Persistent Lung Inflammation After Clinical Resolution of Community-Acquired Pneumonia as Measured by 18FDG-PET/CT Imaging
2021; Elsevier BV; Volume: 160; Issue: 2 Linguagem: Inglês
10.1016/j.chest.2021.02.048
ISSN1931-3543
AutoresVicente F. Corrales–Medina, Robert A. deKemp, Julio A. Chirinos, Wanzhen Zeng, Jerry Wang, Grant Waterer, Rob Beanlands, Girish Dwivedi,
Tópico(s)Respiratory viral infections research
ResumoBackgroundSurvivors of community-acquired pneumonia (CAP) are at increased risk of cardiovascular disease, cognitive and functional decline, and death, but the mechanisms remain unknown.Research QuestionDo CAP survivors have evidence of increased inflammatory activity in their lung parenchyma on 2-deoxy-2-[18F]fluoro-d-glucose (18FDG)-PET/CT imaging after clinical resolution of infection?Study Design and MethodsWe obtained 18FDG-PET/CT scans from 22 CAP survivors during their hospitalization with pneumonia (acute CAP) and 30 to 45 days after hospital discharge (post-CAP). In each set of scans, we assessed the lungs for foci of increased 18FDG uptake by visual interpretation and by total pulmonary glycolytic activity (tPGA), a background-corrected measure of total metabolic activity (as measured by 18FDG uptake). We also measured, post-CAP, the glycolytic activity of CAP survivor lung areas with volumes similar to the areas in 28 matched historical control subjects without pneumonia.ResultsOverall, 68% of CAP survivors (95% CI, 45%-85%) had distinct residual areas of increased 18FDG uptake in their post-CAP studies. tPGA decreased from 821.5 (SD, 1,140.2) in the acute CAP period to 80.0 (SD, 81.4) in the post-CAP period (P = .006). The tPGA post-CAP was significantly higher than that in lung areas of similar volume in control subjects (80.0 [SD, 81.4] vs –19.4 [SD, 5.9]; P < .001).InterpretationAn important proportion of CAP survivors have persistent pulmonary foci of increased inflammatory activity beyond resolution of their infection. As inflammation contributes to cardiovascular disease, cognitive decline, functional waning, and mortality risk in the general population, this finding provides a plausible mechanism for the increased morbidity and mortality that have been observed post-CAP. Survivors of community-acquired pneumonia (CAP) are at increased risk of cardiovascular disease, cognitive and functional decline, and death, but the mechanisms remain unknown. Do CAP survivors have evidence of increased inflammatory activity in their lung parenchyma on 2-deoxy-2-[18F]fluoro-d-glucose (18FDG)-PET/CT imaging after clinical resolution of infection? We obtained 18FDG-PET/CT scans from 22 CAP survivors during their hospitalization with pneumonia (acute CAP) and 30 to 45 days after hospital discharge (post-CAP). In each set of scans, we assessed the lungs for foci of increased 18FDG uptake by visual interpretation and by total pulmonary glycolytic activity (tPGA), a background-corrected measure of total metabolic activity (as measured by 18FDG uptake). We also measured, post-CAP, the glycolytic activity of CAP survivor lung areas with volumes similar to the areas in 28 matched historical control subjects without pneumonia. Overall, 68% of CAP survivors (95% CI, 45%-85%) had distinct residual areas of increased 18FDG uptake in their post-CAP studies. tPGA decreased from 821.5 (SD, 1,140.2) in the acute CAP period to 80.0 (SD, 81.4) in the post-CAP period (P = .006). The tPGA post-CAP was significantly higher than that in lung areas of similar volume in control subjects (80.0 [SD, 81.4] vs –19.4 [SD, 5.9]; P < .001). An important proportion of CAP survivors have persistent pulmonary foci of increased inflammatory activity beyond resolution of their infection. As inflammation contributes to cardiovascular disease, cognitive decline, functional waning, and mortality risk in the general population, this finding provides a plausible mechanism for the increased morbidity and mortality that have been observed post-CAP. Survivors of community-acquired pneumonia (CAP) remain at increased risk of cardiovascular disease, cognitive decline, functional waning, and death for months after clinical resolution of their infection, but the mechanisms for this increased morbidity and mortality post-CAP are unknown.1Mortensen E.M. Kapoor W.N. Chang C.C. Fine M.J. Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia.Clin Infect Dis. 2003; 37: 1617-1624Crossref PubMed Scopus (136) Google Scholar, 2Davydow D.S. Hough C.L. Levine D.A. Langa K.M. Iwashyna T.J. Functional disability, cognitive impairment, and depression after hospitalization for pneumonia.Am J Med. 2013; 126: 615-624.e5Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 3Corrales-Medina V.F. Alvarez K.N. Weissfeld L.A. et al.Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease.JAMA. 2015; 313: 264-274Crossref PubMed Scopus (280) Google Scholar, 4Corrales-Medina V.F. Taljaard M. Yende S. et al.Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults.Am Heart J. 2015; 170: 306-312Crossref PubMed Scopus (38) Google Scholar, 5Shah F.A. Pike F. Alvarez K. et al.Bidirectional relationship between cognitive function and pneumonia.Am J Respir Crit Care Med. 2013; 188: 586-592Crossref PubMed Scopus (113) Google Scholar In the general population, increased inflammatory activity has been implicated in the progression of all these outcomes (cardiovascular disease, cognitive and functional decline, and death).6Jenny N.S. French B. Arnold A.M. et al.Long-term assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars.J Gerontol A Biol Sci Med Sci. 2012; 67: 970-976Crossref PubMed Scopus (89) Google Scholar Therefore, lingering increased inflammatory activity beyond clinical resolution of CAP has been proposed as a plausible mechanism for the heightened morbidity and mortality that follow this infection.7Yende S. D'Angelo G. Kellum J.A. et al.Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis.Am J Respir Crit Care Med. 2008; 177: 1242-1247Crossref PubMed Scopus (295) Google Scholar However, an objective source for enduring increased inflammatory activity post-CAP has never been demonstrated. Radiographic lung infiltrates that can persist for weeks and, in some cases, months after resolution of pneumonia in a significant proportion of CAP survivors are well described, but the biological significance of this observation is unknown.8Jay S.J. Johanson Jr., W.G. Pierce A.K. The radiographic resolution of Streptococcus pneumoniae pneumonia.N Engl J Med. 1975; 293: 798-801Crossref PubMed Scopus (101) Google Scholar, 9Bruns A.H. Oosterheert J.J. Prokop M. Lammers J.W. Hak E. Hoepelman A.I. Patterns of resolution of chest radiograph abnormalities in adults hospitalized with severe community-acquired pneumonia.Clin Infect Dis. 2007; 45: 983-991Crossref PubMed Scopus (48) Google Scholar, 10El Solh A.A. Aquilina A.T. Gunen H. Ramadan F. Radiographic resolution of community-acquired bacterial pneumonia in the elderly.J Am Geriatr Soc. 2004; 52: 224-229Crossref PubMed Scopus (56) Google Scholar In this study, we used PET/CT imaging with 2-deoxy-2-[18F]fluoro-d-glucose (18FDG-PET/CT) to investigate whether CAP survivors have persistent foci of increased inflammatory activity in their lung parenchyma after their infection has clinically resolved. This study was approved by the Ottawa Health Science Network Research Ethics Board (reference 20130822-01H), and all participants provided written informed consent. We enrolled consecutive ambulatory community-dwelling adults ≥ 65 years of age admitted to the Ottawa Hospital (ON, Canada) between August 2015 and January 2018 who had (1) no hospitalizations in the previous 14 days; (2) at least one respiratory symptom consistent with pneumonia (new or worsening cough, new or worsening dyspnea, new or worsening sputum production, change in the quality of baseline sputum production, or chest pain made worse with inspiration) of ≤ 2 weeks in duration (to avoid inclusion of more chronic forms of pneumonia); (3) a chest radiograph with a new infiltrate consistent with pneumonia; and (4) a serum C-reactive protein (CRP) ≥ 15 mg/L (drawn in the first 72 h of hospitalization). The latter criterion was aimed at minimizing the inclusion of patients whose clinical presentation was not secondary to an acute infectious process (ie, COPD exacerbation or heart failure).11Bafadhel M. Clark T.W. Reid C. et al.Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD.Chest. 2011; 139: 1410-1418Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 12Justo D. Lachmi S. Saar N. et al.C-reactive protein velocity following antibiotics in patients with chronic obstructive pulmonary disease exacerbation and community acquired pneumonia.Eur J Intern Med. 2009; 20: 518-521Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 13Bobylev A. Rachina S. Avdeev S. Mladov V. Diagnosis on community-acquired pneumonia (CAP) in patients with congestive heart failure (CHF).Eur Respir J. 2017; 50: PA4521Google Scholar, 14Pereira J. Ribeiro A. Ferreira-Coimbra J. et al.Is there a C-reactive protein value beyond which one should consider infection as the cause of acute heart failure?.BMC Cardiovasc Disord. 2018; 18: 40Crossref PubMed Scopus (3) Google Scholar In addition, we excluded patients who (1) had a baseline (pre-CAP) functional status that would make it difficult for them to return for follow-up examinations after hospital discharge; (2) showed no clinical improvement after 48 h of CAP guideline-concordant antibiotic therapy15Mandell L.A. Wunderink R.G. Anzueto A. et al.Infectious Diseases Society of America; American Thoracic SocietyInfectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.Clin Infect Dis. 2007; 44: S27-S72Crossref PubMed Scopus (4458) Google Scholar; or (3) had any known immunodeficiency or active malignancy. The latter two criteria were aimed at minimizing the enrollment of patients at high risk of not surviving the acute CAP episode. We selected patients ≥ 65 years of age because this is the age group with the highest burden of CAP16Heo J.Y. Song J.Y. Disease burden and etiologic distribution of community-acquired pneumonia in adults: evolving epidemiology in the era of pneumococcal conjugate vaccines.Infect Chemother. 2018; 50: 287-300Crossref PubMed Scopus (8) Google Scholar, 17File Jr., T.M. Marrie T.J. Burden of community-acquired pneumonia in North American adults.Postgrad Med. 2010; 122: 130-141Crossref PubMed Scopus (326) Google Scholar, 18Fry A.M. Shay D.K. Holman R.C. Curns A.T. Anderson L.J. Trends in hospitalizations for pneumonia among persons aged 65 years or older in the United States, 1988-2002.JAMA. 2005; 294: 2712-2719Crossref PubMed Scopus (335) Google Scholar and its postinfection complications (increased risk of cardiovascular disease, cognitive decline, functional waning, and death, among others).1Mortensen E.M. Kapoor W.N. Chang C.C. Fine M.J. Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia.Clin Infect Dis. 2003; 37: 1617-1624Crossref PubMed Scopus (136) Google Scholar, 2Davydow D.S. Hough C.L. Levine D.A. Langa K.M. Iwashyna T.J. Functional disability, cognitive impairment, and depression after hospitalization for pneumonia.Am J Med. 2013; 126: 615-624.e5Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 3Corrales-Medina V.F. Alvarez K.N. Weissfeld L.A. et al.Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease.JAMA. 2015; 313: 264-274Crossref PubMed Scopus (280) Google Scholar, 4Corrales-Medina V.F. Taljaard M. Yende S. et al.Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults.Am Heart J. 2015; 170: 306-312Crossref PubMed Scopus (38) Google Scholar, 5Shah F.A. Pike F. Alvarez K. et al.Bidirectional relationship between cognitive function and pneumonia.Am J Respir Crit Care Med. 2013; 188: 586-592Crossref PubMed Scopus (113) Google Scholar Thus, any demonstration of persistent lung inflammation after CAP would have the highest clinical implications in this age group. Patients also had to be stable enough to be transported to the 18FDG-PET/CT suite safely and endure the technical requirements of this test. As a result, patients who were hemodynamically unstable, requiring vasopressors, or needing high O2 supplements or mechanical ventilation were not included. We performed serial 18FDG-PET/CT imaging with a Discovery 690 scanner (GE Healthcare) 48 to 96 h after participants' hospitalization ("acute-CAP" studies) and 30 to 45 days after their hospital discharge ("post-CAP" studies). 18FDG-PET/CT was used for the measurement of inflammation in the current study. In the absence of other causes of increased metabolic activity including benign and malignant lesions or an active infectious process, uptake of 18FDG (a radiolabeled glucose analog) in lungs reflects increased inflammatory activity because of the higher metabolic rate of inflammatory cells compared with vascular and parenchymal cells.8Jay S.J. Johanson Jr., W.G. Pierce A.K. The radiographic resolution of Streptococcus pneumoniae pneumonia.N Engl J Med. 1975; 293: 798-801Crossref PubMed Scopus (101) Google Scholar PET/CT studies were analyzed by level 3-qualified experts. A first assessment included the visual characterization of patterns of 18FDG uptake in the lung parenchyma of CAP survivors from the acute- to post-CAP states (ie, resolution, improvement but still with distinct areas of increased 18FDG uptake, and overall unchanged or worsening). A background-corrected measure of total metabolic activity (similar to the total lesion glycolysis used in patients with cancer), the total pulmonary glycolytic activity (tPGA), was calculated in 18FDG-PET/CT studies.19Larson S.M. Erdi Y. Akhurst T. et al.Tumor treatment response based on visual and quantitative changes in global tumor glycolysis using PET-FDG imaging: the visual response score and the change in total lesion glycolysis.Clin Positron Imaging. 1999; 2: 159-171Crossref PubMed Scopus (484) Google Scholar,20Mayerhoefer M.E. Staudenherz A. Kiesewetter B. et al.Pre-therapeutic total lesion glycolysis on [18F]FDG-PET enables prognostication of 2-year progression-free survival in MALT lymphoma patients treated with CD20-antibody-based immunotherapy.Mol Imaging Biol. 2019; 21: 1192-1199Crossref PubMed Scopus (5) Google Scholar A case of CAP of the right middle lung lobe in shown in Figure 1. In short, we used the semiautomated program Hybrid Viewer (Hermes Medical Solutions) to define, from the coregistered images of the PET and CT scans, the entire three-dimensional volume of each lung (right and left). Each lung volume was then divided, when appropriate, into two separate subvolumes: (1) the distinct areas of increased 18FDG uptake that corresponded with lung infiltrates on CT imaging (VOLPNA), and (2) the complementary lung with otherwise unremarkable (ie, "background") 18FDG uptake (VOLBKG). The mean 18FDG standardized uptake value (SUV) was measured in each subvolume (SUVPNA and SUVBKG). The pneumonia glycolytic activity (PGA) of each lung was then estimated as follows: PGA = VOLPNA × (SUVPNA – SUVBKG). Depending on whether there were areas of pneumonia in only one or both lungs, the tPGA for each 18FDG-PET/CT study was estimated by adding the PGAs of each lung (right and left) in the said study. Post-CAP 18FDG-PET/CT studies in which no apparent distinct area of increased 18FDG uptake was identified were arbitrarily assigned a volume of 0 and, accordingly, also a tPGA value of 0. We prospectively calculated the Pneumonia Severity Index (PSI) score for each patient at the time of their hospital presentation.21Fine M.J. Auble T.E. Yealy D.M. et al.A prediction rule to identify low-risk patients with community-acquired pneumonia.N Engl J Med. 1997; 336: 243-250Crossref PubMed Scopus (3604) Google Scholar We measured CRP serum levels within the first 72 h of hospitalization (24-48 h before the first 18FDG-PET/CT study) and on the same day of the post-CAP 18FDG-PET/CT studies. We also identified historical control subjects matched to patients with CAP by age and sex. These control subjects had clinically indicated 18FDG-PET/CT studies for evaluation of possible malignancy but benign final diagnoses. On the basis of the average VOLPNA volumes from the post-CAP patient studies, spheres one-half this volume were drawn at random central locations in both lungs of each historical control. These spheres were treated the same way as the "pneumonia" areas in CAP survivors, and their glycolytic activity was computed using the same method as described above. We did this to estimate the expected glycolytic activity of lung areas with volumes similar to the areas with increased 18FDG uptake in the post-CAP studies of participants with CAP, but in patients who do not have history of this infection. About two-thirds of elderly CAP survivors exhibit persistent pneumonia-associated radiographic infiltrates after CAP clinical resolution.10El Solh A.A. Aquilina A.T. Gunen H. Ramadan F. Radiographic resolution of community-acquired bacterial pneumonia in the elderly.J Am Geriatr Soc. 2004; 52: 224-229Crossref PubMed Scopus (56) Google Scholar 18FDG-PET/CT is a more sensitive technique for lung parenchymal abnormalities than radiographs. Our study was powered to detect a 65% prevalence of persistent inflammatory foci in lung parenchyma of elderly CAP survivors with a margin of error of 20% and a confidence level of 95%. Using descriptive, χ2, and t-test (paired and independent sample) statistics, as appropriate, we compared baseline characteristics of patients with CAP vs control subjects, and the tPGA and CRP serum levels of patients with CAP in the acute-CAP vs post-CAP states. For comparisons between the post-CAP tPGA of patients with CAP vs the lung volume-matched glycolytic activity of control subjects, we used simple linear regression with the post-CAP tPGA values (for patients with CAP) or the lung volume-matched glycolytic activity values (for control subjects) as the outcome, pneumonia vs control as the exposure, and any baseline characteristic that differed between groups (with a P significance level of < .2) as covariate(s). We also explored correlations between CRP and PSI values with tPGA, using the Pearson coefficient of correlation. κ statistics was used to measure the concordance between tPGA values and visual interpretation of scans. A two-tailed P value < .05 was considered statistically significant. Statistical analyses were performed with the Matlab statistics and machine learning toolbox (Matlab 2016b; MathWorks). A flow diagram of the recruitment process in our study is presented in e-Figure 1. We initially enrolled 28 patients in the acute phase of CAP. However, six declined to return for their post-CAP examinations and were subsequently excluded. As a result, 22 patients with completed acute- and post-CAP examinations are included in this report. We also identified 28 matched historical control subjects. The baseline clinical characteristics of the participants with pneumonia and control subjects are presented in Table 1.Table 1Clinical Characteristics of Patients With Community-Acquired Pneumonia and Control SubjectsBaseline CharacteristicPatients With CAP (n = 22)Control Subjects (n = 22)P ValueAge, mean ± SD, y79 ± 977 ± 8.552Sex (male), No. (%)11 (50)15 (54).802History of: Heart failure, No. (%)7 (32)1 (4).023 Coronary artery disease, No. (%)6 (27)7 (25).856 Stroke, No. (%)0 (0)6 (21).028 Hypertension, No. (%)7 (32)16 (57).074 Dyslipidemia, No. (%)9 (41)17 (61).164 Smoking, No. (%)8 (36)7 (25).384 COPD, No. (%)8 (36)8 (29).558 Diabetes, No. (%)6 (27)4 (14).254 End-stage renal disease, No. (%)0 (0)0 (0)NAPSI score, mean ± SD97 ± 26NANALength of hospital stay, mean ± SD, d4 ± 1NANACAP = community-acquired pneumonia; NA = not applicable; PSI = Pneumonia Severity Index. Open table in a new tab CAP = community-acquired pneumonia; NA = not applicable; PSI = Pneumonia Severity Index. Representative patterns of 18FDG uptake in lung parenchyma from the acute-CAP to the post-CAP studies are presented in Figure 2. Overall, 15 CAP survivors (68.2%; 95% CI, 45.1%-85.2%) still showed distinct areas of increased 18FDG uptake (improved, unchanged, or worsened from previous) in their post-CAP studies. Strong agreement (κ = 0.80) was found between the expert reader's visual interpretation of direction and magnitude of change in FDG uptake from acute to postpneumonia scans and the difference in tPGA values between the two scans. The progression of tPGA from the acute-CAP to post-CAP period in each patient with CAP is depicted in e-Figure 2. tPGA decreased significantly from 821.5 (SD, 1,140.2) to 80.0 (SD, 81.4) in the acute- and post-CAP periods, respectively (P = .006). However, post-CAP tPGA values in CAP survivors were still significantly higher than zero (P < .001), and also higher than glycolytic activity values of volume-matched lung areas in control subjects (80.0 [SD, 81.4] vs –19.4 [SD, 5.9]; adjusted P < .001) (Fig 3). PSI score values did not correlate with acute- or post-CAP tPGA values (r2, 0.007 [P = .701] and r2, 0.002 [P = .817], respectively). Serum CRP values decreased significantly from the acute-CAP to the post-CAP period (112.5 [SD, 60.2] mg/L vs 7.8 [SD, 12.3] mg/L, respectively; P < .001). Acute-CAP CRP levels correlated directly with acute-CAP tPGA values (r2, 0.34; P = .002) but not with post-CAP tPGA values (r2, 0.0009; P = .893). Post-CAP CRP values did not correlate with acute- or post-CAP tPGA values (r2, 0.003; P = .800; and r2, 0.0002; P = .940, respectively). The difference in CRP levels between acute-CAP and post-CAP values correlated with the difference in tPGA between acute-CAP and post-CAP values (r2, 0.39; P = .002). To the best of our knowledge, this is the first series of CAP survivors investigated by 18FDG-PET/CT imaging. Herein, we demonstrate that a significant proportion of CAP survivors (68.2% in our study) continue having distinct foci of increased inflammatory activity in their lung parenchyma for several weeks after the clinical resolution of their infection. Although persistent radiographic lung parenchymal infiltrates after clinical resolution of pneumonia are well described among CAP survivors,8Jay S.J. Johanson Jr., W.G. Pierce A.K. The radiographic resolution of Streptococcus pneumoniae pneumonia.N Engl J Med. 1975; 293: 798-801Crossref PubMed Scopus (101) Google Scholar,9Bruns A.H. Oosterheert J.J. Prokop M. Lammers J.W. Hak E. Hoepelman A.I. Patterns of resolution of chest radiograph abnormalities in adults hospitalized with severe community-acquired pneumonia.Clin Infect Dis. 2007; 45: 983-991Crossref PubMed Scopus (48) Google Scholar we are not aware of any previous report (in humans or otherwise) documenting residual biologically active parenchymal abnormalities in the lungs of such patients. Increased uptake of 18FDG (a glucose analog) denotes increased cellular metabolic activity. In tissues of mostly uniform cellular metabolic activity with no meaningful glucose storage capacity, such as the lung parenchyma,22Young S.L. Tierney D.F. Metabolic activity of the lung.Int Anesthesiol Clin. 1977; 15: 1-17Crossref PubMed Scopus (2) Google Scholar focal increased 18FDG uptake in PET images reflects malignancy or infectious/inflammatory activity.23Vaidyanathan S. Patel C.N. Scarsbrook A.F. Chowdhury F.U. FDG PET/CT in infection and inflammation: current and emerging clinical applications.Clin Radiol. 2015; 70: 787-800Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar In our population of CAP survivors, their initial syndromic presentation consistent with pneumonia, their acutely elevated CRP levels, their clinical response to pneumonia-directed therapy, and the dynamic change in 18FDG uptake over time make it all but certain that the residual areas of focal increased 18FDG uptake seen in their lung parenchyma in the post-CAP studies represent residual foci of inflammatory activity related to the (by then treated) index infection. However, the clinical significance of this finding and the nature of the local inflammatory cells and humoral mediators that contribute to this residual inflammation remain unknown. Our estimation of tPGA is similar to the estimation of total lesion glycolysis for lung cancer lesions.19Larson S.M. Erdi Y. Akhurst T. et al.Tumor treatment response based on visual and quantitative changes in global tumor glycolysis using PET-FDG imaging: the visual response score and the change in total lesion glycolysis.Clin Positron Imaging. 1999; 2: 159-171Crossref PubMed Scopus (484) Google Scholar,20Mayerhoefer M.E. Staudenherz A. Kiesewetter B. et al.Pre-therapeutic total lesion glycolysis on [18F]FDG-PET enables prognostication of 2-year progression-free survival in MALT lymphoma patients treated with CD20-antibody-based immunotherapy.Mol Imaging Biol. 2019; 21: 1192-1199Crossref PubMed Scopus (5) Google Scholar In our study, tPGA is a background-corrected measure of the total metabolic activity (as measured by 18FDG uptake) of lung areas seemingly affected by pneumonia. tPGA allowed us to estimate not only the magnitude of decrease in metabolic activity associated with—presumed—pneumonia lesions from the acute-CAP to the post-CAP periods but also the magnitude of the residual increased pneumonia-associated metabolic activity in affected lung areas in CAP survivors relative to volume-matched lung areas in control subjects without recent pneumonia (about 4-fold higher in our study). At present, however, we can make no inference about the clinical significance of these differences. The lack of association between PSI and tPGA (both at the acute-CAP and post-CAP periods) is not unexpected. While tPGA is an approximation of the total metabolic activity associated with discrete pneumonia lesions, PSI is a validated 20-item (three demographic criteria, five preexisting comorbidities, five physical examination findings, and seven selected laboratory and radiographic findings) score built to predict 30-day mortality of patients presenting with CAP to an ED.21Fine M.J. Auble T.E. Yealy D.M. et al.A prediction rule to identify low-risk patients with community-acquired pneumonia.N Engl J Med. 1997; 336: 243-250Crossref PubMed Scopus (3604) Google Scholar Thus, any putative association of tPGA with clinical outcomes (short or longer term) will require confirmation with dedicated investigations. Serum CRP is an acute-phase reactant that is widely used as unspecific marker of inflammation.24Gabay C. Kushner I. Acute-phase proteins and other systemic responses to inflammation.N Engl J Med. 1999; 340: 448-454Crossref PubMed Scopus (4762) Google Scholar Serum CRP elevations have been broadly associated with the activity of infections and inflammatory rheumatologic conditions.25Ticinesi A. Lauretani F. Nouvenne A. et al.C-reactive protein (CRP) measurement in geriatric patients hospitalized for acute infection.Eur J Intern Med. 2017; 37: 7-12Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar,26Rhodes B. Furnrohr B.G. Vyse T.J. C-reactive protein in rheumatology: biology and genetics.Nat Rev Rheumatol. 2011; 7: 282-289Crossref PubMed Scopus (113) Google Scholar In response to an acute inflammatory insult, CRP levels peak in the early phase of the inflammatory response.24Gabay C. Kushner I. Acute-phase proteins and other systemic responses to inflammation.N Engl J Med. 1999; 340: 448-454Crossref PubMed Scopus (4762) Google Scholar Predictably, serum CRP values correlated with tPGA at the acute-CAP period. However, at the post-CAP period, no such association was demonstrated. Inflammation is one of the most dynamic and multifaceted biological processes with a variety of triggers, cellular and humoral actors, and regulatory pathways.24Gabay C. Kushner I. Acute-phase proteins and other systemic responses to inflammation.N Engl J Med. 1999; 340: 448-454Crossref PubMed Scopus (4762) Google Scholar,27Netea M.G. Balkwill F. Chonchol M. et al.A guiding map for inflammation.Nat Immunol. 2017; 18: 826-831Crossref PubMed Scopus (225) Google Scholar CRP, therefore, may not be a suitable biomarker for the postinfection inflammatory activity in lung parenchyma demonstrated our study and dedicated investigations will be needed to identify more accurate biomarkers of this occurrence. Such investigations, along with the development of animal models of this observation should assist in the elucidation of the biological processes governing this phenomenon. Radiographic lung infiltrates that outlive the clinical resolution of CAP have been well described.8Jay S.J. Johanson Jr., W.G. Pierce A.K. The radiographic resolution of Streptococcus pneumoniae pneumonia.N Engl J Med. 1975; 293: 798-801Crossref PubMed Scopus (101) Google Scholar,9Bruns A.H. Oosterheert J.J. Prokop M. Lammers J.W. Hak E. Hoepelman A.I. Patterns of resolution of chest radiograph abnormalities in adults hospitalized with severe community-acquired pneumonia.Clin Infect Dis. 2007; 45: 983-991Crossref PubMed Scopus (48) Google Scholar It intuitively follows that such residual radiographic abnormalities post-CAP should correspond to the areas of persistent inflammatory activity demonstrated in our study. However, the validity and strength of such association will also need to be tested in dedicated studies. Inflammatory activity is associated with the progression of cardiovascular disease, cognitive and functional decline, and mortality risk in the general population.6Jenny N.S. French B. Arnold A.M. et al.Long-term assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars.J Gerontol A Biol Sci Med Sci. 2012; 67: 970-976Crossref PubMed Scopus (89) Google Scholar The risk of these outcomes also increases after CAP and remains elevated for months after resolution of the infection.1Mortensen E.M. Kapoor W.N. Chang C.C. Fine M.J. Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia.Clin Infect Dis. 2003; 37: 1617-1624Crossref PubMed Scopus (136) Google Scholar, 2Davydow D.S. Hough C.L. Levine D.A. Langa K.M. Iwashyna T.J. Functional disability, cognitive impairment, and depression after hospitalization for pneumonia.Am J Med. 2013; 126: 615-624.e5Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 3Corrales-Medina V.F. Alvarez K.N. Weissfeld L.A. et al.Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease.JAMA. 2015; 313: 264-274Crossref PubMed Scopus (280) Google Scholar, 4Corrales-Medina V.F. Taljaard M. Yende S. et al.Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults.Am Heart J. 2015; 170: 306-312Crossref PubMed Scopus (38) Google Scholar, 5Shah F.A. Pike F. Alvarez K. et al.Bidirectional relationship between cognitive function and pneumonia.Am J Respir Crit Care Med. 2013; 188: 586-592Crossref PubMed Scopus (113) Google Scholar Our novel finding of lingering foci of inflammatory activity in the lung parenchyma of CAP survivors provides a plausible mechanism for this increased morbidity and mortality post-CAP and its contribution to this phenomenon needs to be further investigated in experimental and clinical studies.1Mortensen E.M. Kapoor W.N. Chang C.C. Fine M.J. Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia.Clin Infect Dis. 2003; 37: 1617-1624Crossref PubMed Scopus (136) Google Scholar, 2Davydow D.S. Hough C.L. Levine D.A. Langa K.M. Iwashyna T.J. Functional disability, cognitive impairment, and depression after hospitalization for pneumonia.Am J Med. 2013; 126: 615-624.e5Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 3Corrales-Medina V.F. Alvarez K.N. Weissfeld L.A. et al.Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease.JAMA. 2015; 313: 264-274Crossref PubMed Scopus (280) Google Scholar, 4Corrales-Medina V.F. Taljaard M. Yende S. et al.Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults.Am Heart J. 2015; 170: 306-312Crossref PubMed Scopus (38) Google Scholar, 5Shah F.A. Pike F. Alvarez K. et al.Bidirectional relationship between cognitive function and pneumonia.Am J Respir Crit Care Med. 2013; 188: 586-592Crossref PubMed Scopus (113) Google Scholar Such investigations, along with the elucidation of the biological pathways driving post-CAP lung inflammation, could then inform therapeutic interventions targeting this phenomenon to improve post-CAP outcomes. This is especially relevant to post-CAP cardiovascular risk because directed antiinflammatory interventions have already proven beneficial in other (non-CAP) high-cardiovascular-risk groups.28Ridker P.M. Everett B.M. Thuren T. et al.Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. 2017; 377: 1119-1131Crossref PubMed Scopus (3525) Google Scholar,29Tardif J.C. Kouz S. Waters D.D. et al.Efficacy and safety of low-dose colchicine after myocardial infarction.N Engl J Med. 2019; 381: 2497-2505Crossref PubMed Scopus (694) Google Scholar Our study is limited by its relatively small sample size. In addition, we were unable to determine the full duration of increased lung FDG uptake, as we did not perform further 18F-FDG beyond the 4 to 6 weeks post-CAP. Because of our sample size, we could not explore associations with incident adverse clinical events known to be associated with CAP in the medium and long term.1Mortensen E.M. Kapoor W.N. Chang C.C. Fine M.J. Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia.Clin Infect Dis. 2003; 37: 1617-1624Crossref PubMed Scopus (136) Google Scholar, 2Davydow D.S. Hough C.L. Levine D.A. Langa K.M. Iwashyna T.J. Functional disability, cognitive impairment, and depression after hospitalization for pneumonia.Am J Med. 2013; 126: 615-624.e5Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 3Corrales-Medina V.F. Alvarez K.N. Weissfeld L.A. et al.Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease.JAMA. 2015; 313: 264-274Crossref PubMed Scopus (280) Google Scholar, 4Corrales-Medina V.F. Taljaard M. Yende S. et al.Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults.Am Heart J. 2015; 170: 306-312Crossref PubMed Scopus (38) Google Scholar, 5Shah F.A. Pike F. Alvarez K. et al.Bidirectional relationship between cognitive function and pneumonia.Am J Respir Crit Care Med. 2013; 188: 586-592Crossref PubMed Scopus (113) Google Scholar We enrolled only patients aged > 65 years who were clinically stable enough to endure the technical requirements for the performance of a 18FDG-PET/CT scan in the acute phase of CAP, and had a baseline (pre-CAP) functional level that would make it likely for them to return for their convalescent examinations. Therefore, it is unknown whether our observations apply to younger age groups, individuals with worse systemic compromise from CAP or worse baseline functional status. We used the PSI as a surrogate for severity of CAP, as previously reported.21Fine M.J. Auble T.E. Yealy D.M. et al.A prediction rule to identify low-risk patients with community-acquired pneumonia.N Engl J Med. 1997; 336: 243-250Crossref PubMed Scopus (3604) Google Scholar However, PSI is highly age dependent, and it has been suggested that other tools such as the IDSA/ATS criteria for severe CAP are better measures of disease severity.30Metlay J.P. Waterer G.W. Long A.C. 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. 2019; 200: e45-e67Crossref PubMed Scopus (842) Google Scholar Unfortunately, we did not evaluate those other tools. As the serum CRP measurements used for inclusion in our study (ie, CRP ≥ 15 mg/L) were not drawn at the time of patients' presentation to hospital but within 72 h of hospital admission, it is possible that we selected for patients prone to more prolonged inflammatory responses (as opposed to patients with a tendency to resolve their acute inflammatory responses quickly). Finally, although we assessed associations between lung FDG uptake and CRP, we did not evaluate other more specific inflammatory pathways that could be linked to persistent lung inflammation after CAP. In conclusion, an important proportion of CAP survivors demonstrate persistently increased inflammatory activity in their lung parenchyma well beyond clinical resolution of their infection. This novel finding provides a plausible mechanism that might contribute to the adverse morbidity and mortality that follow CAP.Take-home PointsStudy Question: Do community-acquired pneumonia (CAP) survivors have evidence of increased inflammatory activity in their lung parenchyma on 2-deoxy-2-[18F]fluoro-d-glucose (18FDG)-PET/CT imaging after clinical resolution of infection?Results: In this study of 22 CAP survivors and 28 control subjects, 68% of CAP survivors had distinct residual areas of increased 18FDG uptake in their post-CAP scans. Furthermore, the post-CAP scans of the pneumonia survivors showed significantly higher inflammatory activity compared with control subjects.Interpretation: Persistent pulmonary foci of increased inflammatory activity beyond clinical resolution of the infection may provide a plausible mechanism for the increased morbidity and mortality observed post-CAP. Study Question: Do community-acquired pneumonia (CAP) survivors have evidence of increased inflammatory activity in their lung parenchyma on 2-deoxy-2-[18F]fluoro-d-glucose (18FDG)-PET/CT imaging after clinical resolution of infection? Results: In this study of 22 CAP survivors and 28 control subjects, 68% of CAP survivors had distinct residual areas of increased 18FDG uptake in their post-CAP scans. Furthermore, the post-CAP scans of the pneumonia survivors showed significantly higher inflammatory activity compared with control subjects. Interpretation: Persistent pulmonary foci of increased inflammatory activity beyond clinical resolution of the infection may provide a plausible mechanism for the increased morbidity and mortality observed post-CAP. Author contributions: V. F. C.-M. and G. D. led the project and are responsible for all content in the manuscript. All of the authors approved the analysis plan. R. A. DeK., W. Z., and J. W. performed the analyses. V. F. C.-M. and G. D. drafted the manuscript. All of the authors contributed to interpretation of the Results and revision of the manuscript for important intellectual content, and approved its submission. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: J. A. C. has consulted for Sanifit, Bayer, Bristol-Myers Squibb, OPKO Healthcare, Ironwood, Akros Pharma, Merck, Pfizer, Edwards Lifesciences, Microsoft, and Fukuda-Denshi. J. A. C. received research grants from the National Institutes of Health , the American College of Radiology Network, Fukuda-Denshi, Bristol-Myers Squibb, and Microsoft. R. A. deK. reports grants, consulting fees, and license revenues from Jubilant DraxImage and the University of Ottawa Heart Institute Foundation (UOHI), outside the submitted work. R. S. B. reports grants and honoraria from Lantheus Medical Imaging, grants and honoraria from Jubilant DraxImage, and grants from GE Healthcare , outside the submitted work. R. S. B. B. is a Career Investigator supported but the Heart and Stroke Foundation of Ontario and a Tier 1 Research Chair supported by the University of Ottawa . J. A. C. is supported by the National Institutes of Health [NIH grants R01-HL121510-01A1 , R61-HL146390 , R01-AG058969 , 1R01HL104106 , P01HL094307 , and R56 HL136730 ]. G. D. was supported by a CIHR new investigator salary support award while at UOHI. At present, G. D. is Wesfarmers Chair in Cardiology at the University of Western Australia with an adjunct professor appointment at UOHI. This study was performed at UOHI. G. D. reports three paid lectures from AstraZeneca, Pfizer, and Amgen not related to the topic in this manuscript. G. D. provides consultancy services to Artrya Pty Ltd. None declared (V. F. C.-M., W. Z., J. W.). Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. 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