Journal Information
Vol. 58. Issue 3.
Pages 208-210 (March 2022)
Download PDF
More article options
Vol. 58. Issue 3.
Pages 208-210 (March 2022)
Full text access
What's Next in Pneumonia?
¿Qué nos depara el futuro de la neumonía?
Catia Cilloniza,b,c, Antoni Torresa,b,c,
Corresponding author

Corresponding author.
a Department of Pneumology, Hospital Clinic of Barcelona, Spain
b August Pi i Sunyer Biomedical Research Institute – IDIBAPS, University of Barcelona, Spain
c Biomedical Research Networking Centers in Respiratory Diseases (Ciberes), Barcelona, Spain
This item has received
Article information
Full Text
Download PDF
Full Text

Pneumonia remains the leading infectious cause of death for all ages worldwide.1 Due to the progressively aging population globally, the proportion of very old patients (VOP80 years) hospitalized with pneumonia continues to rise; similarly, the proportion of VOP requiring treatment in intensive care units (ICU) is increasing.2 VOP are at a high risk of pneumonia due to multiple chronic comorbidities, immunosenescence, malnutrition, frailty and polypharmacy. This same group also faces a higher likelihood of severe pneumonia and mortality.3 Conversely, pneumonia disproportionately affects children under five years old. In 2019, the respiratory disease claimed the lives of 672,000 children aged less than five years.1 This means that a child who has not even turned five years old will die every 47s due to pneumonia.1 No doubt remains that pneumonia is a major burden on global health. Yet, despite that, there are still several challenges and controversies related to critical aspects of pneumonia management and prevention.

Early-risk severity stratification and appropriate antimicrobial therapy have been well-established to be integral components in improving pneumonia outcomes. However, there are no risk stratification tools to guide management of pneumonia in VOP and children requiring intensive care. The most widely used severity scores, like PSI and CURB65, perform well in predicting 30-day mortality; however, these same scores fall short when it comes to predicting the need for ICU admission. The first upcoming challenge in pneumonia will be to continue research that demonstrates the usefulness of severity scores in predicting which patients would benefit from more aggressive treatments and ICU care.

Additionally, early identification of pneumonia-causing microorganisms is essential in implementing adequate antimicrobial therapy. Indeed, a patient's prognosis could benefit significantly from adequate microbial treatment.4 However, we can only identify the microbial cause of pneumonia in approximately 50% of cases. While a detection of specific pathogens such as respiratory viruses have improved via the application of molecular techniques,5 more must be done. The lack of standardization of these techniques limits their full integration in clinical practice. Additionally, result interpretation can be ambiguous with respect to pathogen detection and colonization/infection determination. As the current COVID-19 pandemic has demonstrated, the role of molecular tests in detecting pathogens, including emergent viruses like severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2), is becoming more pivotal.

In the coming years, a second challenge of pneumonia research will be to evaluate the usefulness, applicability and standardization of molecular testing in detecting pneumonia pathogens and related resistance to improve and personalize the management and care for patients with community-acquired pneumonia (CAP). Currently, Streptococcus pneumoniae and influenza virus are the most common causes of pneumonia. Although multidrug-resistant (MDR) pathogens present in a lower proportion in CAP, especially in severe cases, the impact of such microbes on clinical outcomes is huge.5,6 It will therefore be important to continue research also on the utility of scores that predict patients at risk of drug-resistant microorganisms like PES pathogens (Pseudomonas aeruginosa, extended-spectrum β-lactamase-producing Enterobacterales, and methicillin-resistant Staphylococcus aureus) that recently have emerged as causes of CAP.6,7

In the last ten years, scores assessing the potential risk of MDR pathogens in patients with CAP have come into development.8–11 However, the scores present a higher variability on the assigned weight to each variable investigated, and variability in the thresholds for patients at risk of MDR pathogens is present. Interestingly, the PES score7 has showed a high negative predictive value (98%), making it possibly an important tool to rule out patients with CAP who do not need antibiotic coverage against PES pathogens. However, future studies are needed to support the therapeutic clinical decision-making processes, especially as it relates to cases caused by MDR pathogens others than PES microorganism. For example, carbapenem-resistant Enterobacterales or Acinetobacter baumanni are MDR pathogens that are associated with higher morbidity and mortality despite low frequency of such microorganisms in this series of patients.12–14

At the same time, mounting evidence supports considering the immunological profile of patients with CAP as a useful tool in assessing severity and prognosis in pneumonia.15,16 Researchers have found that the lymphopenic CAP (L-CAP) phenotype was associated to increased severity, mortality and a dysregulated immunological response in patients with CAP.15,17 In patients with CAP and sepsis, lymphopenia was also reported to be associated with an increased risk of ICU admission and 30-day mortality.18 The neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein-to-lymphocyte ratio have also shown to be simple to use and extremely good markers of severity in pneumonia.19,20 NLR integrates two types of immune responses to infection (neutrophilia and lymphopenia), making it a substantial prognostic marker in pneumonia.19,21,22 Importantly, these markers are easily obtainable at hospital admission; clinicians should therefore implement them in clinical practice.

Recent studies have also explored the application of machine learning algorithms to support clinical decisions related to CAP.23–25 It is the latest interesting approach in managing pneumonia. However, validations of the algorithms developed are necessary to implement such a tool in the future.

Continuing, due to the difficulty posed in determining microbial etiology, antibiotic therapy for pneumonia must be empirical.4 Controversy concerning what empirical antibiotic therapy is the most adequate for pneumonia, especially in severe cases, very old and/or immunocompromised patients, is present, though. Similarly, there has yet to be an established consensus on the optimal duration of antibiotic therapy in cases of pneumonia. Compounding this is the added, continuous debate about what indications are adequate for corticosteroid use, especially in light of the recent impact of corticosteroids in patients with severe COVID-19.26,27 Lastly, despite great efforts made by an expert panel to develop clinical guidelines, there are still gaps in the quality and quantity of studies on which the guidelines are based. The majority of studies are observational, and there are few randomized controlled trials (RCT). Also, most studies have focused on non-severe pneumonia and in immunocompetent individuals. As a result of such study characteristics, information regarding the very old population is limited and thereby places a cap on generalizations. Studies undertaken in the future will need to consider different antibiotic regimens, newer antibiotics and antibiotic therapy duration, especially in those patients who are critically ill, very old or immunocompromised. Furthermore, prospective studies will need to provide a better characterization of patients with pneumonia who could stand to benefit from corticosteroids as adjunctive therapy. New data of this nature would address existing disparities in these important issues on pneumonia.

Of note, we would like to reiterate that pneumonia is a preventable disease with well-known risk factors.4,28–30 Effective vaccines such as Haemophilus influenzae type b, pneumococcal and influenza vaccine could reduce the burden of pneumonia on the most vulnerable populations globally. For example, pneumococcal conjugate vaccines (PCVs) have significantly reduced pneumococcal disease worldwide.31 However, there are limitations in serotype coverage by PCV13 vaccine due to the evolution and emergence of new pneumococcal serotypes.32 Developing new formulation of PCV vaccines—such as the 20-valent PCV (PCV20) that contains the capsular polysaccharide conjugates of serotypes present in the PCV13 plus 7 new serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F)33 and the 15-valent PCV (PCV15) that contain scapsular polysaccharide conjugates of serotypes present in the PCV13 plus serotypes 22F and 33F34—are essential to reduce the burden of pneumococcal disease. However, while European vaccination programs are well-established for children and adults,35 vaccination coverage remains suboptimal among the adult population. Low- and middle-income countries experience low vaccination coverage. According to the World Health Organization, approximately 19 million children aged<1 year have not received basic vaccines, including the pneumococcal vaccination.36 In the next, few years, routine vaccination programs for children and adults will require a boost in support and uptake worldwide.

Finally, it is vital to remark the importance of preventing aspiration pneumonia. This type of pneumonia remains poorly recognized, even though it has increased especially among very old, frail patients and is a cause of severe disease.37 Studies focusing on preventive strategies for modifiable risk factors, such as oropharynx colonization, modifying gastric pH and dysphagia, are necessary to reduce their prevalence.

This all stated, we believe that governments must invest more in clinical research on pneumonia and strengthen investigation teams as they strive to pursue high-quality evidence related to different aspects of pneumonia. Although the COVID-19 pandemic has placed great pressure on health systems across the globe, governmental actions of such a magnitude would serve to create specific, national strategies to control pneumonia and improve vaccine uptake, risk factors, diagnosis and treatment of pneumonia. Only through developing concrete approaches and bettering the quantity and quality of scientific evidence on pneumonia will we be able to reduce the high burden of pneumonia and avoid deaths of the most vulnerable populations.

GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020;396:1204–22.
C. Cillóniz, C. Dominedò, J.M. Pericàs, D. Rodriguez-Hurtado, A. Torres.
Community-acquired pneumonia in critically ill very old patients: a growing problem.
Eur Respir Rev, 29 (2020), pp. 190126
C. Cillóniz, C. Dominedò, A. Ielpo, M. Ferrer, A. Gabarrús, D. Battaglini, et al.
Risk and prognostic factors in very old patients with sepsis secondary to community-acquired pneumonia.
J Clin Med, 8 (2019), pp. 961
J.P. Metlay, G.W. Waterer, A.C. Long, A. Anzueto, J. Brozek, K. Crothers, et al.
Diagnosis and treatment of adults with community-acquired pneumonia an official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America.
Am J Respir Crit Care Med, 200 (2019), pp. e45-e67
A. Torres, C. Cilloniz, M.S. Niederman, R. Menéndez, J.D. Chalmers, R.G. Wunderink, et al.
Nat Rev Dis Primers, 7 (2021), pp. 25
C. Cilloniz, C. Dominedo, H.J. Peroni, P. Di Giannatale, C. Garcia-Vidal, A. Gabarrus, et al.
Difficult to treat microorganisms in patients over 80 years with community-acquired pneumonia: the prevalence of PES pathogens.
Eur Respir J, 56 (2020), pp. 2000773
E. Prina, O.T. Ranzani, E. Polverino, C. Cillóniz, M. Ferrer, L. Fernandez, et al.
Risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia.
Ann Am Thorac Soc, 12 (2015), pp. 153-160
A.F. Shorr, M.D. Zilberberg, S.T. Micek, M.H. Kollef.
Prediction of infection due to antibiotic-resistant bacteria by select risk factors for health care-associated pneumonia.
Arch Intern Med, 168 (2008), pp. 2205-2210
S. Aliberti, M. Di Pasquale, A.M. Zanaboni, R. Cosentini, A.M. Brambilla, S. Seghezzi, et al.
Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia.
Clin Infect Dis, 54 (2012), pp. 470-478
S.C. Park, E.Y. Kim, Y.A. Kang, M.S. Park, Y.S. Kim, S.K. Kim, et al.
Validation of a scoring tool to predict drug-resistant pathogens in hospitalised pneumonia patients.
Int J Tuberc Lung Dis, 17 (2013), pp. 704-709
Y. Shindo, R. Ito, D. Kobayashi, M. Ando, M. Ichikawa, A. Shiraki, et al.
Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia.
Am J Respir Crit Care Med, 188 (2013), pp. 985-995
N. Narayanan, T. Lin, D. Vinarov, T. Bucek, L. Johnson, C. Mathew, et al.
Relationship between multidrug-resistant enterobacterales and obesity in older adults.
Infect Drug Resist, 14 (2021), pp. 2527-2532
M. Falcone, G. Tiseo, F. Menichetti.
Community-acquired pneumonia owing to multidrug-resistant pathogens: a step toward an early identification.
Ann Am Thorac Soc, 18 (2021), pp. 211-213
C. Cillóniz, C. Dominedò, A. Torres.
Multidrug resistant gram-negative bacteria in community-acquired pneumonia.
J.F. Bermejo-Martin, R. Almansa, M. Martin-Fernandez, R. Menendez, A. Torres.
Immunological profiling to assess disease severity and prognosis in community-acquired pneumonia.
Lancet Respir Med, 5 (2017), pp. e35-e36
R. Méndez, R. Menéndez, I. Amara-Elori, L. Feced, A. Piró, P. Ramírez, et al.
Lymphopenic community-acquired pneumonia is associated with a dysregulated immune response and increased severity and mortality.
J Infect, 78 (2019), pp. 423-431
J.F. Bermejo-Martin, C. Cilloniz, R. Mendez, R. Almansa, A. Gabarrus, A. Ceccato, et al.
Lymphopenic community acquired pneumonia (L-CAP), an immunological phenotype associated with higher risk of mortality.
EBioMedicine, 24 (2017), pp. 231-236
C. Cilloniz, H.J. Peroni, A. Gabarrús, C. García-Vidal, J.M. Pericàs, J. Bermejo-Martin, et al.
Lymphopenia is associated with poor outcomes of patients with community-acquired pneumonia and sepsis.
Open Forum Infect Dis, 8 (2021), pp. ofab169
H. Lee, I. Kim, B.H. Kang, S.-J. Um.
Prognostic value of serial neutrophil-to-lymphocyte ratio measurements in hospitalized community-acquired pneumonia.
PLOS ONE, 16 (2021), pp. e0250067
C. Cillóniz, A. Torres, C. Garcia-Vidal, E. Moreno-Garcia, R. Amaro, N. Soler, et al.
The value of C-reactive protein-to-lymphocyte ratio in predicting the severity of SARS-CoV-2 pneumonia.
Arch Bronconeumol, 57 (2021), pp. 79-82
Y.L. Ge, H.F. Zhang, Q. Zhang, X.Y. Zhu, C.H. Liu, N. Wang, et al.
Neutrophil-to-lymphocyte ratio in adult community-acquired pneumonia patients correlates with unfavorable clinical outcomes.
Clin Lab, 65 (2019),
E. Cataudella, C.M. Giraffa, S. Di Marca, A. Pulvirenti, S. Alaimo, M. Pisano, et al.
Neutrophil-to-lymphocyte ratio: an emerging marker predicting prognosis in elderly adults with community-acquired pneumonia.
J Am Geriatr Soc, 65 (2017), pp. 1796-1801
C. Garcia-Vidal, G. Sanjuan, P. Puerta-Alcalde, E. Moreno-García, A. Soriano.
Artificial intelligence to support clinical decision-making processes.
EBioMedicine, 46 (2019), pp. 27-29
S. Gonem, W. Janssens, N. Das, M. Topalovic.
Applications of artificial intelligence and machine learning in respiratory medicine.
L. Li, L. Qin, Z. Xu, Y. Yin, X. Wang, B. Kong, et al.
Using artificial intelligence to detect COVID-19 and community-acquired pneumonia based on pulmonary CT: evaluation of the diagnostic accuracy.
Radiology, 296 (2020), pp. E65-E71
P. Horby, W.S. Lim, J.R. Emberson, M. Mafham, J.L. Bell, RECOVERY Collaborative Group, et al.
Dexamethasone in hospitalized patients with Covid-19.
N Engl J Med, 384 (2021), pp. 693-704
D. Chaudhuri, K. Sasaki, A. Karkar, S. Sharif, K. Lewis, M.J. Mammen, et al.
Corticosteroids in COVID-19 and non-COVID-19 ARDS: a systematic review and meta-analysis.
Intensive Care Med, 47 (2021), pp. 521-537
A. Torres, W.E. Peetermans, G. Viegi, F. Blasi.
Risk factors for community-acquired pneumonia in adults in Europe: a literature review.
Thorax, 68 (2013), pp. 1057-1065
J.S. Bradley, C.L. Byington, S.S. Shah, B. Alverson, E.R. Carter, C. Harrison, et al.
The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.
Clin Infect Dis, 53 (2011), pp. e25-e76
R. Menéndez, C. Cilloniz, P.P. España, J. Almirall, A. Uranga, R. Méndez, et al.
Community-acquired pneumonia. Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) Guidelines. 2020 update.
Arch Bronconeumol, 56 (2020), pp. 1-10
P.L. Wantuch, F.Y. Avci.
Invasive pneumococcal disease in relation to vaccine type serotypes.
Hum Vaccin Immunother, 15 (2019), pp. 874-875
A. Torres, R. Menéndez, P.P. España, J.A. Fernández-Villar, J.M. Marimón, C. Cilloniz, et al.
The evolution and distribution of pneumococcal serotypes in adults hospitalized with community acquired pneumonia in Spain using serotype specific urinary antigen detection test: the CAPA study, 2011–2018.
Clin Infect Dis, (2021), pp. ciab307
D. Hurley, C. Griffin, M. Young Jr., D.A. Scott, M.W. Pride, I.L. Scully, et al.
Safety tolerability, and immunogenicity of a 20-valent Pneumococcal Conjugate Vaccine (PCV20) in adults 60 to 64 years of age.
Clin Infect Dis, (2020), pp. ciaa1045
D. Greenberg, P.A. Hoover, T. Vesikari, C. Peltier, D.C. Hurley, R.D. McFetridge, et al.
Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) in healthy infants.
Vaccine, 36 (2018), pp. 6883-6891
D.C. Cassimos, E. Effraimidou, S. Medic, T. Konstantinidis, M. Theodoridou, H.C. Maltezou.
Vaccination programs for adults in Europe, 2019.
Vaccines (Basel), 8 (2020), pp. 34
Immunization coverage. World Health Organization (WHO). 2020. [accessed 9.07.21].
J. Almirall, R. Boixeda, M.C. de la Torre, A. Torres.
Aspiration pneumonia: a renewed perspective and practical approach.
Respir Med, 185 (2021), pp. 106485
Copyright © 2021. SEPAR
Archivos de Bronconeumología
Article options

Are you a health professional able to prescribe or dispense drugs?