Validation of the 2017 Japanese Adult Pneumonia Guidelines: A Retrospective Cohort Study
Masahiro Aoshima1,*, Kei Nakashima1, Makito Yaegashi2, Atsushi Shiraishi3
1Kameda Medical Center, Department of Pulmonology, Kamogawa, Japan
2Kameda Medical Center, Department of General Internal Medicine, Kamogawa, Japan
3Kameda Medical Center, Emergency and Trauma Center, Kamogawa, Japan
*Corresponding author: Masahiro Aoshima, Kameda Medical Center, Department of Pulmonology, 929 Higashi-cho, Kamogawa-City, Chiba 296-8602, Japan, Tel: 81425776967; Fax: 81425776967; E-mail: firstname.lastname@example.org
Received Date: May 06, 2020; Accepted Date: June 15, 2020; Published: June 21, 2020
Citation: Masahiro Aoshima, Kei Nakashima, Makito Yaegashi, Atsushi Shiraishi, Validation of the 2017 Japanese adult pneumonia guidelines: a retrospective cohort study, J clinical Case Rep Case Stud 2020: 77-84.
Background: In 2017, the Japanese Respiratory Society issued updated Adult Pneumonia Guidelines (JRSGL2017). These guidelines contain an algorithm for empiric antibiotic selection based on 3 indicators of the probability of sepsis: quick Sepsis-related Systemic Organ Failure Assessment, pneumonia severity, and the likelihood of infection caused by an antimicrobial-resistant pathogen. This study aimed to validate the JRSGL2017 algorithm.
Methods: We evaluated consecutive patients admitted to our department from October 2014 to April 2016 with community-onset pneumonia and risk factors for healthcare-associated pneumonia. Based on the JRSGL2017 algorithm, the initial treatment strategy was classified as escalation (narrow-spectrum antibiotics), de-escalation with monotherapy (a single broad-spectrum antibiotic), or de-escalation with combination therapy. Based on a comparison to the antibiotics recommended and those actually used, we classified the therapy as algorithm concordant or algorithm discordant. The primary endpoint was 30-day mortality.
Results: A total of 225 patients were included in the analysis. Ninety-nine, 120, and 6 patients were treated according to the escalation strategy, the de-escalation with monotherapy strategy, and the de-escalation with combination therapy strategy, respectively. The initial treatment was algorithm concordant and algorithm discordant in 108 and 117 patients, respectively. The 30-day mortality was 4/108 (3.7%) and 9/117 (7.7%) for the algorithm-concordant and algorithm-discordant groups, respectively (odds ratio [OR]: 0.46, 95% CI: 0.10–1.72). In a subgroup analysis, propensity-matched on disease severity, the mortality was the same (3/30) in both groups. Overall, 95.7% of the discordant group was treated with narrow-spectrum antimicrobials according to the de-escalation strategy, and 87.0% of the concordant group was treated according to the escalation strategy.
Conclusion: Initial treatment with narrow-spectrum antibiotics in patients meeting the de-escalation strategy criteria did not adversely affect the outcome. Empiric therapy using the JRSGL2017 algorithm might lead to overuse of broad-spectrum antibiotics in patients with community-onset pneumonia and a risk of healthcare-associated pneumonia.
Keywords: Community-onset pneumonia; Healthcare-associated pneumonia; Hospital-acquired pneumonia; Antimicrobial therapy; Japanese Respiratory Society Adult Pneumonia Guidelines 2017
In 2017, the Japanese Respiratory Society issued updated Adult Pneumonia Guidelines (JRSGL2017) . Healthcare-associated pneumonia (HCAP) was not included in the updated hospital-acquired and ventilator-associated pneumonia (HAP/VAP) guidelines issued by Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) in 2016, because many validated studies have shown that patients with HCAP are not at high risk of infections caused by multidrug-resistant (MDR) pathogens . However, the category of HCAP is still used in Japan. According to JRSGL2017, patients with HCAP should be treated the same as patients with hospital-acquired pneumonia (HAP). The JRSGL2017 include a proposed algorithm for empiric antibiotic selection according to 3 indicators: the presence of sepsis, the severity of the pneumonia, and the risk of drug-resistant pathogens; then initial treatment policies recommended as “escalation”, “de-escalation with monotherapy”, or “de-escalation with combination therapy” based on this algorithm. The JRSGL2017 recommended that “escalation should be started with narrow-spectrum antibiotics; “de-escalation with monotherapy” should be started with broad-spectrum antibiotics; and “de-escalation with combination therapy” should be started with broad-spectrum antibiotics combined with other anti-pseudomonal agents (see Supplementary Information).
We hypothesized that antibiotic selection using the algorithm for treating HAP may lead to overuse of broad-spectrum antibiotics in patients with community-onset pneumonia (COP) with HCAP risk. The aim of this study is to examine the association between algorithm-discordant treatment and mortality in COP with HCAP risk.
Materials and Methods
Study design and participants
Consecutive COP patients admitted in Kameda Medical Center between October, 2014 and April, 2016 with at least one HCAP risk factor, following previous ATS/IDSA HAP/VAP/HCAP guidelines  were evaluated retrospectively. The study was approved by the Ethical Committee of the Kameda Medical Center (No. 19-162), and the study was conducted in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived because it was a retrospective study.
The study patients’ treatment was classified according to the JRSGL2017 algorithm as “escalation”, “de-escalation with monotherapy”, or “de-escalation with combination therapy”. The study patients’ treatment was further classified as “concordant” if the treatment specified by the algorithm was consistent with the antibiotics used, and “discordant” if the treatment was inconsistent with the algorithm used. The names of the antibiotics recommended for “escalation”, “de-escalation with monotherapy”, and “de-escalation with combination therapy” are provided in the Supplementary Information.
The causative pathogen was presumed based on the isolation of specific pathogens in specimens obtained from respiratory tract or on the basis of clinical and epidemiologic evidence . The diagnosis of pneumococcal pneumonia was based on a positive culture in a specimen obtained from the respiratory tract or blood, or testing positive for pneumococcal urinary antigen, based on recommendations of the Centers for Disease Control and Prevention .
The primary outcome was 30-day mortality. The secondary outcome was 90-day mortality. To minimize the possibility of confounding due to pneumonia severity, the adjusted 30-day mortality was calculated on 30 matched pairs after propensity-score matching using the 5 covariates in the CURB-65 criteria for assessing the severity of COP (confusion, blood urea nitrogen >7 mmol/L, respiratory rate ≥30 breaths/minute, blood pressure <90 mmHg systolic or <60 mmHg diastolic, and age ≥65 years).
The chi square test was used to compare categorical variables. P-values <0.05 were considered statistically significant. All statistical analyses were performed using R, version 3.22 (The R Foundation for Statistical Computing, Vienna, Austria, http://www.R-project.org/).
A total of 227 patients with COP and at risk of HCAP were identified. Two patients were excluded, because there was no record of a quick Sepsis-related Organ Failure Assessment (qSOFA) score, leaving 225 patients to be included in the analysis [Figure 1]. Of the patients, 99 were classified as requiring escalation therapy, 120 were classified as requiring de-escalation with monotherapy, and 6 were classified as requiring de-escalation with combination therapy, based on the JRSGL2017 algorithm. The 3 groups had a similar age distribution: 77 years (interquartile range [IQR]: 67-83 years), 87 years (IQR: 72-86.3 years), and 78.5 years (IQR: 76.3-80.8 years) in the escalation, de-escalation with monotherapy, and de-escalation with combination therapy groups, respectively). There were more males than females in all 3 groups (66/99 [66.7%], 77/120 [64.2%], and 6/6 [100%] in the escalation, de-escalation with monotherapy, and de-escalation with combination therapy groups, respectively).
Figure 1: Flow chart showing patient selection and classification of the antibiotic treatment that they received.
COP, community-onset pneumonia; HCAP, healthcare-associated pneumonia; qSOFA, quick Sepsis-related Organ Failure Assessment
Presumed causative pathogens
The 3 most frequently isolated pathogens were Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenza (H. influenzae) and Moraxella catarrhalis [Figure 2]. Because there were only 6 patients in de-escalation with combination therapy group the de-escalation with monotherapy group and de-escalation with combination therapy group were combined. There was no significant difference in the causative pathogens between the escalation and de-escalation groups.
Figure 2: Distribution of the presumed causative pathogens in adults with community-onset pneumonia according to the antibiotic treatment strategy described in the 2017 Japanese Respiratory Society adult pneumonia guidelines
H. influenzae, Haemophilus influenzae; M. catarrhalis, Moraxella catarrhalis; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; P. aeruginosa, Pseudomonas aeruginosa; S. pneumoniae, Streptococcus pneumoniae
The values above each bar are P-values which were calculated using the Chi-square test.
Concordance with empiric antibiotic policy based on the algorithm in the 2017 Japan Respiratory Society adult pneumonia guidelines
Based on the comparison of the antibiotics actually with those recommended in terms of the JRSGL2017 algorithm. In the escalation group, 94.9% were algorithm concordant, compared to 11.7% and 0% of the de-escalation with monotherapy and de-escalation with combination therapy groups, respectively [Table 1].
Table 1: Concordance between the antibiotic treatment received and the recommended empiric antibiotic treatment based on the 2017 Japanese Respiratory Society adult pneumonia guidelines for adults with community-onset pneumonia
The 30-day morality was 4/108 (3.7%) and 9/117 (7.7%) for the algorithm-concordant and algorithm-discordant groups, respectively (OR: 0.46, 95% CI:0.10–1.72). the 90-day mortality was 7/108 (6.5%) and 13/117 (11.1%) for the algorithm-concordant, and algorithm-discordant groups, respectively (OR: 0.55, 95% CI:0.18–1.58) [Table 2].
Table 2: Crude 30-day and 90-day mortality among adults with community-onset pneumonia according to concordance of therapy with the 2017 Japanese Respiratory Society adult pneumonia guidelines. CI, confidence interval; OR, odds ratio; ref, reference
The characteristics of the propensity-matched sample, matching on pneumonia severity using the 5 CURB-65 covariates, are shown in [Table 3]. In the propensity-matched sample, the 30-day morality was the same /30, 10.0%) in the algorithm-concordant and the algorithm-discordant groups (OR: 1.00, 95% CI: 0.19–5.40).
Table 3: Adjusted 30-day mortality among adults with community-onset pneumonia after propensity-score matching using the 5 CURB-65 criteria
BP, blood pressure; BUN, blood urea nitrogen; OR, odds ratio; RR, respiratory rate; SMD, standardized mean difference
In this study, the 30-day and 90-day mortality were higher in the algorithm-discordant group and the algorithm-concordant group, but the difference was not statistically significant. In the subgroup analysis propensity-matched on disease severity, the 30-day mortality was identical in both groups, indicating that there was no clinically significant difference in the outcome according to whether the initial treatment was concordant with the JRSGL2017 algorithm. There was also no statistically significant difference in the distribution of the causative pathogens between the escalation and de-escalation groups. Pneumococcus, H. influenzae and Moraxella accounted for 40% of all the causative pathogens, and Pseudomonas and Gram-negative enteric bacteria were uncommon.
Previously, HCAP was included in HAP/AVP practice guidelines  because of presumed high risk of MDR pathogens. However, several studies showed that patients having HCAP are not at high risk of MDR pathogens [6-10]. Because patients with HCAP are initially cared for in emergency departments like those with community-acquired pneumonia (CAP), HCAP is not included in the present HAP/VAP guidelines . The American Thoracic Society and the Infectious Diseases Society of America has recommended abandoning the use of the category HCAP to guide selection of adults with CAP to receive broad-spectrum antibiotic therapy . We have previously placed HCAP and CAP in the same category, namely community-onset pneumonia (COP), without distinction . HCAP and HAP are not defined based on symptoms or clinical criteria, but based on the likely source of the infection. The definition, symptoms, and pathogens associated with HCAP and HAP are summarized in [Table 4]. However, the JRSGL2017 includes HCAP in the same category as HAP . Adults with pneumonia are assessed as having a high risk of MDR pathogens if ≥2 of the following indicators are present: (1) Intravenous administration of antibiotics within the previous 90 days; (2) History of hospitalization for ≥2 days within the previous 90 days; (3) Immunosuppressive state; or (4) Low daily life activity (Eastern Cooperative Oncology Group Performance Status 3 or more, Barthel index <50, gait inability, or undernutrition requiring supplementary feeding such as tube feeding or total parenteral nutrition). All 4 indicators are characteristics which define HCAP. Thus, many patients with HCAP are assessed as being at risk of infections caused by MDR pathogens. These criteria were based on a study by Shindo et al.  which was conducted in patients with CAP or HCAP. This previous study found that physicians were able to predict drug resistance in patients with CAP or HCAP by taking the cumulative number of the risk factors into account. However, opponents of this approach have reasoned that adults with pneumonia in whom drug-resistant pathogens are isolated, do not necessarily require broad-spectrum antibiotics . In a previous study, we found that in patients with HCAP, the cure rate and the 30-day mortality rate did not differ according to whether the patient received the recommended initial treatment . In that study, the primary risk factors for 30-day mortality were underlying conditions such as diabetes, low serum albumin, the pneumonia severity according to the A-DROP score (see Supplemental Information), and imaging showing extensive pneumonia. Thus, the severity of pneumonia, rather than risk of resistant bacteria, should be the primary consideration .
Basically, we performed sputum Gram staining and chose the initial antibiotics. More than half of our antibiotic selection was discordant with the algorithm given in the JRSGL2017. The algorithm-discordant treatment was not associated with a significantly increased risk of death in patients with COP with a high risk of HCAP in either the crude or the adjusted analyses. In other words, treatment with narrow-spectrum antibiotics for the cases who were recommended for broad-spectrum antibiotics was not associated with significantly increased mortality. This algorithm might overestimate the risk of drug-resistant pathogens and the necessity of broad-spectrum antibiotics.
There are several limitations to our study. First, this study was a single-center, retrospective cohort study. Second, it is unclear how representative the study patients were of Japanese patients with COP and a risk of HCAP. Although standardization was not possible, characteristics of study population such as age, sex, distribution of presumed causative pathogens are likely to have been similar to that of the general COP population in Japan .
Third, we have unique practices regarding the management of COP in our hospital. We tested performed sputum Gram staining and performed rapid antigen tests on all patients with pneumonia, and chose the initial antibiotic based on these findings. Fourth, there was a low prevalence of drug-resistant pathogens, possibly related to antimicrobial stewardship provided by the infection control team.
Despite the above limitations, our results suggest that empiric therapy using the JRSGL 2017 algorithm might lead to overuse of broad-spectrum antibiotics in patients with COP and a risk of HCAP.
Initial treatment with narrow-spectrum antibiotics in patients who meet the criteria for the de-escalation policy based on JRSGL2017 algorithm may not adversely affect the outcomes. Empiric therapy using this algorithm might lead to overuse of broad-spectrum antibiotics in patients with COP and a risk of HCAP.
Conflicts of interest
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
All authors declare that they made an individual contribution to the article, and approved the final version of the manuscript and its submission for publication.
We would like to thank Editage (www.editage.com) for English language editing.
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