Can Clinical Findings at Admission Allow Withholding of Antibiotics in Patients Hospitalized for Community Acquired Pneumonia when a Test for a Respiratory Virus is Positive?

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Ryan Ward, Alejandro J. Gonzalez, Justin A. Kahla, Daniel M. Musher This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4618989/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Jan, 2025 Read the published version in Pneumonia → Version 1 posted 13 You are reading this latest preprint version Abstract Background. Current guidelines recommend empiric antibiotic therapy for patients who require hospitalization for community-acquired pneumonia (CAP). We sought to determine whether clinical, imaging or laboratory features in patients hospitalized for CAP in whom PCR is positive for a respiratory virus enabled exclusion of bacterial coinfection so that antibiotics could be withheld. Methods. For this prospective study, we selected patients in whom an etiologic diagnosis was likely to be reached, namely those who provided a high-quality sputum sample at or shortly after admission, and in whom PCR was done to test for a respiratory virus. We performed quantitative bacteriologic studies on sputum to determine the presence of bacterial infection or coinfection and reviewed all clinical, imaging and laboratory studies. Results. Of 122 patients, 77 (63.1%) had bacterial infection, 16 (13.1%) viral infection, and 29 (23.8%) bacterial/viral coinfection. Although upper respiratory symptoms were more common in patients with viral pneumonia, and white blood cell (WBC) counts were higher in patients with bacterial pneumonia, no clinical, laboratory or imaging findings allowed exclusion of bacterial coinfection in patients who tested positive for a respiratory virus. A greater proportion of patients with bacterial/viral coinfection (30%) were admitted or transferred to the ICU during their hospital course, compared to 17% and 19% of patients with bacterial or viral infection, respectively (p<.05). Conclusions. If a test for a respiratory virus test is positive in a patient hospitalized for CAP, no sufficiently differentiating features exclude bacterial coinfection, thereby supporting the recommendation that empiric antibiotics be administered to all patients who are sufficiently ill to require hospitalization for CAP. community acquired pneumonia viral pneumonia bacterial pneumonia bacterial-viral coinfection Figures Figure 1 BACKGROUND Community-acquired pneumonia (CAP) may result from infection by recognized bacterial pathogens, bacteria that have traditionally been regarded as commensal bacteria but have recently been shown to cause pneumonia, respiratory viruses, or bacterial/viral coinfection [ 1 – 5 ]. Empiric antibacterial therapy is recommended for most patients hospitalized for CAP [ 6 ], as it is difficult to identify the underlying cause of infection; even the most exhaustive prospective studies utilizing conventional microbial techniques generally fail to identify an etiologic agent in > 50% of cases [ 1 , 2 ]. The principal reason for this failure is that, except in the small proportion of patients who have positive blood cultures, diagnosis of bacterial infection requires a vald sputum sample for Gram stain, culture and/or molecular analysis [ 7 – 10 ]. At the time of hospitalization for CAP, a substantial proportion of patients are unable to provide a valid sputum sample, and timely administration of empiric antibiotics rapidly eradicates infecting bacteria from sputum [ 11 ]. Polymerase chain reaction (PCR) is increasingly available to identify the presence of a respiratory virus, and results may be positive within a few hours of presentation to hospital. This availability together with increasing concern about potential harm by antibiotics [ 12 ], suggests that some patients hospitalized for pneumonia, namely those who test positive for a respiratory virus should not receive antibiotic therapy. The problems of withholding antibiotics in patients with CAP with a PCR that identifies a respiratory virus are that: (1) bacterial coinfection is common in viral pneumonia; and (2) exclusion of a bacterial etiology requires a high-quality sputum specimen. Numerous reports show that about one-third of patients hospitalized with viral pneumonia have bacterial coinfection [ 4 , 13 – 16 ]. Now that commensal flora have been found to cause CAP [ 3 ], the proportion with bacterial coinfection is probably even greater. And a substantial proportion of patients who are hospitalized for pneumonia are unable to provide a high-quality sputum specimen at admission. Prior studies have varied in their ability to distinguish bacterial infection alone or bacterial/viral coinfection from viral infection alone [ 1 , 5 , 17 , 18 ]. Such a diagnostic distinction could inform the decision to initiate antibiotic therapy in patients with CAP whose PCR is positive for a respiratory virus at the time of diagnosis. While elevated white blood cell (WBC) counts and serum procalcitonin are associated with bacterial infection, the absence of leukocytosis or a high procalcitonin does not preclude a bacterial etiology [ 19 – 21 ]. Similarly, while chest imaging showing multifocal or patchy pneumonia is conventionally associated with viral infection and consolidation with bacterial pneumonia, significant overlap with bacterial pneumonia has been reported [ 22 , 23 ]. The purpose of the present study was to determine whether differences in the clinical presentation of pneumonia due to bacterial infection, viral infection or bacterial/viral coinfection are consistent enough to justify withholding empiric antibiotics in patients admitted for CAP who test positive for a respiratory virus. METHODS Patient Selection We studied a convenience sample of patients admitted to the Michael E. DeBakey VA Medical Center with a diagnosis of CAP between September 1, 2017, and December 31, 2019 (pre-COVID). Detailed methods were previously described [ 3 ]. Briefly, on select days, the principal investigator (DMM) examined all Gram-stained sputum samples submitted to the Clinical Microbiology Laboratory in the preceding 24 hours. For all high-quality specimens (defined as showing > 25WBC/epithelial cell), the electronic medical record was reviewed to identify patients who: (1) were freshly admitted from the community; (2) had a newly recognized pulmonary infiltrate and (3) had ≥ 2 of the following findings: fever, increased cough, sputum production or shortness of breath, rales, confusion or hypoxia. Patients who met the above criteria were included in the present study if they also underwent PCR testing for respiratory viruses on a nasopharyngeal specimen at or soon after admission. The purpose of this selection process was to obtain a series of patients in whom an etiologic diagnosis had the best chance of being made, although inclusion only of patients who provided purulent sputum may cause an inherent selection bias (see Discussion, below). Some of these patients were also included in a prior report on the etiology of CAP [ 3 ]. This research was approved by the Institutional Review Boards of Baylor College of Medicine and the Michael E. DeBakey VA Medical Center. Diagnostic Studies An aliquot of sputum from patients who met inclusion criteria, was drawn into 1 ml micropipetters using pipet tips with the ends cut to enlarge the aperture; detailed methods have been published previously [ 3 ]. Sputum was liquefied with 2% N-acetyl cysteine, and bacteria were quantified by making serial 10-fold dilutions and streaking 10 µL aliquots on blood and chocolate agar. Recognized bacterial pathogens, if present at ≥ 10 5 per ml, and commensal bacteria if present at ≥ 10 6 per ml were identified by standard microbiologic techniques with verification by MALDI-TOF. All patients had nasopharyngeal swabs for PCR to identify respiratory viruses, Mycoplasma pneumoniae and Chlamydophila ia pneumoniae . Blood cultures, urine studies for pneumococcus and Legionella antigens, plasma procalcitonin, and B-natriuretic peptide were collected in > 95% of cases. Chart Review Thorough review of each patient’s admitting electronic medical record including all notes by nurses, emergency room doctors, medical students, residents and attendings was performed, and data were recorded for age, sex, race, ethnicity, smoking and alcohol use, other comorbidities such as chronic obstructive pulmonary disease (COPD), heart disease, immunodeficiency (induced by immunosuppressive drugs, hematologic malignancy, or chronic immunodeficiency such as AIDS), and date of death. Clinical symptoms reported at the time of admission, vital signs, and radiographic findings were also recorded. Symptoms such as rhinorrhea, sneezing, or sinus pressure were collectively listed as upper respiratory infection (URI) symptoms. The pneumonia severity index (PSI) [ 24 ] was calculated for each patient. Determining Etiology Patients whose sputum contained ≥ 10 5 colony-forming units (cfu)/mL of a recognized bacterial pathogen (such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumoninae ) or ≥ 10 6 cfu/mL of commensal bacteria (such as Streptococcus mitis or Corynebacteria spp) were categorized as having bacterial infection; note that criteria for inclusion were more stringent for commensal bacteria, Microscopic examination of Gram-stained sputum, completed before culture results were available, uniformly agreed with findings of quantitative bacteriology [ 3 , 25 ]. Cases in which PCR of a nasopharyngeal swab revealed a respiratory virus were diagnosed with viral infection. Patients who met criteria for bacterial infection were and also had a positive viral PCR were regarded as having bacterial/viral coinfection. These criteria were used to stratify pneumonia into 5 etiologic groups: pneumonia due to (1) recognized bacterial pathogens; (2) respiratory viruses; (3) coinfection by a recognized bacterial pathogen and a respiratory virus; (4) commensal bacteria; and (5) coinfection by commensal bacteria and a respiratory virus. In some analyses, data from Groups 1 and 4 are presented as bacterial infection, Group 2 as viral infection and Groups 3 and 5 as bacterial/viral coinfection. Statistics Fisher’s Exact and Kruskal-Wallis tests were performed for categorical and continuous variables, respectively, and are displayed in Table 1 . Median serum procalcitonin values for each etiologic group were compared using analysis of variance and Tukey tests of significance. Fisher’s Exact and Kruskal-Wallis tests compared data in patients with recognized bacterial pathogens and commensal flora, and in some comparisons, results from these two groups were combined and are presented as ‘bacterial pneumonia.’ RESULTS Patients The mean age was 69, and 117 (95.9%) of the patients were male. Based on self-identification in the medical records, 73 (59.9%) patients were white, 41 (33.6%) were Black, and 8 (6.6%) patients did not have a race documented; 10 (8.2%) patients were of Hispanic ethnicity. The median time to antibiotic administration before a high-quality sputum sample was provided was 0 hr (range 0–12). Eighty (65.6%) patients had received no antibiotics, and an additional 9.0% had received antibiotics for < 2 hours prior to sputum collection. Diagnostic Categories Overall, 77 (63.1%) patients had bacterial infection, 56 with recognized bacterial pathogens and 21 with commensal bacteria. Sixteen (13.1%) had viral infection, and 29 (23.8%) had bacterial and viral coinfection. There were no significant differences in age, race, or ethnicity among these etiologic groups. Past Medical History, Exposures Patients with bacterial infection tended to be more likely to have a smoking history than patients with viral infection or bacterial/viral coinfection (70.1% vs 50.0%, and 51.7%, respectively, p = 0.12). Patients with bacterial infection and bacterial/viral coinfection were significantly more likely to have underlying lung disease than patients with viral infection (58.4% and 48.3%, vs. 25.0%, respectively, (p = 0.05). No differences were observed among groups with regards to alcohol use disorder, immunosuppression, or mean hemoglobin A1c values. There was no difference in the proportion of patients who self-reported recent exposure to sick contacts amongst the three groups (bacterial infection 8%, viral infection 19%, bacterial/viral coinfection 18%, p = 0.18). Symptoms and Subjective Findings Patients with bacterial infection were less likely to report URI symptoms than patients with viral or bacterial/viral coinfection (6.5%, 31.3% and 24.1%, respectively, p = 0.004). Patients with bacterial infection tended to be less likely than those with viral or bacterial/viral coinfection to report subjective fever (29.9% vs 43.8.% or 48.3%) and cough (58.4% vs 75.0% or 75.9%, respectively (differences not significant, p > 0.05). No differences were observed in the proportions of patients reporting shortness of breath (75.3%, 75%, 75.9%, p = 1.0) or sputum production (33.8%, 43.8%, 41.4, p = 0.38) for the three groups, respectively. Objective Findings No significant differences among the three groups were observed in mean body temperature, heart rate, respiratory rate, O2 saturation, or diastolic blood pressure at the time of admission, although patients with bacterial pneumonia had a lower mean systolic blood pressure (122 mmHg) than those with viral infection (134 mmHg) or bacterial/viral coinfection (134 mmHg, p = 0.047). Somewhat surprisingly, patients in these three groups did not differ in their imaging findings, as rates of lobar consolidation, multifocal consolidation, new pleural effusion, and atelectasis were similar. Fifty percent of patients with viral pneumonia had lobar consolidation on chest radiography, and 19.5% of patients with bacterial infection alone had multifocal areas of consolidation. Patients with bacterial infection or bacterial/viral coinfection had significantly higher WBC counts on admission (12,990 WBC/mm 3 , and 12,200 cells/mm 3 ) compared to patients with viral infection (8,560 cells/mm 3 ) (p < 0.005). Median procalcitonin at admission was 0.25, 0.27, and 0.37 ng/mL for patients in these three groups, respectively (p = 0.85) (Fig. 1 ). The proportions of patients whose serum troponin at admission exceeded 0.03 ng/mL were similar, ranging from 31.3–37.9%, p = 0.85). Pneumonia severity index scores were highest for patients with bacterial pneumonia (101.6, 89.9 and 90.5 for the three groups of patients, respectively), but the differences were not significant (p = 0.18). No significant diffeences were noted between patients who had pneumonia due to recognized bacterial pathogens when compared to those with pneumonia due to commensal flora. Combinations of factors A previous study from our medical center [ 1 ] suggested that a bacterial etiology was likely in patients with pneumonia if ≥ 2 of the following findings were present: negative viral PCR panel, no sick contact, WBC > 11,000 cells/ mm 3 , and procalcitonin > 0.25 ng/mL. Each patient was scored according to these criteria (without consideration of a negative viral PCR which was an inclusion criterion) and the test was found to be 88.8% sensitive (95% CI: 81.4–93.5) but only 45.5% specific (95% CI: 21.3–72.0) for correctly identifying patients with either bacerial infection or bacterial/viral coinfection, as opposed to patients with viral infection alone. Using the bacterial prevalence of 0.87 in our sample, the negative predictive value of this test was 0.38. Outcomes No significant differences in rates of respiratory failure requiring intubation were seen among groups, but a significantly greater proportion of patients with bacterial/viral coinfection (30%) were admitted or transferred to the ICU during their hospital course, compared to 17% and 19% of patients with bacterial or viral infection, respectively (p < 0.05). There were no differences among the groups in mortality at 14 or 90 days after admission. DISCUSSION In this study, we sought to determine whether clinical, laboratory and imaging features of patients hospitalized for CAP and test positive for a respiratory virus are sufficiently distinct to safely avoid empiric antibiotic therapy at admission. Our study differs from previous ones, as we only included patients who provided a high-quality purulent sputum at or shortly after admission, and all cases underwent quantitative bacteriologic testing of sputum with inclusion of recognized bacterial pathogens and commensal bacteria. Admittedly, reliance on a valid sputum sample introduces a selection bias, although with this methodology we were able to achieve an etiologic diagnosis in every case and could, with high likelihood, rule in or out a bacterial infection. Our results show that, in patients hospitalized for pneumonia, the clinical presentation, laboratory and radiologic findings do not differ sufficiently among those with bacterial or viral infection or bacterial/viral coinfection to exclude the presence of bacterial infection. An exception would be the absence of bacteria on microscopic examination of a truly purulent sputum sample from a patient who has not received an antibiotic. Otherwise, there were no differences among patients that would support a decision to withhold antibiotic treatment. These findings support current ATS/IDSA guidelines that recommend antibiotic therapy in all patients who are sick enough to be hospitalized for CAP even if they test positive for the presence of a respiratory virus [[Jones BE, Ramirez JA, Oren E, Soni NJ, Sullivan LR, Restrepo MI, Musher DM et al, Diagnosis and Management of Community-acquired Pneumonia:An Official American Thoracic Society / Infectious Diseases Society of America Clinical Practice Guideline, Clin Infect Dis, in press, 2024; MAY NOT ADD THIS REF UNTIL AFTER GUIDELINES ARE PUBLISHED]]. Patients with bacterial pneumonia were more likely to have been smokers and to have chronic pulmonary disease. Upper respiratory symptoms were more common in patients with viral pneumonia, and WBC counts were higher in patients with bacterial pneumonia, but there was substantial overlap. The similarity in radiologic findings, with the finding of consolidation in viral pneumonia, is especially worth noting, since it is at odds with earlier reports [ 26 , 27 ]. A unique feature of this study is the inclusion of patients who were infected with commensal bacteria, a finding that was made possible by the use of quantitative bacteriology and MALDI-TOF idenfication of all organisms. This is also the first study to compare clinical features of pneumonia due to recognized bacterial pathogens and commensal bacteria; interestingly, no differences were observed. We found that patients with bacterial pneumonia were unlikely to have URI symptoms, and patients with viral pneumonia were more likely to be immunocompromised, as has been reported previously [ 15 ]. Interestingly, although this study was confined to patients who produced frankly purulent sputum, 13% of our patients had only viral infection, emphasizing that patients with purely viral pneumonia clearly may produce purulent sputum. Contrary to conventional teaching [ 27 ], we did not observe differences in imaging findings such as lobar consolidation, multifocal involvement, pleural effusion, or atelectasis among the three groups. Because previous studies did not have adequate sputum samples on all their patients, they may have diagnosed viral pneumonia when bacterial coinfection was actually present. Existing literature regarding the utility of peripheral WBC counts in differentiating bacterial from viral pneumonia present inconsistent results. Some studies, including our own [ 1 ], found higher median peripheral WBC counts in bacterial than in viral infection, while others have found no significant difference [ 28 ]. A very high serum procalcitonin level, observed in 3 patients, suggested bacterial infection but there was great variability in results, and procalcitonin was normal in 29.3% patients with bacterial infection, indicating that a decision to treat with, or to withhold antibiotics can not be based on this test [ 19 , 21 ]. The primary objective of the present study was to determine, in patients with CAP and a documented respiratory virus by PCR, the possibility of excluding a bacterial etiology in order to avoid prescribing empiric antibiotic therapy. Current guidelines recommend empiric antibiotics for patients who are hospitalized with CAP [ 5 ]. However, debate persists regarding the appropriateness of antibiotics in patients with a positive viral PCR test and negative or inconclusive bacterial microbiological testing [[Jones et al after publication of new guuidelines]]. A receiver-operator curve suggested that a patient with a positive viral PCR, known sick contact, normal WBC, and normal procalcitonin might not require immediate antibiotics. However, the negative predictive value of this tool was only 0.38 and therefore can not be used to justify withholding antibiotics. Thus, our study further supports consensus guidelines for initiating empiric antibiotic therapy in all patients who are deemed sufficiently ill to require hospitalization for CAP even if a respiratory virus is shown to be present [[Jones et al after publication of new guidelines]] This study has several limitations. The total number of patients is small and it was done at a single center, but this kind of intense study is unlikely to be done in large groups of patients, and a single center assures uniform quality of laboratory work. The population consisted largely of older men, many of whom had comorbidities, and all of whom were hospitalized. Patients were only included if they provided high-quality purulent sputum; this inclusion bias was felt to be necessary because, without a high-quality sputum specimen, the diagnosis of bacterial pneumonia can not be established in about one-half of cases. The standard teaching that viral infection does not cause purulent sputum was not supported by our results. Finally, the number of patients with a pure viral pneumonia was too small to allow for meaningful comparisons in some categories, potentially limiting the generalizability of our results, although this degree of overlap in small numbers of cases probably means that a physician caring for an individual patient can not make therapeutic decisions based on any of the criteria studied. In conclusion, the present study shows modest differences in clinical presentation of patients with bacterial and viral pneumonia or bacterial/viral coinfection, with substantial overlap in symptoms, laboratory, and imaging findings, precluding the ability to identify patients who may not require antibiotic therapy. If empiric antibiotics are to be withheld in patients hospitalized for CAP, further studies are needed to identify potential biomarkers or other clinical signs that can more clearly exclude a bacterial etiology. Declarations Ethics approval and consent to participate: This protocol was approved by the Institutional Review Board, Baylor College of Medicine, protocol H-29468 Consent for publication: None required Availability of data and materials: Excel file spread sheets with anonymized data are available upon request to [email protected] Competing interests: None Funding: None Authors' contributions: All laboratory work was done by DMM. All four authors participated in obtaining data from medical records, analyzing data, and writing and editing the manuscript, and all approved the final version that is being submitted. Acknowledgements: None References Musher DM, Roig IL, Cazares G, Stager C, Logan N, Safar H. Can an etiologic agent be identified in adults who are hospitalized for community-acquired pneumonia: Results of a one-year study. J Infect. 2013;67:11–8. Jain S, Self WH, Wunderink RG, et al. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015;373:415–27. Musher DM, Jesudasen SS, Barwatt JW, Cohen DN, Moss BJ, Rodriguez-Barradas MC. Normal Respiratory Flora as a Cause of Community-Acquired Pneumonia. Open Forum Infect Dis. 2020;7(9):ofaa307. Shoar S, Musher DM. Etiology of community-acquired pneumonia in adults: a systematic review. Pneumonia (Nathan). 2020; 12: 11. 2020 Oct 5:12:11. 10.1186/s41479-020-00074-3 . eCollection 2020. 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Characteristic All patients ( n = 122) Bacterial infection ( n = 77, 63%) Viral infection ( n = 16, 13%) Bacterial/viral co-infection ( n = 29, 24%) P value Mean age, years (SD) 69.3 (9.9) 69.9 (9.67) 67.4 (9.51) 68.4 (10.48) 0.56 Sex, n (%) Male 117 (95.9) 75 (97.4) 16 (100) 26 (90) 0.21 History of smoking, n (%) Smokers 76 (62.3) 54 (70.1) 8 (50) 15 (51.7) 0.12 Comorbidity, n (%) Alcohol use disorder 21 (17.2) 14 (18.2) 2 (12.5) 5 (17.2) 0.94 Lung disease 62 (50.8) 45 (58.4) 4 (25) 14 (48.3) 0.05 Immunosuppression 30 (24.6) 18 (23.4) 5 (31.3) 7 (24.1) 0.78 Heart disease 46 (37.7) 33 (42.9) 3 (18.8) 9 (31) 0.15 Mean Hgb A1C (SD) 6.29 (1.26) 6.43 (1.39) 6.01 (0.84) 6.09 (1.02) 0.3 Outcomes Respiratory failure, n (%) 9 (7.4) 6 (7.8) 3 (18.8) 4 (13.8) 0.29 ICU admission, n (%) 23 (18.9) 13 (16.9) 3 (18.8) 7 (24.1) 0.7 14-day mortality, n (%) 7 (5.7) 5 (6.5) 2 (12.5) 0 (0) 0.16 90-day mortality, n (%) 22 (18.0) 17 (22.1) 3 (18.8) 2 (6.9) 0.19 Subjective History Fever, n (%) 44 (36.1) 23 (29.9) 7 (43.8) 14 (48.3) 0.17 Cough, n (%) 79 (64.8) 45 (58.4) 12 (75) 22 (75.9) 0.18 Shortness of breath, n (%) 82 (67.2) 58 (75.3) 12 (75) 22 (75.9) 1 Sputum production, n (%) 42 (34.4) 23 (33.8) 7 (43.8) 12 (41.4) 0.38 URI symptoms, n (%) 17 (13.9) 5 (6.5) 5 (31.3) 7 (24.1) 0.004 Objective Findings Vital signs Mean temperature, °F (SD) 99.13 (1.35) 99.06 (1.24) 99.01 (1.15) 99.46 (1.67) 0.51 Mean respiratory rate, breaths/min (SD) 21.72 (12.3) 22.42 (14.97) 21.06 (4.12) 20.5 (3.84) 0.64 Mean heart rate, beats/min (SD) 98.63 (20.8) 99.04 (21.3) 97.13 (21.7) 98.5 (18.7) 0.99 Mean O2 saturation, % (SD) 92.2 (5.48) 92.01 (5.97) 90.8 (6.01) 90.41 (2.93) 0.32 Mean SBP, mmHg (SD) 126.4 (24.5) 121.73 (22.75) 134.06 (31.6) 134.17 (21.9) 0.047 Mean DBP, mmHg (SD) 74.6 (15) 72.18 (14.48) 76.75 (17) 79.66 (13.8) 0.09 Imaging findings Lobar consolidation, n (%) 71 (58.2) 47 (61) 8 (50) 16 (55.2) 0.64 Multifocal consolidation, n (%) 25 (20.5) 15 (19.5) 2 (12.5) 8 (27.6) 0.48 Pleural effusion, n (%) 20 (16.4) 12 (15.6) 5 (31.3) 2 (10.3) 0.11 Atelectasis, n (%) 28 (23) 14 (18.1) 7 (43.8) 8 (27.6) 0.07 Laboratory values Mean BNP, pg/mL (SD) 347.4 (546) 56.18 (379.3) 348 (523) 342 (830) 0.11 Mean lactate, mmol/L (SD) 2.01 (1.1) 0.28 (0.52) 2.2 (1.32) 1.08 (0.78) 0.95 Mean WBC, cells/µL (SD) 12,420 (5,800) 11,470 (5,2450) 8,560 (3,540) 11,730 (6,100) 0.005 Mean procalcitonin, ng/mL (SD) 3.76 (14.9) 6.12 (22.3) 0.78 (0.94) 1.03 (1.52) 0.85 Mean PSI score (SD) 99.3 (34.7) 101.6 (30.2) 89.93 (34) 90.48 (27.55) 0.18 Troponin > 0.03 ng/ml, n (%) 41.(33.6) 25 (32.5) 5 (31.3) 11 (37.9) 0.85 P values refer to the null hypothesis that the distribution of each variable does not differ between etiological groups. For continuous variables (age, A1C, vital signs, and laboratory values) a Kruskal-Wallis test was used. For dichotomous variables, a Fisher’s Exact test was used. Parentheses included represent the standard deviations of mean values. For values presented as whole numbers, parentheses represent the proportion of each respective group. Abbreviations: BNP-B-type natriuretic peptide; DBP-diastolic blood pressure; Hgb A1c-Hemoglobin A1C; PSI-Pneumonia Severity Index; SBP-systolic blood pressure; SD-standard deviation; WBC-white blood cell. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 05 Jan, 2025 Read the published version in Pneumonia → Version 1 posted Editorial decision: Revision requested 25 Jul, 2024 Reviews received at journal 15 Jul, 2024 Reviews received at journal 12 Jul, 2024 Reviewers agreed at journal 11 Jul, 2024 Reviews received at journal 08 Jul, 2024 Reviewers agreed at journal 08 Jul, 2024 Reviewers agreed at journal 06 Jul, 2024 Reviewers agreed at journal 05 Jul, 2024 Reviewers agreed at journal 05 Jul, 2024 Reviewers invited by journal 05 Jul, 2024 Editor assigned by journal 24 Jun, 2024 Submission checks completed at journal 24 Jun, 2024 First submitted to journal 21 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4618989","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":326278076,"identity":"9ad43cb1-ced0-40fe-9e30-7c5e19d2cf30","order_by":0,"name":"Ryan Ward","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"","lastName":"Ward","suffix":""},{"id":326278077,"identity":"b4fe84a0-9f3b-4316-94f1-0ffcafd06b07","order_by":1,"name":"Alejandro J. Gonzalez","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Alejandro","middleName":"J.","lastName":"Gonzalez","suffix":""},{"id":326278078,"identity":"a6566908-e9a4-4c9d-b2fa-1adbb5dd80e2","order_by":2,"name":"Justin A. Kahla","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Justin","middleName":"A.","lastName":"Kahla","suffix":""},{"id":326278079,"identity":"1ce03de4-afaa-42cf-b228-12652c2caa6f","order_by":3,"name":"Daniel M. Musher","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYDCCAyBUAGLxAHEF0VoMYFrOEKmFAa6FsY0IHXzHzx488MGAIdrg/NmDjyvnHZZn4F98TAKfFskzeQkHZxgw5G64kZdseHbbYcMGiWdpeLUYHMgxOMwD1sJjJtm4LY2xQeKMsQFeLeffGBz+A9Jy/oz5z8Y5afaEtdwA2sIA0nIgx4yxscEmsYG/x/ABXr/ceGNwsMdAInfmjRxjyYZjNsltEmyJeLXwnc8x/vCjwia37/wZw48NNRK2/fyHDxzApwUKkIKITSKBCA2ogJ8YO0bBKBgFo2AkAQA2b1DChFCV8gAAAABJRU5ErkJggg==","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Daniel","middleName":"M.","lastName":"Musher","suffix":""}],"badges":[],"createdAt":"2024-06-21 18:54:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4618989/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4618989/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41479-024-00153-9","type":"published","date":"2025-01-05T15:57:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60624819,"identity":"c47afd05-8771-4a94-93aa-2623be1c762e","added_by":"auto","created_at":"2024-07-18 22:17:38","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":120673,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Forrest plot showing white blood cell counts for each group. (B) Forrest plot showing procalcitonin for each group.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4618989/v1/024dcc6790fc79831f5a8602.jpeg"},{"id":73093478,"identity":"3f3c65dc-c34a-4fd5-9086-101563a913df","added_by":"auto","created_at":"2025-01-06 16:20:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":711221,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4618989/v1/5eabf802-65bb-4863-b0da-71c9fb861422.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Can Clinical Findings at Admission Allow Withholding of Antibiotics in Patients Hospitalized for Community Acquired Pneumonia when a Test for a Respiratory Virus is Positive?","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eCommunity-acquired pneumonia (CAP) may result from infection by recognized bacterial pathogens, bacteria that have traditionally been regarded as commensal bacteria but have recently been shown to cause pneumonia, respiratory viruses, or bacterial/viral coinfection [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Empiric antibacterial therapy is recommended for most patients hospitalized for CAP [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], as it is difficult to identify the underlying cause of infection; even the most exhaustive prospective studies utilizing conventional microbial techniques generally fail to identify an etiologic agent in \u0026gt;\u0026thinsp;50% of cases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The principal reason for this failure is that, except in the small proportion of patients who have positive blood cultures, diagnosis of bacterial infection requires a vald sputum sample for Gram stain, culture and/or molecular analysis [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. At the time of hospitalization for CAP, a substantial proportion of patients are unable to provide a valid sputum sample, and timely administration of empiric antibiotics rapidly eradicates infecting bacteria from sputum [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePolymerase chain reaction (PCR) is increasingly available to identify the presence of a respiratory virus, and results may be positive within a few hours of presentation to hospital. This availability together with increasing concern about potential harm by antibiotics [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], suggests that some patients hospitalized for pneumonia, namely those who test positive for a respiratory virus should not receive antibiotic therapy. The problems of withholding antibiotics in patients with CAP with a PCR that identifies a respiratory virus are that: (1) bacterial coinfection is common in viral pneumonia; and (2) exclusion of a bacterial etiology requires a high-quality sputum specimen. Numerous reports show that about one-third of patients hospitalized with viral pneumonia have bacterial coinfection [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Now that commensal flora have been found to cause CAP [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], the proportion with bacterial coinfection is probably even greater. And a substantial proportion of patients who are hospitalized for pneumonia are unable to provide a high-quality sputum specimen at admission.\u003c/p\u003e \u003cp\u003ePrior studies have varied in their ability to distinguish bacterial infection alone or bacterial/viral coinfection from viral infection alone [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Such a diagnostic distinction could inform the decision to initiate antibiotic therapy in patients with CAP whose PCR is positive for a respiratory virus at the time of diagnosis. While elevated white blood cell (WBC) counts and serum procalcitonin are associated with bacterial infection, the absence of leukocytosis or a high procalcitonin does not preclude a bacterial etiology [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Similarly, while chest imaging showing multifocal or patchy pneumonia is conventionally associated with viral infection and consolidation with bacterial pneumonia, significant overlap with bacterial pneumonia has been reported [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe purpose of the present study was to determine whether differences in the clinical presentation of pneumonia due to bacterial infection, viral infection or bacterial/viral coinfection are consistent enough to justify withholding empiric antibiotics in patients admitted for CAP who test positive for a respiratory virus.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Selection\u003c/h2\u003e \u003cp\u003eWe studied a convenience sample of patients admitted to the Michael E. DeBakey VA Medical Center with a diagnosis of CAP between September 1, 2017, and December 31, 2019 (pre-COVID). Detailed methods were previously described [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Briefly, on select days, the principal investigator (DMM) examined all Gram-stained sputum samples submitted to the Clinical Microbiology Laboratory in the preceding 24 hours. For all high-quality specimens (defined as showing\u0026thinsp;\u0026gt;\u0026thinsp;25WBC/epithelial cell), the electronic medical record was reviewed to identify patients who: (1) were freshly admitted from the community; (2) had a newly recognized pulmonary infiltrate and (3) had\u0026thinsp;\u0026ge;\u0026thinsp;2 of the following findings: fever, increased cough, sputum production or shortness of breath, rales, confusion or hypoxia. Patients who met the above criteria were included in the present study if they also underwent PCR testing for respiratory viruses on a nasopharyngeal specimen at or soon after admission. The purpose of this selection process was to obtain a series of patients in whom an etiologic diagnosis had the best chance of being made, although inclusion only of patients who provided purulent sputum may cause an inherent selection bias (see Discussion, below). Some of these patients were also included in a prior report on the etiology of CAP [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This research was approved by the Institutional Review Boards of Baylor College of Medicine and the Michael E. DeBakey VA Medical Center.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic Studies\u003c/h2\u003e \u003cp\u003eAn aliquot of sputum from patients who met inclusion criteria, was drawn into 1 ml micropipetters using pipet tips with the ends cut to enlarge the aperture; detailed methods have been published previously [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Sputum was liquefied with 2% N-acetyl cysteine, and bacteria were quantified by making serial 10-fold dilutions and streaking 10 \u0026micro;L aliquots on blood and chocolate agar. Recognized bacterial pathogens, if present at \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;10\u003csup\u003e5\u003c/sup\u003e per ml, and commensal bacteria if present at \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;10\u003csup\u003e6\u003c/sup\u003e per ml were identified by standard microbiologic techniques with verification by MALDI-TOF. All patients had nasopharyngeal swabs for PCR to identify respiratory viruses, \u003cem\u003eMycoplasma pneumoniae\u003c/em\u003e and \u003cem\u003eChlamydophila ia pneumoniae\u003c/em\u003e. Blood cultures, urine studies for pneumococcus and \u003cem\u003eLegionella\u003c/em\u003e antigens, plasma procalcitonin, and B-natriuretic peptide were collected in \u0026gt;\u0026thinsp;95% of cases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eChart Review\u003c/h2\u003e \u003cp\u003eThorough review of each patient\u0026rsquo;s admitting electronic medical record including all notes by nurses, emergency room doctors, medical students, residents and attendings was performed, and data were recorded for age, sex, race, ethnicity, smoking and alcohol use, other comorbidities such as chronic obstructive pulmonary disease (COPD), heart disease, immunodeficiency (induced by immunosuppressive drugs, hematologic malignancy, or chronic immunodeficiency such as AIDS), and date of death. Clinical symptoms reported at the time of admission, vital signs, and radiographic findings were also recorded. Symptoms such as rhinorrhea, sneezing, or sinus pressure were collectively listed as upper respiratory infection (URI) symptoms. The pneumonia severity index (PSI) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] was calculated for each patient.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eDetermining Etiology\u003c/h2\u003e \u003cp\u003ePatients whose sputum contained\u0026thinsp;\u0026ge;\u0026thinsp;10\u003csup\u003e5\u003c/sup\u003e colony-forming units (cfu)/mL of a recognized bacterial pathogen (such as \u003cem\u003eStreptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumoninae\u003c/em\u003e) or \u0026ge;\u0026thinsp;10\u003csup\u003e6\u003c/sup\u003e cfu/mL of commensal bacteria (such as \u003cem\u003eStreptococcus mitis\u003c/em\u003e or \u003cem\u003eCorynebacteria\u003c/em\u003e spp) were categorized as having bacterial infection; note that criteria for inclusion were more stringent for commensal bacteria, Microscopic examination of Gram-stained sputum, completed before culture results were available, uniformly agreed with findings of quantitative bacteriology [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Cases in which PCR of a nasopharyngeal swab revealed a respiratory virus were diagnosed with viral infection. Patients who met criteria for bacterial infection were and also had a positive viral PCR were regarded as having bacterial/viral coinfection. These criteria were used to stratify pneumonia into 5 etiologic groups: pneumonia due to (1) recognized bacterial pathogens; (2) respiratory viruses; (3) coinfection by a recognized bacterial pathogen and a respiratory virus; (4) commensal bacteria; and (5) coinfection by commensal bacteria and a respiratory virus. In some analyses, data from Groups 1 and 4 are presented as bacterial infection, Group 2 as viral infection and Groups 3 and 5 as bacterial/viral coinfection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eFisher\u0026rsquo;s Exact and Kruskal-Wallis tests were performed for categorical and continuous variables, respectively, and are displayed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Median serum procalcitonin values for each etiologic group were compared using analysis of variance and Tukey tests of significance. Fisher\u0026rsquo;s Exact and Kruskal-Wallis tests compared data in patients with recognized bacterial pathogens and commensal flora, and in some comparisons, results from these two groups were combined and are presented as \u0026lsquo;bacterial pneumonia.\u0026rsquo;\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThe mean age was 69, and 117 (95.9%) of the patients were male. Based on self-identification in the medical records, 73 (59.9%) patients were white, 41 (33.6%) were Black, and 8 (6.6%) patients did not have a race documented; 10 (8.2%) patients were of Hispanic ethnicity. The median time to antibiotic administration before a high-quality sputum sample was provided was 0 hr (range 0\u0026ndash;12). Eighty (65.6%) patients had received no antibiotics, and an additional 9.0% had received antibiotics for \u0026lt;\u0026thinsp;2 hours prior to sputum collection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic Categories\u003c/h2\u003e \u003cp\u003eOverall, 77 (63.1%) patients had bacterial infection, 56 with recognized bacterial pathogens and 21 with commensal bacteria. Sixteen (13.1%) had viral infection, and 29 (23.8%) had bacterial and viral coinfection. There were no significant differences in age, race, or ethnicity among these etiologic groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePast Medical History, Exposures\u003c/h2\u003e \u003cp\u003ePatients with bacterial infection tended to be more likely to have a smoking history than patients with viral infection or bacterial/viral coinfection (70.1% vs 50.0%, and 51.7%, respectively, p\u0026thinsp;=\u0026thinsp;0.12). Patients with bacterial infection and bacterial/viral coinfection were significantly more likely to have underlying lung disease than patients with viral infection (58.4% and 48.3%, vs. 25.0%, respectively, (p\u0026thinsp;=\u0026thinsp;0.05). No differences were observed among groups with regards to alcohol use disorder, immunosuppression, or mean hemoglobin A1c values. There was no difference in the proportion of patients who self-reported recent exposure to sick contacts amongst the three groups (bacterial infection 8%, viral infection 19%, bacterial/viral coinfection 18%, p\u0026thinsp;=\u0026thinsp;0.18).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSymptoms and Subjective Findings\u003c/h2\u003e \u003cp\u003ePatients with bacterial infection were less likely to report URI symptoms than patients with viral or bacterial/viral coinfection (6.5%, 31.3% and 24.1%, respectively, p\u0026thinsp;=\u0026thinsp;0.004). Patients with bacterial infection tended to be less likely than those with viral or bacterial/viral coinfection to report subjective fever (29.9% vs 43.8.% or 48.3%) and cough (58.4% vs 75.0% or 75.9%, respectively (differences not significant, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). No differences were observed in the proportions of patients reporting shortness of breath (75.3%, 75%, 75.9%, p\u0026thinsp;=\u0026thinsp;1.0) or sputum production (33.8%, 43.8%, 41.4, p\u0026thinsp;=\u0026thinsp;0.38) for the three groups, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eObjective Findings\u003c/h2\u003e \u003cp\u003eNo significant differences among the three groups were observed in mean body temperature, heart rate, respiratory rate, O2 saturation, or diastolic blood pressure at the time of admission, although patients with bacterial pneumonia had a lower mean systolic blood pressure (122 mmHg) than those with viral infection (134 mmHg) or bacterial/viral coinfection (134 mmHg, p\u0026thinsp;=\u0026thinsp;0.047). Somewhat surprisingly, patients in these three groups did not differ in their imaging findings, as rates of lobar consolidation, multifocal consolidation, new pleural effusion, and atelectasis were similar. Fifty percent of patients with viral pneumonia had lobar consolidation on chest radiography, and 19.5% of patients with bacterial infection alone had multifocal areas of consolidation. Patients with bacterial infection or bacterial/viral coinfection had significantly higher WBC counts on admission (12,990 WBC/mm\u003csup\u003e3\u003c/sup\u003e, and 12,200 cells/mm\u003csup\u003e3\u003c/sup\u003e) compared to patients with viral infection (8,560 cells/mm\u003csup\u003e3\u003c/sup\u003e) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.005). Median procalcitonin at admission was 0.25, 0.27, and 0.37 ng/mL for patients in these three groups, respectively (p\u0026thinsp;=\u0026thinsp;0.85) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The proportions of patients whose serum troponin at admission exceeded 0.03 ng/mL were similar, ranging from 31.3\u0026ndash;37.9%, p\u0026thinsp;=\u0026thinsp;0.85). Pneumonia severity index scores were highest for patients with bacterial pneumonia (101.6, 89.9 and 90.5 for the three groups of patients, respectively), but the differences were not significant (p\u0026thinsp;=\u0026thinsp;0.18). No significant diffeences were noted between patients who had pneumonia due to recognized bacterial pathogens when compared to those with pneumonia due to commensal flora.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCombinations of factors\u003c/h2\u003e \u003cp\u003eA previous study from our medical center [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] suggested that a bacterial etiology was likely in patients with pneumonia if\u0026thinsp;\u0026ge;\u0026thinsp;2 of the following findings were present: negative viral PCR panel, no sick contact, WBC\u0026thinsp;\u0026gt;\u0026thinsp;11,000 cells/ mm\u003csup\u003e3\u003c/sup\u003e, and procalcitonin\u0026thinsp;\u0026gt;\u0026thinsp;0.25 ng/mL. Each patient was scored according to these criteria (without consideration of a negative viral PCR which was an inclusion criterion) and the test was found to be 88.8% sensitive (95% CI: 81.4\u0026ndash;93.5) but only 45.5% specific (95% CI: 21.3\u0026ndash;72.0) for correctly identifying patients with either bacerial infection or bacterial/viral coinfection, as opposed to patients with viral infection alone. Using the bacterial prevalence of 0.87 in our sample, the negative predictive value of this test was 0.38.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eNo significant differences in rates of respiratory failure requiring intubation were seen among groups, but a significantly greater proportion of patients with bacterial/viral coinfection (30%) were admitted or transferred to the ICU during their hospital course, compared to 17% and 19% of patients with bacterial or viral infection, respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There were no differences among the groups in mortality at 14 or 90 days after admission.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we sought to determine whether clinical, laboratory and imaging features of patients hospitalized for CAP and test positive for a respiratory virus are sufficiently distinct to safely avoid empiric antibiotic therapy at admission. Our study differs from previous ones, as we only included patients who provided a high-quality purulent sputum at or shortly after admission, and all cases underwent quantitative bacteriologic testing of sputum with inclusion of recognized bacterial pathogens and commensal bacteria. Admittedly, reliance on a valid sputum sample introduces a selection bias, although with this methodology we were able to achieve an etiologic diagnosis in every case and could, with high likelihood, rule in or out a bacterial infection.\u003c/p\u003e \u003cp\u003eOur results show that, in patients hospitalized for pneumonia, the clinical presentation, laboratory and radiologic findings do not differ sufficiently among those with bacterial or viral infection or bacterial/viral coinfection to exclude the presence of bacterial infection. An exception would be the absence of bacteria on microscopic examination of a truly purulent sputum sample from a patient who has not received an antibiotic. Otherwise, there were no differences among patients that would support a decision to withhold antibiotic treatment. These findings support current ATS/IDSA guidelines that recommend antibiotic therapy in all patients who are sick enough to be hospitalized for CAP even if they test positive for the presence of a respiratory virus [[Jones BE, Ramirez JA, Oren E, Soni NJ, Sullivan LR, Restrepo MI, Musher DM et al, Diagnosis and Management of Community-acquired Pneumonia:An Official American Thoracic Society / Infectious Diseases Society of America Clinical Practice Guideline, Clin Infect Dis, in press, 2024; MAY NOT ADD THIS REF UNTIL AFTER GUIDELINES ARE PUBLISHED]]. Patients with bacterial pneumonia were more likely to have been smokers and to have chronic pulmonary disease. Upper respiratory symptoms were more common in patients with viral pneumonia, and WBC counts were higher in patients with bacterial pneumonia, but there was substantial overlap. The similarity in radiologic findings, with the finding of consolidation in viral pneumonia, is especially worth noting, since it is at odds with earlier reports [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA unique feature of this study is the inclusion of patients who were infected with commensal bacteria, a finding that was made possible by the use of quantitative bacteriology and MALDI-TOF idenfication of all organisms. This is also the first study to compare clinical features of pneumonia due to recognized bacterial pathogens and commensal bacteria; interestingly, no differences were observed.\u003c/p\u003e \u003cp\u003eWe found that patients with bacterial pneumonia were unlikely to have URI symptoms, and patients with viral pneumonia were more likely to be immunocompromised, as has been reported previously [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Interestingly, although this study was confined to patients who produced frankly purulent sputum, 13% of our patients had only viral infection, emphasizing that patients with purely viral pneumonia clearly may produce purulent sputum. Contrary to conventional teaching [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], we did not observe differences in imaging findings such as lobar consolidation, multifocal involvement, pleural effusion, or atelectasis among the three groups. Because previous studies did not have adequate sputum samples on all their patients, they may have diagnosed viral pneumonia when bacterial coinfection was actually present.\u003c/p\u003e \u003cp\u003eExisting literature regarding the utility of peripheral WBC counts in differentiating bacterial from viral pneumonia present inconsistent results. Some studies, including our own [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], found higher median peripheral WBC counts in bacterial than in viral infection, while others have found no significant difference [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. A very high serum procalcitonin level, observed in 3 patients, suggested bacterial infection but there was great variability in results, and procalcitonin was normal in 29.3% patients with bacterial infection, indicating that a decision to treat with, or to withhold antibiotics can not be based on this test [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe primary objective of the present study was to determine, in patients with CAP and a documented respiratory virus by PCR, the possibility of excluding a bacterial etiology in order to avoid prescribing empiric antibiotic therapy. Current guidelines recommend empiric antibiotics for patients who are hospitalized with CAP [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, debate persists regarding the appropriateness of antibiotics in patients with a positive viral PCR test and negative or inconclusive bacterial microbiological testing [[Jones et al after publication of new guuidelines]]. A receiver-operator curve suggested that a patient with a positive viral PCR, known sick contact, normal WBC, and normal procalcitonin might not require immediate antibiotics. However, the negative predictive value of this tool was only 0.38 and therefore can not be used to justify withholding antibiotics. Thus, our study further supports consensus guidelines for initiating empiric antibiotic therapy in all patients who are deemed sufficiently ill to require hospitalization for CAP even if a respiratory virus is shown to be present [[Jones et al after publication of new guidelines]]\u003c/p\u003e \u003cp\u003eThis study has several limitations. The total number of patients is small and it was done at a single center, but this kind of intense study is unlikely to be done in large groups of patients, and a single center assures uniform quality of laboratory work. The population consisted largely of older men, many of whom had comorbidities, and all of whom were hospitalized. Patients were only included if they provided high-quality purulent sputum; this inclusion bias was felt to be necessary because, without a high-quality sputum specimen, the diagnosis of bacterial pneumonia can not be established in about one-half of cases. The standard teaching that viral infection does not cause purulent sputum was not supported by our results. Finally, the number of patients with a pure viral pneumonia was too small to allow for meaningful comparisons in some categories, potentially limiting the generalizability of our results, although this degree of overlap in small numbers of cases probably means that a physician caring for an individual patient can not make therapeutic decisions based on any of the criteria studied.\u003c/p\u003e \u003cp\u003eIn conclusion, the present study shows modest differences in clinical presentation of patients with bacterial and viral pneumonia or bacterial/viral coinfection, with substantial overlap in symptoms, laboratory, and imaging findings, precluding the ability to identify patients who may not require antibiotic therapy. If empiric antibiotics are to be withheld in patients hospitalized for CAP, further studies are needed to identify potential biomarkers or other clinical signs that can more clearly exclude a bacterial etiology.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003eEthics approval and consent to participate: \u0026nbsp;This protocol was approved by the Institutional Review Board, Baylor College of Medicine, protocol H-29468\u003c/li\u003e\n \u003cli\u003eConsent for publication: \u0026nbsp;None required\u003c/li\u003e\n \u003cli\u003eAvailability of data and materials: \u0026nbsp;Excel file spread sheets with anonymized data are available upon request to [email protected]\u003c/li\u003e\n \u003cli\u003eCompeting interests: \u0026nbsp;None\u003c/li\u003e\n \u003cli\u003eFunding: \u0026nbsp;None\u003c/li\u003e\n \u003cli\u003eAuthors\u0026apos; contributions: \u0026nbsp;All laboratory work was done by DMM. \u0026nbsp;All four authors participated in obtaining data from medical records, analyzing data, and writing and editing the manuscript, and all approved the final version that is being submitted.\u003c/li\u003e\n \u003cli\u003eAcknowledgements: \u0026nbsp;None\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMusher DM, Roig IL, Cazares G, Stager C, Logan N, Safar H. Can an etiologic agent be identified in adults who are hospitalized for community-acquired pneumonia: Results of a one-year study. J Infect. 2013;67:11\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJain S, Self WH, Wunderink RG, et al. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015;373:415\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMusher DM, Jesudasen SS, Barwatt JW, Cohen DN, Moss BJ, Rodriguez-Barradas MC. Normal Respiratory Flora as a Cause of Community-Acquired Pneumonia. Open Forum Infect Dis. 2020;7(9):ofaa307.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShoar S, Musher DM. Etiology of community-acquired pneumonia in adults: a systematic review. Pneumonia (Nathan). 2020; 12: 11. 2020 Oct 5:12:11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s41479-020-00074-3\u003c/span\u003e\u003cspan address=\"10.1186/s41479-020-00074-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. eCollection 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuuskanen O, Lahti E, Jennings LC, Murdoch DR. Viral pneumonia. Lancet. 2011;377:1264\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMetlay JP, Waterer GW, Long AC, 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(7):e45\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohansson N, Kalin M, Tiveljung-Lindell A, Giske CG, Hedlund J. Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods. Clin Infect Dis. 2010;50(2):202\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWolff BJ, Bramley AM, Thurman KA, et al. Improved Detection of Respiratory Pathogens by Use of High-Quality Sputum with TaqMan Array Card Technology. J Clin Microbiol. 2017;55:110\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGadsby NJ, Dunn JJ, Johnson CL, et al. Discordance between semi-quantitative nucleic acid detection of bacteria and quantitative bacteriology in sputum from patients with pneumonia. J Infect. 2023;86:607\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRothe K, Spinner CD, Panning M, et al. Evaluation of a multiplex PCR screening approach to identify community-acquired bacterial co-infections in COVID-19: a multicenter prospective cohort study of the German competence network of community-acquired pneumonia (CAPNETZ). Infection. 2021;49:1299\u0026ndash;306.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMusher DM, Montoya R, Wanahita A. Diagnostic value of microscopic examination of gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia. Clin Infect Dis. 2004;39:165\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVaughn VM, Flanders SA, Snyder A, et al. Excess Antibiotic Treatment Duration and Adverse Events in Patients Hospitalized With Pneumonia: A Multihospital Cohort Study. Ann Intern Med. 2019;171:153\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnstone J, Majumdar SR, Fox JD, Marrie TJ. Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation. Chest. 2008;134:1141\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJennings LC, Anderson TP, Beynon KA, et al. Incidence and characteristics of viral community-acquired pneumonia in adults. Thorax. 2008;63:42\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrotty MP, Meyers S, Hampton N, et al. Epidemiology, Co-Infections, and Outcomes of Viral Pneumonia in Adults: An Observational Cohort Study. Med (Baltim). 2015;94(50):e2332. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MD.0000000000002332\u003c/span\u003e\u003cspan address=\"10.1097/MD.0000000000002332\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFalsey AR, Becker KL, Swinburne AJ, et al. Bacterial complications of respiratory tract viral illness: a comprehensive evaluation. J Infect Dis. 2013;208:432\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuijskens EGW, Koopmans M, Palmen FMH, van Erkel AJM, Mulder PGH, Rossen JWA. The value of signs and symptoms in differentiating between bacterial, viral and mixed aetiology in patients with community-acquired pneumonia. J Med Microbiol. 2014;63(Pt 3):441\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHedberg P, Johansson N, Ternhag A, Abdel-Halim L, Hedlund J, Naucler P. Bacterial co-infections in community-acquired pneumonia caused by SARS-CoV-2, influenza virus and respiratory syncytial virus. BMC Infect Dis. 2022;22(1):108. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12879-022-07089-9\u003c/span\u003e\u003cspan address=\"10.1186/s12879-022-07089-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSelf WH, Balk RA, Grijalva CG, et al. Procalcitonin as a Marker of Etiology in Adults Hospitalized with Community-Acquired Pneumonia. Clin Infect Dis. 2017;65(2):183\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cid/cix317\u003c/span\u003e\u003cspan address=\"10.1093/cid/cix317\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKorppi M, Kroger L, Laitinen M. White blood cell and differential counts in acute respiratory viral and bacterial infections in children. Scand J Infect Dis. 1993;25(4):435\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamat IS, Ramachandran V, Eswaran H, Guffey D, Musher DM. Procalcitonin to Distinguish Viral From Bacterial Pneumonia: A Systematic Review and Meta-analysis. Clin Infect Dis. 2020;70(3):538\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYadav R, Sahoo D, Graham R. Thoracic imaging in COVID-19. Cleve Clin J Med. 2020;87(8):469\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStefanidis K, Konstantelou E, Yusuf GT, et al. Radiological, epidemiological and clinical patterns of pulmonary viral infections. Eur J Radiol. 2021;136:109548.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAujesky D, Fine MJ. The pneumonia severity index: a decade after the initial derivation and validation. Clin Infect Dis. 2008;47(Suppl 3):S133\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOgawa H, Kitsios GD, Iwata M, Terasawa T. Sputum Gram Stain for Bacterial Pathogen Diagnosis in Community-acquired Pneumonia: A Systematic Review and Bayesian Meta-analysis of Diagnostic Accuracy and Yield. Clin Infect Dis. 2020;71(3):499\u0026ndash;513.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranquet T. Imaging of pulmonary viral pneumonia. Radiology. 2011;260(1):18\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim EA, Lee KS, Primack SL et al. Viral pneumonias in adults: radiologic and pathologic findings. Radiographics. 2002; 22 Spec No: S137-49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim JE, Kim UJ, Kim HK, et al. Predictors of viral pneumonia in patients with community-acquired pneumonia. PLoS ONE. 2014;9(12):e114710.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical presentations of patients with pneumonia.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients (\u003cem\u003en\u003c/em\u003e = 122)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBacterial infection (\u003cem\u003en\u003c/em\u003e = 77, 63%)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eViral infection (\u003cem\u003en\u003c/em\u003e = 16, 13%)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBacterial/viral co-infection (\u003cem\u003en\u003c/em\u003e = 29, 24%)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean age, years (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69.3 (9.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.9 (9.67)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67.4 (9.51)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.4 (10.48)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e117 (95.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 (97.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (100)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26 (90)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of smoking, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmokers\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (62.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (70.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (50)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 (51.7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidity, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol use disorder\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (17.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (18.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (12.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (17.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung disease\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (50.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (58.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (25)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (48.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunosuppression\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (24.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (23.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (31.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (24.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart disease\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (37.7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (42.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (31)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean Hgb A1C (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.29 (1.26)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.43 (1.39)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.01 (0.84)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.09 (1.02)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory failure, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (7.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (7.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (13.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU admission, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (18.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (16.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (24.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14-day mortality, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (5.7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (6.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (12.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e90-day mortality, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (18.0)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (22.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (6.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSubjective History\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (36.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (29.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (48.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79 (64.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (58.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (75)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22 (75.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShortness of breath, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (67.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (75.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (75)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22 (75.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSputum production, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (34.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (33.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (41.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eURI symptoms, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (13.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (6.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (31.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (24.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eObjective Findings\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVital signs\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean temperature, °F (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99.13 (1.35)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99.06 (1.24)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99.01 (1.15)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e99.46 (1.67)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean respiratory rate, breaths/min (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.72 (12.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.42 (14.97)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.06 (4.12)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20.5 (3.84)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean heart rate, beats/min (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98.63 (20.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99.04 (21.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97.13 (21.7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e98.5 (18.7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean O2 saturation, % (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92.2 (5.48)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92.01 (5.97)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90.8 (6.01)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90.41 (2.93)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean SBP, mmHg (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e126.4 (24.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e121.73 (22.75)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e134.06 (31.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e134.17 (21.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.047\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean DBP, mmHg (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.6 (15)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.18 (14.48)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76.75 (17)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e79.66 (13.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImaging findings\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLobar consolidation, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (58.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (61)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (50)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (55.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultifocal consolidation, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (20.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (19.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (12.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (27.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePleural effusion, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (16.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (15.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (31.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (10.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtelectasis, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (23)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (18.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (27.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory values\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean BNP, pg/mL (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e347.4 (546)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56.18 (379.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e348 (523)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e342 (830)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean lactate, mmol/L (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.01 (1.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.28 (0.52)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.2 (1.32)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.08 (0.78)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean WBC, cells/µL (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12,420 (5,800)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11,470 (5,2450)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8,560 (3,540)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11,730 (6,100)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean procalcitonin, ng/mL (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.76 (14.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.12 (22.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78 (0.94)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.03 (1.52)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean PSI score (SD)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99.3 (34.7)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e101.6 (30.2)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e89.93 (34)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90.48 (27.55)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTroponin \u0026gt; 0.03 ng/ml, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.(33.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (32.5)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (31.3)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (37.9)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eP values refer to the null hypothesis that the distribution of each variable does not differ between etiological groups. For continuous variables (age, A1C, vital signs, and laboratory values) a Kruskal-Wallis test was used. For dichotomous variables, a Fisher’s Exact test was used. Parentheses included represent the standard deviations of mean values. For values presented as whole numbers, parentheses represent the proportion of each respective group.\u003c/p\u003e\u003cp\u003eAbbreviations: \u0026nbsp;BNP-B-type natriuretic peptide; DBP-diastolic blood pressure; Hgb A1c-Hemoglobin A1C; PSI-Pneumonia Severity Index; SBP-systolic blood pressure; SD-standard deviation; WBC-white blood cell.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pneumonia","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pneu","sideBox":"Learn more about [Pneumonia](http://pneumonia.biomedcentral.com)","snPcode":"41479","submissionUrl":"https://submission.nature.com/new-submission/41479/3","title":"Pneumonia","twitterHandle":"@pneumoniajourn","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"community acquired pneumonia, viral pneumonia, bacterial pneumonia, bacterial-viral coinfection","lastPublishedDoi":"10.21203/rs.3.rs-4618989/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4618989/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground. \u003c/strong\u003eCurrent guidelines recommend empiric antibiotic therapy for patients who require hospitalization for community-acquired pneumonia (CAP). We sought to determine whether clinical, imaging or laboratory features in patients hospitalized for CAP in whom PCR is positive for a respiratory virus enabled exclusion of bacterial coinfection so that antibiotics could be withheld.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods. \u003c/strong\u003eFor this prospective study, we selected patients in whom an etiologic diagnosis was likely to be reached, namely those who provided a high-quality sputum sample at or shortly after admission, and in whom PCR was done to test for a respiratory virus. We performed quantitative bacteriologic studies on sputum to determine the presence of bacterial infection or coinfection and reviewed all clinical, imaging and laboratory studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults. \u003c/strong\u003eOf\u003cstrong\u003e \u003c/strong\u003e122 patients, 77 (63.1%) had bacterial infection, 16 (13.1%) viral infection, and 29 (23.8%) bacterial/viral coinfection. Although upper respiratory symptoms were more common in patients with viral pneumonia, and white blood cell (WBC) counts were higher in patients with bacterial pneumonia, no clinical, laboratory or imaging findings allowed exclusion of bacterial \u0026nbsp;coinfection in patients who tested positive for a respiratory virus. A greater proportion of patients with bacterial/viral coinfection (30%) were admitted or transferred to the ICU during their hospital course, compared to 17% and 19% of patients with bacterial or viral infection, respectively (p\u0026lt;.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions. \u003c/strong\u003e\u0026nbsp;If a test for a respiratory virus test is positive in a patient hospitalized for CAP, no sufficiently differentiating features exclude bacterial coinfection, thereby supporting the recommendation that empiric antibiotics be administered to all patients who are sufficiently ill to require hospitalization for CAP.\u003c/p\u003e","manuscriptTitle":"Can Clinical Findings at Admission Allow Withholding of Antibiotics in Patients Hospitalized for Community Acquired Pneumonia when a Test for a Respiratory Virus is Positive?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 22:17:34","doi":"10.21203/rs.3.rs-4618989/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-25T15:28:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-15T16:17:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-12T17:32:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"137064254462715195463254705807742633586","date":"2024-07-11T06:56:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-08T15:56:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"67630695132753462366279848249970733951","date":"2024-07-08T15:28:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"213177103764906830704855890305344255405","date":"2024-07-06T07:37:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"24747854696820260836352927744956825914","date":"2024-07-05T20:29:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"34380007723699650443758896022365870270","date":"2024-07-05T18:05:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-05T17:36:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-24T06:48:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-24T06:46:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pneumonia","date":"2024-06-21T18:53:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pneumonia","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pneu","sideBox":"Learn more about [Pneumonia](http://pneumonia.biomedcentral.com)","snPcode":"41479","submissionUrl":"https://submission.nature.com/new-submission/41479/3","title":"Pneumonia","twitterHandle":"@pneumoniajourn","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a12be50e-1a4d-4b53-9446-f0829c86ce0e","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-06T16:04:12+00:00","versionOfRecord":{"articleIdentity":"rs-4618989","link":"https://doi.org/10.1186/s41479-024-00153-9","journal":{"identity":"pneumonia","isVorOnly":false,"title":"Pneumonia"},"publishedOn":"2025-01-05 15:57:06","publishedOnDateReadable":"January 5th, 2025"},"versionCreatedAt":"2024-07-18 22:17:34","video":"","vorDoi":"10.1186/s41479-024-00153-9","vorDoiUrl":"https://doi.org/10.1186/s41479-024-00153-9","workflowStages":[]},"version":"v1","identity":"rs-4618989","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4618989","identity":"rs-4618989","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}