Graphical abstract
Overview of the study. CAP: community-acquired pneumonia.
Abstract
Background
Halm's clinical stability criteria have long guided antibiotic treatment and hospital discharge decisions for patients hospitalised with community-acquired pneumonia (CAP). Originally introduced in 1998, these criteria were established based on a relatively small and select patient population. Consequently, our study aims to reassess their applicability in the management of CAP in a contemporary real-world setting.
Methods
This cohort study included 2918 immunocompetent patients hospitalised with CAP from three hospitals in Denmark between 2017 and 2020. The primary outcome was time to achieve clinical stability as defined by Halm's criteria. Additionally, we examined recurrence of clinical instability and severe complications. Cumulative incidence function or Kaplan–Meier survival curves were used to analyse these outcomes, considering competing risks.
Results
The study population primarily comprised elderly individuals (median age 75 years) with significant comorbidities. The median time to clinical stability according to Halm's criteria was 4 days, with one-fifth experiencing recurrence of instability after early clinical response (stability within 3 days). Severe complications within 30 days mainly comprised mortality, with rates of 5.1% (64/1257) overall in those with early clinical response, 1.7% (18/1045) in the subgroup without do-not-resuscitate orders and 17.3% (276/1595) among the rest.
Conclusion
Halm's clinical stability criteria effectively classify CAP patients with different disease courses, yet achieving stability required more time in this ageing population with substantial comorbidities and more severe disease. Early clinical response indicates reduced risk of complications, especially in those without do-not-resuscitate orders.
Shareable abstract
Halm's criteria still classify patients with community-acquired pneumonia effectively, yet present-day cases may require more time for stability. Early clinical response indicates low complication risk, especially among those without treatment limitations. https://bit.ly/3SHHpdk
Introduction
Clinical stability has for decades served as a valuable marker of improvement in patients hospitalised with community-acquired pneumonia (CAP). In 1998, Halm et al. [1] introduced criteria for assessing clinical stability in CAP management. These criteria, in addition to normal mental status and the ability to eat, establish specific thresholds for five common vital signs: systolic blood pressure, heart rate, respiratory rate, oxygen saturation and body temperature.
In clinical decision making, the resolution of abnormal vital signs holds significance. It helps clinicians in determining when to 1) transition from intravenous to oral antibiotics, 2) discontinue antibiotic therapy and 3) discharge patients from the hospital [2, 3]. Halm's criteria are incorporated in the major clinical guidelines on treatment duration [4, 5] and have been adopted by the US Food and Drug Administration as an early clinical end-point in trials evaluating new antibiotic drugs [6]. However, few studies have replicated or validated the original study, and none have done so on a large real-world population [7–11]. In addition, the population studied by Halm et al. [1] may not accurately represent those encountered in present-day clinical care, given that the study was conducted on relatively young individuals (median age 58 years) with predominantly mild disease enrolled in 1991–1994. Further, treatment strategies have evolved since then.
An early clinical response in CAP is defined as achieving clinical stability within 3–4 days of hospitalisation [6]. In light of the growing issue of antimicrobial resistance, there is increased interest in tailoring CAP treatment based on individual clinical responses [12, 13]. For instance, individuals that achieve an early clinical response have a non-inferior outcome with shorter antimicrobial treatments compared to longer treatments [14, 15]. To assess the current importance of clinical stability classification in CAP, our study aimed to evaluate Halm's criteria in a contemporary real-world population of patients hospitalised with CAP by 1) describing the time to achieve clinical stability, 2) characterising individuals who achieve an early clinical response, and 3) assessing the risk of instability recurrence and severe complications subsequent to clinical stability.
Methods
Study design
This study is a multicentre cohort study based on an extension of the optiCAP cohort [16] including individuals hospitalised with CAP. The cohort was established through pre-planned regular journal audits, enabling prospective data collection as previously described [16]. Analyses for this study were performed retrospectively.
Participants and settings
The target population was adults (age ≥18 years) diagnosed and hospitalised with CAP who were immunocompetent. The study population included individuals consecutively hospitalised with CAP at three academic hospitals in the Capital Region of Denmark between November 2017 and July 2020. CAP was defined as a new infiltrate on chest radiography and at least one symptom or sign compatible with pneumonia as previously described [16]. Patients were considered immunocompromised if they received immunosuppressive therapy, had neutropenia (<1000 µL−1), had HIV infection or had received an organ transplant [16]. In addition, we excluded patients with prior admissions within the last 28 days or active tuberculosis, but included nursing home residents and patients admitted to the intensive care unit (ICU). Individuals could enter the study population only once, i.e. only the first admission during the study period was included.
Variables
An overview of all baseline variables, their definition and data source is presented in supplementary table S1. These included age, sex, smoking status, number of hospitalisations within the previous 3 years, the amount of infiltration on chest radiography, results from blood tests drawn at admission, adequacy of initial antibiotic therapy, vital signs registered at admission, disease severity (according to the CURB-65 score; 1 point for each of confusion, urea ≥7 mmol·L−1, respiratory rate >30 breaths·min−1, blood pressure (systolic <90 mmHg, diastolic ≤60 mmHg), age ≥65 years [17]), comorbidities and comedications.
Clinical stability
Clinical stability was defined in accordance with Halm's criteria as follows: systolic blood pressure ≥90 mmHg, heart rate ≤100 beats·min−1, respiratory rate ≤24 breaths·min−1, body temperature ≤37.8°C and peripheral oxygen saturation ≥90%. Oxygenation saturation was deemed stable when patients no longer needed supplemental oxygen to maintain a saturation ≥90%. For individuals with a chronic oxygen supply of ≤3 L·min−1 documented in their medical records during hospitalisation, stability was reached when their supplemental oxygen requirement returned to this baseline level.
Individuals were considered clinically stable when all five criteria were concurrently met, with each criterion assessed independently using the most extreme daily value.
Early clinical response
Early clinical response was defined as achieving clinical stability, as per the aforementioned criteria, within 3 days of hospital admission.
Outcomes
The primary outcome was time to achieve clinical stability in individuals initially unstable upon hospital admission. The secondary outcomes were 1) risk of recurrence of clinical instability, defined as any parameter of the clinical stability criteria exceeding accepted limits, 2) risk of serious deterioration during admission, defined as the need of vasopressors or admission to an ICU, and 3) risk of severe complications, including all-cause mortality. Severe complications were categorised into CAP-related and CAP-unrelated events, including 1) development of pleural effusion, pleural empyema and lung abscess or 2) occurrence of acute renal failure, myocardial infarction and pulmonal embolism.
Follow-up
Individuals were followed from the day of hospital admission (day 1) until death, emigration or day 90 after admission, whichever occurred first. Severe complications were primarily assessed within a timeframe of 30 days. For time to clinical stability analyses, individuals were followed until they achieved the outcome of interest (clinical stability) or until hospital discharge, after which no additional vital sign recordings were available. In this context, discharge was considered as right-censoring.
Data sources
Data was retrieved from medical records and healthcare registries, including daily vital signs, in-hospital medications, laboratory data, imaging data and in-hospital diagnoses during hospitalisation. Using the Danish unique personal identifier, each individual was linked to nationwide registries containing information on in- and out-hospital contacts (Danish National Patient Registry), prescription data (Danish National Prescription Registry) and vital status (Danish Civil Registration System) [18].
Statistical analysis
Baseline characteristics of the study population are presented with descriptive statistics for both the overall population and subgroups stratified by early clinical response.
Time to achieve clinical stability is presented with cumulative incidence function (CIF) curves and estimated using the Aalen–Johansen estimator, treating death as a competing risk [19]. Among individuals achieving an early clinical response, the risks of subsequent recurrence of instability, severe deterioration during hospitalisation or severe complications following stability were estimated similarly since death may be considered a competing risk. Finally, all-cause mortality was estimated using the Kaplan–Meier estimator and corresponding survival curves are presented.
Subgroup analysis
Time to clinical stability was assessed by disease severity, 10-year age groups and bacterial pathogen to explore their potential impact on the disease course. Disease severity was categorised as low risk (CURB-65 score of 0–1), moderate risk (CURB-65 score 2) or severe risk (CURB-65 score 3–5) [17], which correspond to the Pneumonia Severity Index (PSI) scores used by Halm et al. [1, 20]. Moreover, baseline characteristics were stratified and presented based on the presence of treatment limitations, in terms of do-not-resuscitate orders.
Sensitivity analysis
To address deaths following severe complications, we analysed all-cause mortality within 90 days of admission. To evaluate characteristics, complications and mortality among patients reaching stability beyond day 3, we extended the evaluation time-points to 4 and 5 days, respectively. Acknowledging that patients with COPD often maintain an oxygen saturation level of 88%, we adjusted the criteria for this vital sign accordingly. Furthermore, we investigated the effect on time to achieve stability when patients were considered clinically stable while receiving up to 5 L·min−1 of chronic oxygen supply. Finally, we examined the impact of a more conservative threshold for oxygen saturation at 94% and a less conservative threshold for temperature at 38.3°C.
All statistical analyses were performed using R version 4.2.1 (www.r-project.org). The R package “prodlim” was used for competing risk analysis [21].
Missing data
The amount of missing data at baseline is available from table 1. If one or more values of the clinical stability criteria were missing at a day of hospitalisation, single imputation using the last observed value within this category was performed, assuming that recordings of the specific vital signs were primarily paused or stopped due to observed persisting stability.
TABLE 1.
Baseline characteristics of the study population, overall and stratified by early clinical response
| Overall | Early clinical response | Missing (%) | ||
|---|---|---|---|---|
| Yes | No | |||
| Patients | 2918# | 1257 | 1595 | |
| Age (years) | 75 (63–84) | 74 (62–83) | 75 (64–84) | 0.0 |
| Sex | ||||
| Female | 1451 (49.7) | 609 (48.4) | 811 (50.8) | 0.0 |
| Male | 1467 (50.3) | 648 (51.6) | 784 (49.2) | |
| Smoking status | ||||
| Current smoker | 544 (18.6) | 223 (17.7) | 306 (19.2) | |
| Former smoker | 1120 (38.4) | 489 (38.9) | 609 (38.2) | |
| Never-smoker | 523 (17.9) | 243 (19.3) | 273 (17.1) | |
| Not registered | 731 (25.1) | 302 (24.0) | 407 (25.5) | |
| Previous hospitalisations | 0.0 | |||
| 0 | 906 (31.0) | 408 (32.5) | 478 (30.0) | |
| 1 | 578 (19.8) | 259 (20.6) | 303 (19.0) | |
| 2 | 400 (13.7) | 168 (13.4) | 215 (13.5) | |
| ≥3 | 1034 (35.4) | 422 (33.6) | 599 (37.6) | |
| Multilobar infiltrates on chest radiography | 879 (30.2) | 301 (23.9) | 549 (34.5) | 0.2 |
| ICU at admission (within 48 h) | 70 (2.4) | 6 (0.5) | 62 (3.9) | 0.0 |
| Adequate initial antibiotic therapy | 0.0 | |||
| Yes | 2541 (87.1) | 1123 (89.4) | 1357 (85.1) | |
| No | 117 (4.0) | 45 (3.6) | 72 (4.5) | |
| Not administered | 260 (8.9) | 88 (7.0) | 166 (10.4) | |
| Biochemistry results | ||||
| P-C-reactive protein (mg·L−1) | 100 (45–190) | 98 (45–181) | 100 (44–190) | 1.7 |
| P-C-reactive protein at 72 h (mg·L−1) | 110 (61–176) | 98 (57–150) | 120 (66–200) | 25.6 |
| B-Haemoglobin (mmol·L−1) | 8.0 (7.2–8.7) | 8.0 (7.3–8.7) | 8.0 (7.2–8.8) | 0.4 |
| B-Leukocyte count (×109 L−1) | 12.0 (8.9–16.1) | 12.1 (9.0–16.2) | 11.7 (8.6–15.8) | 0.9 |
| B-Neutrocytes (×109 L−1) | 9.5 (6.7–13.0) | 9.5 (6.7–13.0) | 9.4 (6.7–13.0) | 2.3 |
| B-Lymphocytes (×109 L−1) | 1.1 (0.7–1.6) | 1.2 (0.8–1.7) | 1.0 (0.7–1.5) | 2.3 |
| B-Thrombocytes (×109 L−1) | 259 (198–337) | 269 (207–344) | 251 (191–333) | 2.3 |
| P-Glucose (mmol·L−1) | 7.3 (6.3–8.9) | 7.1 (6.2–8.6) | 7.3 (6.4–9.0) | 20.6 |
| P-Lactate dehydrogenase (U·L−1) | 209 (178–256) | 198 (171–236) | 218 (184–270) | 22.0 |
| P-Creatinine (μmol·L−1) | 80 (62–107) | 78 (62–101) | 81 (62–109) | 0.7 |
| P-Urea (mmol·L−1) | 6.4 (4.4–9.6) | 5.9 (4.2–8.4) | 6.6 (4.7–10.3) | 4.6 |
| P-Albumin (g·L−1) | 32 (28–35) | 33 (29–36) | 31 (28–35) | 1.5 |
| P-Alanine transaminase (U·L−1) | 23 (16–35) | 22 (15–33) | 23 (16–36) | 5.1 |
| P-Bilirubin (µmol·L−1) | 9 (7–14) | 9 (6–14) | 10 (7–14) | 4.8 |
| Vitals¶ | ||||
| Heart rate (beats·min−1) | 98 (86–110) | 95 (84–105) | 100 (88–114) | 0.2 |
| Systolic blood pressure (mmHg) | 119 (107–133) | 121 (110–136) | 118 (105–131) | 0.2 |
| Supplemental oxygen (L·min−1) | 2 (0–4) | 0 (0–2) | 3 (1–5) | 6.2 |
| Need for oxygen supply | 1748 (59.9) | 515 (41.0) | 1174 (73.6) | 0.0 |
| Peripheral oxygen saturation (%) | 94 (91–96) | 95 (93–96) | 93 (90–95) | 0.1 |
| Respiratory rate (breaths·min−1) | 22 (20–25) | 20 (18–23) | 22 (20–28) | 0.5 |
| Temperature (°C) | 37.6 (37.0–38.5) | 37.5 (37.0–38.4) | 37.8 (37.0–38.6) | 0.8 |
| Abnormal mental status | 76 (2.6) | 17 (1.4) | 52 (3.3) | 0.0 |
| CURB-65 score+ | 0.7 | |||
| 0 | 590 (20.4) | 311 (24.7) | 273 (17.2) | |
| 1 | 959 (33.1) | 445 (35.4) | 508 (32.1) | |
| 2 | 879 (30.3) | 372 (29.6) | 492 (631.1) | |
| 3 | 390 (13.5) | 108 (8.6) | 253 (16.0) | |
| 4 | 74 (2.6) | 13 (1.4) | 52 (3.3) | |
| 5 | 7 (0.2) | NA | NA | |
| Comorbidities | ||||
| COPD | 829 (28.4) | 334 (26.6) | 476 (29.9) | 0.0 |
| Asthma | 290 (9.9) | 145 (11.5) | 141 (8.8) | 0.0 |
| Hypertension | 1227 (42.0) | 491 (39.0) | 708 (44.4) | 0.0 |
| Ischaemic heart disease | 514 (17.6) | 200 (15.9) | 300 (18.8) | 0.0 |
| Congestive heart failure | 366 (12.5) | 141 (11.2) | 213 (13.4) | 0.0 |
| Cerebrovascular disease | 502 (17.2) | 192 (15.3) | 298 (18.7) | 0.0 |
| Diabetes mellitus | 507 (17.4) | 206 (16.4) | 279 (17.5) | 0.0 |
| Cancer | 212 (7.3) | 94 (7.5) | 114 (7.1) | 0.0 |
| Liver disease | 63 (2.2) | 22 (1.8) | 39 (2.4) | 0.0 |
| Chronic kidney disease | 160 (5.5) | 66 (5.3) | 88 (5.5) | 0.0 |
| Comedications | ||||
| Antiplatelet drugs | 553 (19.0) | 226 (18.0) | 308 (19.3) | 0.0 |
| Anticoagulant drugs | 451 (15.5) | 163 (13.0) | 271 (17.0) | 0.0 |
| Statins | 655 (22.4) | 247 (19.6) | 386 (24.2) | 0.0 |
| Antibiotics before admission§ | 592 (21.2) | 286 (22.8) | 299 (19.8) | 4.2 |
| Do-not-resuscitate orders | 799 (27.4) | 212 (16.9) | 545 (34.2) | 0.0 |
| Length of hospital stay (days) | 4.8 (2.7–8.0) | 3.7 (2.1–5.7) | 6.1 (3.7–9.9) | |
| Complications | ||||
| ICU admission after day 3 of hospitalisation | 40 (1.4) | 2 (0.2) | 38 (2.4) | |
| 30-day mortality | ||||
| Overall | 340 (11.7) | 64 (5.1) | 276 (17.3) | |
| Patients without treatment limitations | 74 (3.5) | 18 (1.7) | 56 (5.3) | |
| Patients with do-not-resuscitate orders | 266 (33) | 46 (21.7) | 220 (40.4) | |
Data are presented as n, median (interquartile range) or n (%), unless otherwise stated. ICU: intensive care unit; P: plasma; B: blood; NA: not available (not reported due to patient confidentiality issues). #: 66 patients died before assessment at day 3 of hospitalisation; ¶: most extreme value of vital signs recorded at the day of admission; +: 1 point for each of confusion, urea ≥7 mmol·L−1, respiratory rate >30 breaths·min−1, blood pressure (systolic <90 mmHg, diastolic ≤60 mmHg), age ≥65 years [17]; §: antibiotics targeting a lower respiratory tract infection received before admission.
Ethical considerations
Approvals by the Danish Patient Safety Authority (31-1521-101), the Centre for Regional Development in the Capital Region of Denmark (R-20054259) and the Regional Data Protection Centre in the Capital Region of Denmark (P-2020-1116) were obtained, with a waiver of informed consent in accordance with Danish legislation.
Results
Study population
The study included 2918 immunocompetent individuals consecutively hospitalised with radiologically confirmed CAP. They had a median (interquartile range (IQR)) age of 75 (63–84) years and an equal distribution between sexes. Nearly one-third had multilobar infiltration and the majority presented with a CURB-65 score of 1–2 (table 1). Plasma C-reactive protein (CRP) levels were elevated at a median of 100 mg·L−1. Nearly 30% had COPD, while other prevalent comorbidities included cardiometabolic diseases, comprising hypertension, cardiovascular disease and diabetes mellitus. Two-thirds of the population had been hospitalised within the past 3 years. Initially, 2.4% required admission to the ICU, while 27% had treatment limitations, indicated by do-not-resuscitate orders (table 1).
Overall, 91% (2658 individuals) were administered antibiotics suitable for a lower respiratory tract pathogen within 24 h of admission. Of these, 86% received penicillins, 30% macrolides, 7% cephalosporins, 1.4% quinolones and 0.5% carbapenems (supplementary table S2).
Upon admission, 84% (2457 individuals) had at least one sign suggesting clinical instability. Respiratory status was the primary indicator of instability, with 60% requiring supplemental oxygen at a median of 2 L·min−1. Instabilities of heart rate and temperature were also notable, both affecting 42% of patients (table 1).
Onset of clinical stability
Among individuals admitted with at least one sign of clinical instability, 72% (1759 individuals) achieved clinical stability during hospitalisation. The median (IQR) time to clinical stability was 4 (3–10) days and differed according to disease severity, from 3 days in the low-risk group to 6 days in those with high risk (table 2). Time to clinical stability or death is presented with CIF curves in figure 1, while figure 2 shows the time course for reaching each stability criterion separately. Mental status was the first criteria to stabilise, while the need for supplemental oxygen took the longest time (table 3).
TABLE 2.
Time to stability according to disease severity
| Low risk | Moderate risk | High risk | All patients | |
|---|---|---|---|---|
| This study | CURB-65# score 0–1 | CURB-65 score 2 | CURB-65 score 3–5 | |
| Patients | 1263 | 736 | 443 | 2457 |
| Time to stability (days) | 3 (2–7) | 4 (3–11) | 6 (3–59) | 4 (3–10) |
| Halm et al. [1] | PSI¶ class I–III | PSI class IV | PSI class V | |
| Patients | 488 | 142 | 56 | 686 |
| Time to stability (days) | 3 (2–5) | 4 (2–7) | 6 (3–9) | 3 (2–5) |
Data are presented as n or median (interquartile range). PSI: Pneumonia Severity Index. #: 1 point for each of confusion, urea ≥7 mmol·L−1, respiratory rate >30 breaths·min−1, blood pressure (systolic <90 mmHg, diastolic ≤60 mmHg), age ≥65 years [17]; ¶: clinical prediction rule based on demographics, significant comorbidities, certain physical exam findings, laboratory findings and radiographic findings that categorises patients into five risk classes I–V [20].
FIGURE 1.
Time to overall clinical stability and all-cause mortality among individuals with at least one instability criterion at hospital admission. Shading indicates 95% confidence intervals.
FIGURE 2.
Time to clinical stability of individual stability criteria among patients unstable upon hospital admission. a) Systolic blood pressure, heart rate and temperature. b) Oxygen saturation, respiratory rate and need for supplemental oxygen.
TABLE 3.
Time to overall stability and stability for each stability criterion
| Unstable upon hospital admission | Time to stability (days) | |
|---|---|---|
| Overall | 2457 (84) | |
| Halm's criteria# | 4 (3–10) | |
| Temperature ≤38.3°C | 4 (2–9) | |
| Oxygen saturation ≥94% | 6 (3–29) | |
| Each stability criterion (Halm's criteria) | ||
| Systolic blood pressure (≥90 mmHg) | 162 (6) | 2 (2–3) |
| Heart rate (≤100 beats·min−1) | 1235 (42) | 2 (2–4) |
| Respiratory rate (≤24 breaths·min−1) | 724 (25) | 2 (2–4) |
| Temperature (≤37.8°C) | 1219 (42) | 2 (2–3) |
| Oxygen saturation (≥90%) | 459 (16) | 2 (2–3) |
| Need for supplemental oxygen | 1748 (60) | 3 (2–6) |
| Abnormal mental status | 76 (3) | 1 (1–2) |
Data are presented as n (%) or median (interquartile range). #: Halm's criteria: overall clinical stability is defined by having systolic blood pressure ≥90 mmHg, heart rate ≤100 beats·min−1, respiratory rate ≤24 breaths·min−1, temperature ≤37.8°C and oxygen saturation ≥90%, without requiring non-chronic supplemental oxygen and having a normal mental status.
Early clinical response
Within 3 days of admission, 43% (1257 individuals) achieved an early clinical response. This group was characterised by being younger, more often male, having fewer prior hospitalisations, fewer comorbidities and a single infiltrate (table 1). They also presented with less severe disease upon admission, indicated by lower CURB-65 scores. The unstable group, in contrast, required supplemental oxygen at admission in 74% of cases and had more extreme deviations across all initial clinical stability criteria, presented more abnormal levels of inflammatory biomarkers initially and after 72 h, and less often received adequate initial antibiotic therapy (table 1).
Recurrence of instability
Among those with an early clinical response, 20% (257 individuals) experienced a recurrence of clinical instability during hospitalisation. Instability reoccurred within the first 24 h in most patients (median (IQR) 1 (1–3) days). The most frequent criteria for recurrence were heart rate and temperature (supplementary table S3). Individuals who were older, frequent healthcare users, presented with more severe disease and had more comorbidities, especially COPD, diabetes and hypertension, were more likely to experience recurrence (table 4). The presence of Legionella pneumophila, Pseudomonas aeruginosa and Staphylococcus aureus was higher in these cases, while Mycoplasma pneumoniae and Chlamydia pneumoniae were less common.
TABLE 4.
Baseline characteristics of individuals with an early clinical response, stratified by subsequent recurrence of clinical instability
| Recurrence of clinical instability | SMD | ||
|---|---|---|---|
| Yes | No | ||
| Patients | 257 | 1000 | |
| Age (years) | 78 (70–85) | 72 (59–82) | 0.460 |
| Sex | 0.094 | ||
| Female | 115 (44.7) | 494 (49.4) | |
| Male | 142 (55.3) | 506 (50.6) | |
| Smoking status | 0.192 | ||
| Current smoker | 39 (15.2) | 184 (18.4) | |
| Former smoker | 116 (45.1) | 373 (37.3) | |
| Never-smoker | 39 (15.2) | 204 (20.4) | |
| Not registered | 63 (24.5) | 238 (23.8) | |
| Previous hospitalisations | 0.275 | ||
| 0 | 74 (28.8) | 334 (33.4) | |
| 1 | 37 (14.4) | 221 (22.1) | |
| 2 | 37 (14.4) | 131 (13.1) | |
| ≥3 | 109 (42.4) | 313 (31.3) | |
| Multilobar infiltrates on chest radiography | 79 (30.7) | 222 (22.2) | 0.193 |
| Adequate initial antibiotic therapy | 0.295 | ||
| Yes | 244 (94.9) | 879 (87.9) | |
| No | 8 (3.1) | 37 (3.7) | |
| Not administered | 5 (1.9) | 83 (8.3) | |
| Biochemistry results | |||
| P-C-reactive protein (mg·L−1) | 110 (47–190) | 94 (45–179) | 0.166 |
| P-C-reactive protein at 72 h (mg·L−1) | 110 (58–184) | 96 (57–140) | 0.336 |
| B-Haemoglobin (mmol·L−1) | 7.8 (7.0–8.6) | 8.0 (7.3–8.7) | 0.222 |
| B-Leukocyte count (×109 L−1) | 13.3 (9.8–17.1) | 11.8 (8.9–15.9) | 0.171 |
| B-Neutrocytes (×109 L−1) | 10.6 (7.8–14.0) | 9.2 (6.6–13.0) | 0.222 |
| B-Lymphocytes (×109 L−1) | 1.2 (0.7–1.6) | 1.2 (0.8–1.7) | 0.058 |
| B-Thrombocytes (×109 L−1) | 288 (225–381) | 263 (203–337) | 0.248 |
| P-Glucose (mmol·L−1) | 7.5 (6.5–9.6) | 7.0 (6.1–8.3) | 0.290 |
| P-Lactate dehydrogenase (U·L−1) | 208 (169–254) | 197 (172–232) | 0.146 |
| P-Creatinine (µmol·L−1) | 80 (63–124) | 78 (61–98) | 0.317 |
| P-Urea (mmol·L−1) | 6.8 (4.9–10.7) | 5.8 (4.0–8.0) | 0.442 |
| P-Albumin (g·L−1) | 30 (27–34) | 33 (30–36) | 0.430 |
| P-Alanine transaminase (U·L−1) | 20 (15–32) | 22 (15–34) | 0.006 |
| P-Bilirubin (µmol·L−1) | 9 (7–14) | 9 (6–14) | 0.080 |
| Vitals# | |||
| Heart rate (beats·min−1) | 100 (87–110) | 94 (84–104) | 0.316 |
| Systolic blood pressure (mmHg) | 122 (110–139) | 121 (110–135) | 0.044 |
| Supplemental oxygen (L·min−1) | 2 (0–3) | 0 (0–2) | 0.205 |
| Need for oxygen supply | 139 (54.1) | 375 (37.5) | 0.337 |
| Peripheral oxygen saturation (%) | 94 (92–96) | 95 (93–96) | 0.089 |
| Respiratory rate (breaths·min−1) | 20 (20–24) | 20 (18–22) | 0.264 |
| Temperature (°C) | 37.4 (36.9–38.2) | 37.6 (37.0–38.5) | 0.192 |
| Abnormal mental status | 6 (2.3) | 10 (1.0) | 0.104 |
| CURB-65 score¶ | 0.457 | ||
| 0 | 32 (12.5) | 279 (28.1) | |
| 1 | 88 (34.4) | 357 (36.0) | |
| 2 | 97 (37.9) | 275 (27.7) | |
| 3 | 35 (13.7) | 73 (7.4) | |
| 4 | NA | NA | |
| 5 | NA | NA | |
| Comorbidities | |||
| COPD | 86 (33.5) | 248 (24.8) | 0.191 |
| Asthma | 25 (9.7) | 120 (12.0) | 0.073 |
| Hypertension | 129 (50.2) | 361 (36.1) | 0.287 |
| Ischaemic heart disease | 45 (17.5) | 155 (15.5) | 0.054 |
| Congestive heart failure | 33 (12.8) | 108 (10.8) | 0.063 |
| Cerebrovascular disease | 47 (18.3) | 144 (14.4) | 0.105 |
| Diabetes mellitus | 53 (20.6) | 152 (15.2) | 0.141 |
| Cancer | 22 (8.6) | 72 (7.2) | 0.050 |
| Liver disease | 18 (7.0) | 54 (5.4) | 0.066 |
| Chronic kidney disease | 8 (3.1) | 14 (1.4) | 0.115 |
| Comedications | |||
| Antiplatelet drugs | 61 (23.7) | 164 (16.4) | 0.183 |
| Anticoagulant drugs | 39 (15.2) | 124 (12.4) | 0.080 |
| Statins | 57 (22.2) | 190 (19.0) | 0.078 |
| Antibiotics before admission+ | 50 (19.8) | 236 (24.4) | 0.110 |
| Do-not-resuscitate orders | 93 (36.2) | 119 (11.9) | 0.592 |
| Length of hospital stay (days) | 7.9 (5.3–12.1) | 3.1 (1.9–4.4) | 1.236 |
| Mortality | |||
| In-hospital | 17 (6.6) | 1 (0.1) | |
| 30-day | 32 (12.5) | 32 (3.2) | |
Data are presented as n, median (interquartile range) or n (%), unless otherwise stated. SMD: standardised mean difference; P: plasma; B: blood; NA: not available (not reported due to patient confidentiality issues). #: most extreme value of vital signs recorded at the day of admission; ¶: 1 point for each of confusion, urea ≥7 mmol·L−1, respiratory rate >30 breaths·min−1, blood pressure (systolic <90 mmHg, diastolic ≤60 mmHg), age ≥65 years [17]; +: antibiotics targeting a lower respiratory tract infection received before admission.
Severe complications after early clinical response
In the group with early clinical response, 17 (1.4%) out of 1257 experienced severe complications possibly related to CAP after the third day of hospitalisation compared to 24 (1.5%) out of 1595 in the unstable group. For non-CAP-related events, the respective numbers were 10 (1.0%) out of 1257 and 35 (2.2%) out of 1595. These findings correspond to 30-day risks of 1–2% (table 5). Severe deterioration, in terms of ICU admission or vasopressor support, after day 3 was rare, with only two events in the stable group and 39 in the unstable group. Considering in-hospital death as a competing event, the 14-day risks were 1.0% (95% CI 0.0–3.0%) and 3.9% (95% CI 2.5–5.4%) in the two groups, respectively.
TABLE 5.
Severe complications after early clinical response within 30 days of hospital admission
| Severe complications# | Definition | Early clinical response (n=1257) |
No early clinical response (n=1595) |
|---|---|---|---|
| CAP-related | |||
| Pleural effusion | ICD-10: J909, J919 | 8 (0.6) | 20 (1.3) |
| Pleural empyema | ICD-10: J860, J869 | 8 (0.6) | 5 (0.3) |
| Lung abscess | ICD-10: J851, J852 | 4 (0.3) | 4 (0.3) |
| Total | 17 (1.4) | 24 (1.5) | |
| CAP-non-related | |||
| Acute renal failure | ICD-10: N17 | 0 (0) | 14 (0.9) |
| Acute myocardial infarction | ICD-10: I21 | 5 (0.4) | 7 (0.4) |
| Pulmonary embolism | ICD-10: I260, I269 | 5 (0.6) | 14 (0.8) |
| Total | 10 (1.0) | 35 (2.2) | |
| Severe deterioration | |||
| Need for vasopressor | ATC: C01CA03–04, C01CA07, C01CA24 | 2 (0.2) | 32 (2.0) |
| ICU admission | 2 (0.2) | 38 (2.4) | |
| Total | 2 (0.2) | 39 (2.4) | |
| Mortality | |||
| Death | 64 (5.1) | 276 (17.3) | |
Data are presented as n (%). CAP: community-acquired pneumonia; ICU: intensive care unit; ICD-10: International Classification of Diseases, 10th Revision; ATC: Anatomical Therapeutic Chemical Classification. #: patients may present with more than one complication.
Mortality
The Kaplan–Meier survival curve depicting mortality from any cause, stratified by early clinical response, is presented in figure 3. Across groups, the 30-day mortality rates were 64 out of 1257 (5.1%) versus 276 out of 1595 (17.3%) (table 5). Further subgroup analysis based on treatment limitations showed mortality rates of 1.7% versus 5.3% in patients without limitations and 21.7% versus 40.4% in those with do-not-resuscitate orders (table 1 and supplementary tables S4 and S5).
FIGURE 3.
All-cause mortality within 30 days of hospital admission, stratified by early clinical response. Shading indicates 95% confidence intervals.
Subgroup analyses
Individuals aged <55 years had a median time to stability of 3 days, while all older age groups required a median of 4 days (supplementary table S6). Looking at verified bacterial aetiology, individuals infected with Moraxella catarrhalis had the shortest time to stability, while those infected with L. pneumophila had the longest (supplementary table S6).
Sensitivity analyses
Within 90 days of admission, 111 out of 1257 (9%) individuals in the group with early clinical response and 385 out of 1595 (24%) in the unstable group had died after day 3. Adjusting the stability threshold to accept an oxygen saturation level of 88% in COPD patients affected the status of only 82 patients on day 3 and had no impact on the time to achieve clinical stability. Similarly, acknowledging a permissible chronic oxygen supply of up to 5 L·min−1 did not alter the time to clinical stability. When allowing 38.3°C as stable temperature, the median (IQR) time to stability remained at 4 (2–9) days, while requiring an oxygen saturation level of 94% extended the median (IQR) time to overall stability to 6 (3–29) days (table 3).
Extending the timeframe for reaching stability early resulted in an expansion of the stable group to include an additional 334 patients within 4 days, totalling 1591 patients, and 1764 patients within 5 days (supplementary tables S7 and S8). The distribution of severe complications and mortality within 30 days after admission between the stable and unstable group exhibited the same pattern as observed with the 3-day cut-off (supplementary table S9).
Discussion
Principal findings
In this contemporary real-world population of individuals hospitalised with CAP, the median time to achieve clinical stability was 4 days. Altogether, 1257 (43%) had an early clinical response, with 257 individuals experiencing recurrence of instability during hospitalisation. Contrasting those who remained unstable on day 3, the group achieving an early clinical response comprised younger individuals with milder disease and fewer comorbidities. Severe complications, primarily driven by mortality, were less frequent in the stable group, where the mortality rate was <2% in patients without do-not-resuscitate orders.
Research in context
Compared to the original study by Halm et al. [1] and subsequent research [7–10], our study found a slightly longer median time to overall clinical stability, lasting 4 days instead of 3 days. This difference may be ascribed to differences in study populations, particularly evident as the distinction disappeared upon stratification by disease severity. Notably, the interquartile ranges for each risk group were wider in our study, suggesting a more heterogeneous population. Previous studies mainly included younger individuals with select disease severities. For example, Halm et al. [1] examined a subgroup from the Pneumonia PORT study, which, during certain enrolment periods, included only low-risk patients. In contrast, our study included all immunocompetent patients consecutively admitted, regardless of severity, and did not require consent for study participation.
Another factor to consider is the definition of a stable respiratory status. Some studies allowed chronic supplemental oxygen like ours, while others permitted varying levels of non-chronic supplemental oxygen or none at all [1, 7–10]. In our study, the need for supplemental oxygen was the last criterion to stabilise, which could be influenced by the large proportion of individuals with COPD.
Regarding antibiotic therapy, 87% received adequate initial treatment, primarily penicillins, consistent with local susceptibility patterns including low resistance of Streptococcus pneumoniae [22]. Although differences between the stable and unstable groups were small, they could potentially affect the time to achieve clinical stability.
Our subgroup analyses confirm reports from previous studies, emphasising the significance of baseline characteristics in delayed clinical stability. These factors especially include age, initial disease severity, specific comorbidities and possibly the pathogen [7, 8, 10, 23]. In addition, CRP levels at 72 h seemed to consistently differ between the stable and unstable groups, in line with prior research [24].
Consistent with the findings in the study by Halm et al. [1], we observed that relapse to instability predominantly occurred within 24 h following stability. This emphasises the relevance of monitoring patients shortly after stability and aligns with the previously demonstrated impact of instability at discharge on clinical outcomes [25].
Compared with previous reports [1, 7–9], our study showed higher overall mortality rates. Interestingly, upon stratifying patients based on the presence of treatment limitations, we found that the high mortality rate was notably associated with the subset of patients with do-not-resuscitate orders, encompassing more than a quarter of the total population. This level of granular patient analysis represents a novel aspect not thoroughly explored in previous studies [26, 27].
Finally, in line with recent studies on treatment duration among patients achieving early stability, our findings indicate that stability achieved within the first 5 days from admission was associated with a more favourable disease trajectory compared to those who remain unstable.
Strengths and limitations
The primary strengths of this study lie in its large population composed of consecutively admitted individuals, mirroring real-world clinical care, and the depth of the available data. We have included comprehensive data, combining detailed in-hospital records with extensive information from healthcare registries. Moreover, individuals are followed repeatedly each day during hospitalisation and via the registries after discharge, enabling complete follow-up.
Our study does have limitations. First, we lacked an explicit measure for long-term oxygen treatment (LTOT) and therefore relied on the chronic accepted level of supplemental oxygen noted by the clinicians during hospitalisation. While this could potentially lead to an overestimation of the time to clinical stability, it is worth noting that the overall proportion of CAP patients requiring LTOT is relatively low, minimising the impact of this limitation. Second, the many unknown microbiological agents causing pneumonia reflects the real-world setting, but hinders our ability to assess their influence on the results [28]. Third, when examining recurrence of instability and severe complications, our analysis is conditioned on individuals being alive at day 3 after admission, which limits our findings and inferences to this specific population. Consequently, individuals who die shortly after admission are not well described. However, they make up only 2% of the entire study population. In addition, the generalisability of our findings is limited to countries with similar patient populations. Lastly, clinically stable patients likely have their vital signs recorded at larger time intervals. This could potentially lead to less frequent detection of recurrence of instability compared to clinically unstable individuals, making stable patients less likely to experience this event.
Implications of study findings
Our findings support the importance of assessing clinical stability in individuals hospitalised with CAP. Using Halm's clinical stability criteria remains relevant, as patients with an early clinical response follow distinct disease trajectories. However, even among those with an early clinical response, there persists a noteworthy risk of instability recurrence, disease exacerbation and mortality. Nonetheless, the exclusion of patients with do-not-resuscitate orders substantially reduces this risk. Hence, clinicians can generally rely on a favourable disease course following initial stabilisation in patients without treatment limitations. Future studies should strive to establish a combination of prognostic factors, including clinical stability and potentially biomarkers [29, 30], including those assessed at 72 h [24, 30], to develop stratification tools that can facilitate more tailored management strategies. Based on our findings, the clinical stability criteria, while maintaining their current thresholds, should primarily be used to classify patients without do-not-resuscitate orders.
Conclusions
Halm's clinical stability criteria remain applicable for classifying individuals hospitalised with CAP, effectively distinguishing between different disease courses. However, clinicians should note the potential for a prolonged timeline to achieve clinical stability in contemporary cases, probably reflecting an ageing population with increasing complexity due to comorbidities. Importantly, the risk of complications in CAP is low among those with an early clinical response without treatment limitations, suggesting reassurance on overall favourable outcomes in this subgroup.
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Footnotes
Author contributions: Conceptualisation of the study: S. Bastrup Israelsen and T. Benfield. Methodology: S. Bastrup Israelsen and T. Benfield. Data validation: S. Bastrup Israelsen, M. Fally, L. Kolte, P. Ravn and T. Benfield. Formal analysis: S. Bastrup Israelsen. Writing of the initial draft: S. Bastrup Israelsen. Manuscript review and editing: M. Fally, P. Brok Nielsen, L. Kolte, K. Karmark Iversen, P. Ravn and T. Benfield. Supervision of the study: T. Benfield. Funding acquisition: S. Bastrup Israelsen, P. Ravn and T. Benfield. All authors have read and agreed to the final version of the manuscript.
Conflict of interest: T. Benfield reports grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen's Charitable Fund, GSK, Pfizer, Boehringer Ingelheim, Gilead Sciences, MSD, Roche, Novartis and Kancera AB, consultancy fees from GSK and Pfizer, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, AbbVie and AstraZeneca, participation on a data safety monitoring board or advisory board with GSK, Pfizer, Gilead Sciences, MSD, Pentabase, Janssen and AstraZeneca, and receipt of equipment, materials, drugs, medical writing, gifts or other services from Eli Lilly (donation of trial medication (baricitinib)). M. Fally reports leadership roles with the European Respiratory Society (member of the Clinical Practice Guidelines Methodology Network and Secretary of Assembly 10, Group 1 (Bronchiectasis and Respiratory Infections)) and Danish Medical Journal (Associate Editor). The remaining authors have no potential conflicts of interest to disclose.
Support statement: The study was funded by a grant from the Danish Ministry of Health and by the involved hospitals. The funders had no role in the design of the study, data collection, analyses, writing of the manuscript or decision to publish the results. Funding information for this article has been deposited with the Crossref Funder Registry.
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