Pneumonia in the third year of the pandemic: one eye on the pathogens, the other on the host

EditorialPneumonia in the third year of the pandemic: one eye on the pathogens, the other on the hostChristina Julius, Matthias W. Pletz, Jan Rupp, Martin Witzenrath, Grit Barten-Neiner, and Gernot RohdeChristina JuliusCAPNETZ STIFTUNG Geschäftsstelle, Hannover, Germany, Matthias W. PletzCAPNETZ STIFTUNG Geschäftsstelle, Hannover, GermanyInstitute of Infectious Diseases and Infection Control, University Hospital, Jena, Germany, Jan RuppCAPNETZ STIFTUNG Geschäftsstelle, Hannover, GermanyDepartment of Infectious Diseases and Microbiology, University Hospital Schleswig-Holstein, Lübeck, Germany, Martin WitzenrathCAPNETZ STIFTUNG Geschäftsstelle, Hannover, GermanyDepartment of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyGerman Center for Lung Research (DZL), Giessen, Germany, Grit Barten-NeinerCAPNETZ STIFTUNG Geschäftsstelle, Hannover, GermanyBiomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany, and Gernot RohdeCAPNETZ STIFTUNG Geschäftsstelle, Hannover, GermanyBiomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, GermanyDepartment of Respiratory Medicine, Goethe-Universität Frankfurt am Main, Medical Clinic I, Frankfurt am Main, GermanyPublished Online:09 Nov 2022https://doi.org/10.1152/ajplung.00330.2022This is the final version - click for previous versionMoreSectionsPDF (345 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat COMMUNITY-ACQUIRED PNEUMONIA IN 2022World Pneumonia Day 2022 takes place in the third year of the COVID-19 pandemic. In many places of the northern hemisphere where COVID-19 has temporarily constituted the primary cause of death (1), public life is returning to normal. However, it is a new normal that adjusts to recurring outbreaks of emerging variants. In the southern hemisphere and low-income countries, COVID-19 fatality was about twice as high as in the developed world (2), owing to poorer access to medical care and lower standards of living. Lockdown measures have exacerbated economic inequality in these countries (3, 4). Additionally, environmental pollution and climate change have been connected to COVID-19 mortality in particular and respiratory infections in general (5–7) and can be regarded as drivers for global health decline.Already before COVID-19, lower respiratory tract infections such as community-acquired pneumonia (CAP) were among the leading infectious diseases globally (8) and have—with a hospitalization rate of 30%–50% (9), at the example of a German cohort from the CAPNETZ study—both medical and economic relevance. Although SARS-CoV-2 has quickly established itself as an important pathogen of CAP, research indicates with the current season 2022/23, “traditional” CAP pathogens will return (10).With rapid global developments, staying up to date on clinical data on respiratory diseases is of paramount importance.THE CAP PATHOGEN LANDSCAPE HAS CHANGEDThe COVID-19 pandemic has affected the patterns of emergence of other respiratory tract viruses (11). Particularly, the respiratory syncytial virus (RSV) season has shifted (12, 13). Before COVID-19, RSV used to circulate between children each winter. In 2020/21, however, the RSV epidemic did not take place. Instead, RSV returned in the following fall, peaking higher than in previous seasons. Also, the influenza virus was affected: since COVID-19 preventive measures have been implemented into public life on a global scale, influenza seasonal peaks were observed to be lower than usual (14). Interestingly, rhinovirus circulation was demonstrably not altered over the years of the pandemic (15).Ultimately, the emergence of new CAP pathogens such as COVID-19 might have unforeseeable effects. On the one hand, currently there is a public and pharma-industrial focus on disease prevention and diagnostics in the developed world. Alongside public awareness, the vaccination infrastructure and biotech industry around it have been strengthened. This might also benefit the development of vaccinations against other diseases. On the other hand, reduced immunization against common pathogens by natural exposure enhances susceptibility of the population to future epidemics (16). For example, a recent influenza epidemic in Australia affected mainly infants and children (17), possibly reflecting a time-compressed primary infection.COVID-19 also highlighted the limitations of global disease control that seem to be irreconcilable. While some countries, such as China or New Zealand, decided for complete lockdown procedures, following different measures in other parts of the world might be why the virus keeps circulating and rapid mutagenesis was observed.Lastly, COVID-19 has once more shown the constant threat posed by zoonotic diseases, as evidenced also by other viruses that have recently caused epidemics—Ebola, SARS, MERS, and of course, influenza (18).PATHOGEN IDENTIFICATION AND ANTIBIOTIC TREATMENT REQUIRE OUR ATTENTIONTo date, CAP pathogen diagnostic tests are sub-par: the underlying pathogen is identified in only 30%–70% of CAP cases (19). Here, microbial culture methods are still the standard, although more sensitive multiplex-PCR (20) and metagenomics-based methods (21) are available but are not widely accessible. Rapid antigen tests only exist for certain CAP pathogens: SARS-CoV-2, Streptococcus pneumonia, and Legionella spp. (19). Serotype-specific pneumococcus detection has recently been developed (22, 23). It remains to be shown whether improved pathogen characterization leads to better clinical outcome through targeted treatment as opposed to empirical treatment.CAP pathogen statistics are mostly stable within a geographic region with epidemics as special cases. Hence at present, empirical antibiotic treatment is preferred in consideration of the rapid disease progression. For example, both in Germany and in the United States, around 40% of CAP with known pathogen is caused by S. pneumoniae (19, 24). Contrastingly, the COVID-19 pandemic has highlighted the role of explicit pathogen detection and antiviral treatment in CAP, which also influences treatment choices during influenza season. Here, secondary bacterial infection also needs to be considered (19, 25, 26), for which the approach being followed is still empirical.To the detriment of CAP treatment, antibiotic resistance is on the rise (27), which might affect particularly areas with poor availability of second- and third-line drugs. Research to overcome this is currently focusing on a variety of antibacterial mechanisms ranging from whole phage therapy (28) to antisense oligonucleotides (29).CAP PATIENT RISK ASSESSMENT SHOULD INCLUDE COMORBIDITIESCAP diagnosis has a higher in-hospital mortality rate than myocardial infarction, with 13.2% of hospitalized patients with CAP deceasing within the first 3 days (30). The early stages of the disease are highly dynamic and critical deterioration might develop rapidly. The German CAP research network CAPNETZ strives to introduce a standard of risk stratification (19, 31) to recognize low-risk patients who can be discharged with proper medication; and to recognize high-risk patients who should receive intensive care or surveillance.Parameters for low risk are patient age <65 years, maintained functionality (bedrest less than 50% of the day), and absence of instable comorbidities. Especially since COVID-19, it has proven advantageous to include oxygen saturation (over 92%), which can decrease rapidly during disease progression and may present paucisymptomatic in COVID-19.A high-risk patient is recognized predominantly by signs of hypoxemia or sepsis, and requirement of mechanical ventilation or vasopressor therapy. Sepsis co-occurs in up to 50% of hospitalized CAP cases (32). Further, evidence accumulates that CAP interacts strongly with comorbidities.Generally, preexisting instable comorbidities, particularly cardiovascular or chronic lung conditions, are indicative of an increased risk for a severe course of CAP (19). CAP can also affect patient health after recovery (33), enhancing for example the risk for cardiovascular events related to follow-up mortality. In the CAPNETZ cohort, 26% of CAP-related deaths occur outside of the hospital (34). This demonstrates a need for prolonged monitoring and evaluation. In due time, risk stratification of an individual patient may encompass molecular signatures that give advice for the employment of specific adjunctive therapies (35, 36).THE IMMUNE SYSTEM AND CARDIOVASCULAR HEALTH MODULATE DISEASE AND RECOVERYInterestingly, mapping of proteomics markers in COVID-19-hospitalized patients revealed a predictive pattern of disease progression: indicative of a severe disease progression were 22 biomarkers implicated in proinflammation, coagulation, and the complement system (37). It is uncertain whether this is a general or a pathogen-specific infection response.The immunology of CAP is an open topic of discussion. Likely, a decreased cytokine production at older age is linked to higher mortality (30, 38). Further, certain patient polymorphisms in cytokine loci have been linked to increased CAP severity (39, 40). On the other end of the spectrum, cytokine storm and antibody-dependent enhancement are factors in COVID-19 severity (41, 42).Accordingly, adjunctive therapy is discussed as CAP treatment. The risks and benefits for adjunctive therapy need to be evaluated carefully, as potential adverse effects depend on the patient’s comorbidities and other aspects of immunity. For the use of macrolide antibiotics that have an anti-inflammatory effect, an algorithm has been proposed by CAPNETZ to be implemented in the decision-making process (35). Currently, new adjunctive therapies are running clinical trials some of which show potential for decreasing CAP mortality (43, 44).Cardiovascular comorbidities pose a risk for CAP mortality (45), but also CAP increases the risk for future cardiovascular events (46, 47). Although such CAP sequelae have long been known (48, 49), it was now established that also COVID-19 might affect cardiovascular health (50). In the case of pneumococcal pneumonia, this has been associated to pathogen virulence factor pneumolysin both pore-forming activity and platelet activation (51, 52). In the case of COVID-19 host markers of cardiovascular disease were released in response to the acute respiratory distress syndrome (50). “Long-COVID-19” is just one example of post-viral syndromes such as myalgic encephalomyelitis and postural orthostatic tachycardia (53, 54), which might be relevant also in other viral CAP.WHAT HAPPENS NEXT?Mortality due to CAP is still unbearably high. New pathogens, such as SARS-CoV-2, have highlighted the importance of CAP, particularly in vulnerable populations. Much more collaborative international experimental, translational, and clinical research is urgently needed to improve acute management and outcome of the disease and to avoid long-term consequences and complications. The major unmet research needs have been recently published based on the results of an international CAPNETZ retreat (33). Once tackled, hopefully progress can be reported on the next World Pneumonia Days.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSC.J. drafted manuscript; M.W.P., J.R., M.W., G.B.-N., and G.R. edited and revised manuscript; G.R. approved final version of manuscript.REFERENCES1. Schellekens P, Sourrouille D. COVID-19 Mortality in Rich and Poor Countries: A Tale of Two Pandemics? (Online). Policy Research Working Paper No. WPS 9260. Washington, D.C.: World Bank Group. https://documents.worldbank.org/en/publication/documents-reports/documentdetail/559181590712052524/covid-19-mortality-in-rich-and-poor-countries-a-tale-of-two-pandemics [2022 Sept 22].Google Scholar2. 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Morty9 November 2022 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 323, No. 5 More from this issue > Volume 323Issue 5November 2022Pages L611-L614 Crossmark Copyright & PermissionsCopyright © 2022 the American Physiological Society.https://doi.org/10.1152/ajplung.00330.2022PubMed36218260History Received 30 September 2022 Accepted 30 September 2022 Published online 9 November 2022 Published in print 1 November 2022 Keywordscommunity-acquired pneumoniaclinical researchepidemiologypathogenpneumonia Metrics