAP.
„CAP goes along with long term risks. For example, the cardiovascular risk after CAP can be increased for up to 10 years. It is not known whether this risk is connected to specific pathogens or physiological processes, and which consequences this has for monitoring of patients.”
This is true in particular for patients who smoke or are diabetic. It is necessary to develop strategies to prevent cardiovascular complications after CAP. What is known already is that pre-existing cardiac issues are a tell-tale sign of a patient at risk for CAP complications and heart complications.
Bottom line: Pneumonia is a complex condition
The conclusion of leading pulmonologists and microbiologists: CAP has to be viewed as a complex disease which requires assessment of pathogens, immune system, and comorbidities. All things considered, significant advances can be made in CAP diagnostics and therapy. To date, gaps in our understanding of this complexity results in poor evidential foundation for different clinical approaches. A coordinated research progress is required, for which CAPNETZ provides relevant structures and materials. With this, the network is contributing to solutions against respiratory infection.
CAPNETZ: The studies
Despite its medical and health-economical importance, reliable data on CAP have been lacking until the end of the 20th century. The network of competence on CAP was established to close these gaps in information on epidemiology, risk factors, pathogens, resistances, and course of the disease. By establishment of the CAPNETZ study infrastructure in 2002, the foundation was built to advance knowledge and improve treatment of CAP. Ever since, researchers can apply for access to data and biomaterials from CAPNETZ. CAPNETZ does not only support research projects on CAP, but it also implements related study projects, for example:
ABACOPD Study: randomised, double-bling and placebo-controlled study implemented in Germany, which showed that antibiotc use can be reduced for treatment of moderate acute exacerbations of COPD.
PROGNOSIS register study PROGNOSIS is a Germany-wide prospective and representative longitudinal observational register for patients of non-cystic fibrosis bronchiectasis. The bronchiectasis-register was build in cooperation of the Medical School of Hannover and the CAPNETZ STIFTUNG.
pedCAPNETZ: While the CAPNETZ study investigates CAP in adults, pedCAPNETZ was brought to life to investigate children and teenagers with CAP, with the goal of improving disease management for the younger demographic.
BaViFlu is a study to investigate whether POCT (point-of-care testing) for differentiation of bacterial and viral infections of the upper airways can reduce unnecessary usage of antibiotics.
PROGRESS: Through support by the German Ministry of Education and Research a network of 3 related topics aims to reduce occurrence of severe manifestations of pneumonia:
- CAPNETZ: network of competence on community-acquired pneumonia
- SepNet: network of competence on sepsis
- NFGN: national genome research network on infection and inflammation.
To this end the „network of networks“ PROGRESS utilises transcriptomics, proteomics and genomics to identify biomarkers and genetic polymorphisms which are associated to severe cases of CAP.
PROVID collects clinical, molecular, and functional indicators for prognosis, pathomechanisms, and treatment strategies for Covid-19 to improve clinical care.
