Management of the Diagnosis and Treatment of Pneumonia in an Aging Society

Abstract

The diagnosis of pneumonia is based on respiratory and systemic symptoms, blood test findings, chest radiographic findings, and the condition of the patient. Physicians in aging or aged societies such as Japan carefully evaluate the comprehensive situation of each pneumonia patient with adequate evaluation and treatment according to “the Japanese Respiratory Society (JRS) guidelines for the management of pneumonia in adults in 2024.” These guidelines categorize pneumonia into three types: community-acquired, nursing- and healthcare-associated, and hospital-acquired. The selection of treatment settings and empirical antimicrobials for pneumonia depends on pneumonia classification, severity, and risk factors for potential drug-resistant bacteria, as outlined in the JRS guidelines. This review concisely describes the historical evolution of the diagnosis and treatment of pneumonia in elderly societies, including aspiration pneumonia, from multiple perspectives. In addition, it explores the differential diagnoses when antimicrobial treatment for pneumonia is ineffective, highlighting key aspects through chest radiography and computed tomography.

Introduction

According to the 2021 statistics from the Japanese Ministry of Health, Labour and Welfare, “pneumonia” and “aspiration pneumonia” are the primary causes of death in Japan, constituting 4.7% and 3.6% of deaths, respectively. These 2 conditions represent 8.3% of all deaths, rendering them the fourth-most common cause of mortality, followed by malignant neoplasms (24.6%), heart disease (14.8%), and senility (11.4%) (1).

The elderly population in Japan has been rising steadily over the years, with individuals ≥65 years old accounting for ＜5% of the total population in 1950, 7% in 1970, 14% in 1994, and peaking at 28.4% in 2019. In 2019, 13.8% of the total population of Japan was 65-74 years old, while 14.7% were ≥75 years old (1,2). The prevalence of pneumonia and aspiration pneumonia is anticipated to increase with the aging of the population. Consequently, the precise diagnosis and treatment of pneumonia has emerged as a critical issue in Japan, which is an aging society.

Pneumonia is commonly diagnosed based on respiratory and systemic symptoms; physical information, such as oxygen saturation, blood pressure, and pulse rate; laboratory findings; and chest radiographs. Compared with relatively young patients with pneumonia, older adults may not show these typical respiratory and general symptoms and laboratory findings and occasionally have no remarkable subjective symptoms (3). In addition, older adults often present with multiple comorbidities necessitating “poly”-medications. Various diseases and conditions can manifest as infiltrative shadows on chest radiographs and share similar symptoms and laboratory findings with pneumonia. This complexity often complicates an accurate diagnosis of pneumonia.

This review briefly outlines the historical background of Japanese pneumonia guidelines and introduces the latest concepts of “the Japanese Respiratory Society guidelines for the management of pneumonia in adults 2024” (JRS pneumonia guidelines 2024). This highlights the distinguishing aspects between the Japanese and American pneumonia guidelines. Furthermore, this review illustrates the processes of diagnosing pneumonia and differential diagnoses, including bacterial and/or viral infections and aspiration pneumonia, in an aged society. This encompasses appropriate approaches to the differential diagnoses of diseases and conditions that mimic bacterial and/or viral pneumonia, particularly in scenarios where pneumonia is unresponsive to antimicrobial treatment.

The History and Recent Concepts of the Japanese Guidelines of Pneumonia

A short history of the Japanese guidelines for pneumonia

The initial JRS pneumonia guidelines in Japan were introduced in March 2000 (3) as “the Japanese guidelines for the management of community-acquired pneumonia” (the JRS CAP guidelines), with the basic principles of “improvement of pneumonia treatment,” “improvement of national health,” “prevention of bacterial resistance” and “effective use of medical resources.” The guidelines differentiate community-acquired pneumonia (CAP) into mild-to-moderate and severe pneumonia and explain the clinically simple method of distinguishing “bacterial” pneumonia from “atypical” pneumonia (Tables 1, 22).

Table 1.

Differentiation between Bacterial and Atypical Pneumonias and Identification Criteria.

1.	Age under 60 years old
2.	No or minor underlying disease
3.	Obstinate cough
4.	Poor findings on chest auscultation
5.	No sputum production or the causative bacteria cannot be proven by rapid diagnostic methods
6.	Less than 10,000/μL in peripheral blood leukocyte count
When using the above 6 items;
If 4 or more of the 6 items match, atypical pneumonia is suspected
If 3 or less of 6 items match, bacterial pneumonia is suspected
The sensitivity for atypical pneumonia in this case is 77.9%, and the specificity is 93.0%.
When using 5 items from 1 to 5 above;
If 3 or more of the 5 items match, atypical pneumonia is suspected
If 2 or less of 5 items match, bacterial pneumonia is suspected
The sensitivity for atypical pneumonia is 83.9%, and the specificity is 87.0%.

Table 2.

The Definitions of CAP, NHCAP, and HAP in Japan with HCAP in the US.

Definition of CAP
Pneumonia other than NHCAP and HAP
Definition of NHCAP
1.	Pneumonia diagnosed in a resident of an extended care facility or nursing home
2.	Pneumonia diagnosed in a person who has been discharged from a hospital within the preceding 90 days
3.	Pneumonia diagnosed in an elderly or disabled person who is receiving nursing care
4.	Pneumonia diagnosed in a person who is receiving regular endovascular treatment as an outpatient (dialysis, antibiotic therapy, chemotherapy, immunosuppressant therapy)
Standards for nursing care
Patients whose performance status is PS 3 (capable of only limited self-care, confined to bed or a chair more than 50% of their waking hours) or more.
Item 1 includes patients on psychiatric wards.
Definition of HAP
Pneumonia that develops after 48 hours after admission
Definition of HCAP in the United States
•	Any patient who was hospitalized in an acute care hospital for two or more days within 90 days of the infection.
•	Resided in a nursing home or long-term care facility.
•	Received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days of the current infection; or attended.
•	Attended a hospital or hemodialysis clinic.

“Atypical pneumonia” refers to cases where beta-lactam antibiotics are ineffective, but macrolides, tetracyclines, and quinolones prove effective, as seen in pneumonia caused by Mycoplasma pneumoniae, etc. Clinically, distinguishing between bacterial and atypical pneumonia is crucial for appropriate selection of empirically effective antimicrobials. The JRS guidelines for the management of hospital-acquired pneumonia in adults (the JRS HAP guidelines) were published in 2002 (4). Hospital-acquired pneumonia (HAP) is defined as pneumonia that develops ＞48 h after hospitalization. The CAP and HAP guidelines were revised in 2007 and 2008, respectively. These updated versions were deemed more dependable, drawing from evidence accumulated in Japan, and were characterized by increased conciseness and practicality. In addition, alongside CAP and HAP, the new “the JRS guidelines for the management of nursing and healthcare-associated pneumonia” (the JRS NHCAP guidelines) were established in 2011 (5), with its new concept of “nursing and healthcare-associated pneumonia” (NHCAP), which reflects the actual situation of older adult care in Japan, similar to the healthcare-associated pneumonia (HCAP) concept first proposed by the American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) HAP guidelines in 2005 (the ATS/IDSA HAP guidelines 2005) (6). The risk factors for HCAP proposed by the 2005 ATS/IDSA HCAP guidelines were hospitalization for ≥2 days in the preceding 90 days, residence in a nursing home or extended care facility, home infusion therapy (including antibiotics), chronic dialysis within 30 days, home wound care, and family members with multidrug-resistant pathogens. In comparison, the JRS NHCAP guidelines 2011 defined the criteria of NHCAP as any of the following: residence in a nursing home or an extended care ward, discharge from a hospital in the preceding 90 days, an elderly or handicapped patient who needs long-term care with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 3 or 4, or a patient who regularly requires vascular access for dialysis, antimicrobial treatment, chemotherapy, or immunosuppressive therapy in an outpatient setting (5).

The concept of the JRS NHCAP guidelines is unique to the rapidly aging society of Japan, with a primary focus on elderly pneumonia, notably “aspiration pneumonia.” These guidelines also address concerns related to drug-resistant bacteria and ethical considerations in pneumonia management, particularly in older adults. Originally described as a subgroup of pneumonia with a particularly high risk of detecting drug-resistant bacteria among HAP patients, this concept was first introduced as HCAP in the ATS/IDSA HAP guidelines of 2005 (6). However, this concept was subsequently adapted to suit Japan's social and medical context. In Japan, NHCAP is often managed similarly to CAP. It was deemed reasonable to view it as an intermediate category of pneumonia that did not neatly fit the conventional contradiction between CAP and HAP. As the understanding of the degree of drug resistance of the causative bacteria and prognosis (mortality rate) advanced, it became evident that HCAP was more akin to HAP than to CAP. In comparison to patients with CAP, patients with HCAP tended to be older and exhibited more complications. Furthermore, the causative bacteria were not typically Streptococcus pneumoniae or Haemophilus influenzae, which are commonly observed in CAP cases. Instead, they are often highly Gram-negative and prone to drug resistance, such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (6).

The patient population targeted for HCAP is relatively heterogeneous, reflecting the characteristics of the country/region and healthcare facilities. Furthermore, the definitions and social/medical roles of “hospital” hospitals differ significantly between Japan and the United States. In the United States, there are numerous long-term care facilities referred to as “nursing homes” and “geriatric hospitals.” These differences indicate that many pneumonia cases might be classified as HCAP in the United States or HAP in Japan. For example, according to the United States definition, patients who develop aspiration pneumonia while bedridden at home would have HCAP. However, pneumonia patients who have risk factors for resistant bacteria or regularly undergo dialysis are categorized as having CAP rather than HCAP in the United States. Conversely, in Japan, they are classified as NHCAP cases. Furthermore, Japan, being a highly aged society, has unique long-term care facility systems, including “healthcare facilities for the elderly” and “special nursing homes,” along with insurance systems, such as “nursing care level,” which are not present in Europe or the United States.

In 2017, the three Japanese pneumonia guidelines for CAP, NHCAP, and HAP were amalgamated into “the JRS Guidelines for the Management of Pneumonia in Adults 2017” (JRS pneumonia guidelines 2017) (7). This integration embraces the concept of evidence-based medicine and systematic reviews, providing recommendations for clinical inquiries. The JRS pneumonia guidelines 2017 introduced new crucial concepts tailored to the unique characteristics of Japan. These included considerations for variations in patient's social and medical backgrounds, which depend on the classification of the medical system, such as differing definitions of “hospitals,” “care facilities,” and “insurance systems,” distinct from guidelines in other countries. In addition, the guidelines addressed perspectives on expressing patients' end-of-life desires.

In the 2017 JRS pneumonia guidelines, HAP and NHCAP were merged to distinguish patients in the irreversible process of death, such as those in the terminal disease stage or with senility, as distinct medical processes from CAP. Within the HAP and NHCAP categories, physicians are advised to initially evaluate patients' social and medical backgrounds. They should ascertain the risk of aspiration pneumonia and determine whether the patient is in the final stage of the disease or in an end-stage senile state. Subsequently, they should engage in careful consultation with patients and their families, ensuring respectful consideration of the individual's will and quality of life (QOL).

The latest concepts of the Japanese guidelines for pneumonia (the JRS pneumonia guidelines 2024)

The JRS pneumonia guidelines 2017 were refined into the current JRS pneumonia guidelines 2024, which incorporate up-to-date evidence, particularly from Japanese sources. Regarding the pneumonia category of HCAP in the United States, the 2019 ATS/IDSA pneumonia guidelines determined that the HCAP category is no longer utilized and has been merged into CAP (8). HCAP was initially introduced in the ATS/IDSA guidelines 2005 due to the frequent detection of pathogens not covered by the commonly recommended antibiotics. However, accumulated evidence has revealed that the HCAP definition used was inefficient in predicting the detection of drug-resistant bacteria to enhance the prognosis of patients with pneumonia. Despite the significant increase in the use of broad-spectrum antibiotics, the prognosis of patients had not improved.

While the decision was made to discontinue the use of the HCAP category in the United States, the NHCAP category remains in the JRS pneumonia guidelines 2024, reflecting its continued importance in Japan's super-aging society. Compared with patients with CAP, patients with NHCAP are typically relatively old, have reduced activities of daily living (ADL), receive home health care, and have underlying comorbidities. In addition, they are more likely to be affected by aspiration pneumonia than ordinary bacterial pneumonia. Furthermore, the majority of NHCAP patients are late-stage older adults and reside in medical care facilities, contributing to a potential increase in the number of NHCAP cases annually in Japan. Given the increasing clinical significance of NHCAP, particularly in relation to aspiration pneumonia, it is presented before CAP, NHCAP, and HAP in the JRS pneumonia guidelines 2024. Aspiration pneumonia is prevalent in both the CAP and NHCAP categories, underscoring the importance of considering its possibility in all patients with CAP/NHCAP. The prognosis of patients with NHCAP is notably worse than that of patients with CAP, with terminal-stage pneumonia often observed. Therefore, advanced care planning based on patient backgrounds is crucial in clinical practice.

In light of the coronavirus disease 2019 (COVID-19) pandemic, viral pneumonia has become a common etiology of pneumonia and is now discussed before the chapters on CAP, NHCAP, and HAP in the JRS pneumonia guidelines 2024 (9). Another unique concept introduced in these new guidelines is the inclusion of “future questions” in each chapter (9). These highlight areas where the necessary evidence and knowledge are currently lacking, thereby encouraging additional clinical research and evidence to enhance the reliability of future guidelines.

The Diagnosis and Classification of Pneumonia

Bacterial pneumonia

Pneumonia, especially bacterial pneumonia, is commonly diagnosed on the basis of respiratory symptoms (cough, purulent sputum, dyspnea, and chest pain), systemic symptoms (fever, general fatigue, anorexia, and altered consciousness), physical findings of inspiratory coarse (or fine) crackles on chest auscultation, chest radiography or computed tomography (CT) (newly observed pulmonary infiltrative opacities), and laboratory findings [elevated peripheral blood white blood cell (WBC) count, serum C-reactive protein (CRP), and procalcitonin levels] (3).

Older patients with CAP and NHCAP may occasionally not present with typical symptoms of pneumonia, namely a fever, respiratory symptoms, or abnormal test findings, such as an elevated peripheral blood WBC count. In older individuals, pneumonia may progress atypically, with some patients initially exhibiting only a poor appetite without a fever or cough (3). Subsequently, they may develop typical pneumonia symptoms, such as a productive cough and fever, or more severe symptoms, such as respiratory distress or shock. This atypical progression highlights the importance of vigilance. Family members and caregivers must actively and carefully observe subtle signs of pneumonia to facilitate an early diagnosis and treatment.

The A-DROP system in the JRS pneumonia guidelines 2024 for categorizing treatment environments is simple and comprises 5 factors, each assigned 1 point: “Age” (men ＞70 years old, women ＞75 years old), “Dehydration” (blood urea nitrogen ≥21 mg/dL or dehydration), “Respiration” (SpO₂ ≤90% or PaO₂ ≤60 Torr), “Orientation” (a change in consciousness), and “Pressure” (systolic blood pressure ≤90 mmHg). A score of 0 points indicates mild symptoms (outpatient treatment), 1-2 points suggest moderate severity (outpatient or inpatient treatment), 3 points indicate severe symptoms (hospital treatment), and 4-5 points or the presence of shock indicate extremely severe symptoms warranting intensive-care unit admission (3,9).

Systemic inflammatory response syndrome (SIRS) may occur, especially in patients with S. pneumoniae pneumonia, a common causative pathogen of CAP and NHCAP, characterized by sepsis and excessive inflammatory cytokine production. This condition is diagnosed when ≥2 of the following criteria are met: body temperature ＞38 °C or ＜36 °C, heart rate ＞90 beats/min, respiratory rate ＞20 breaths/min or PaCO₂ ＜32 mmHg, WBC count ＞12,000/mm³ or ＜4,000/mm³, or immature granulocytes ＞10% (10). However, it should be noted that the body temperature and WBC count can either increase or decrease in patients with severe pneumonia.

Aspiration pneumonia

Aspiration pneumonia is a significant category of pneumonia in an aging society and is now independently identified as a major item in the JRS pneumonia guidelines 2024 (9). This contrasts with the JRS pneumonia guidelines 2017, where aspiration pneumonia was mentioned only in the HAP/NHCAP chapters. Aspiration pneumonia is defined as pneumonia occurring in individuals at a risk of aspiration. The risks of aspiration can be broadly classified into an impaired swallowing function and gastroesophageal dysfunction. Table 3 outlines the risk factors for aspiration and aspiration pneumonia (JRS pneumonia guidelines 2024) (9). Most cases of aspiration pneumonia are caused by an age-related decline in the systemic function and associated swallowing dysfunction.

Table 3.

Risk of Aspiration and Risk of Pneumonia Due to Aspiration.

Aspiration risks
Cause	Pathological conditions
Decreased swallowing function	Swallowing dysfunction
	Gastroesophageal dysfunction
	Disturbance of consciousness
	General weakness, long-term bed rest
	Cerebrovascular disorder
	Chronic neurological disease (dementia, Parkinson’s disease, etc.)
	Iatrogenic (tracheostomy tube placement, enteral nutrition, head and neck surgery, sedation) drugs, sleeping pills, anticholinergic drugs, etc. that cause dry mouth)
Gastroesophageal dysfunction	Gastroesophageal reflux
	Esophageal dysfunction or stricture
	Iatrogenic (enteral nutrition, gastric resection, etc.)
Risk of pneumonia due to aspiration
Cause	Pathological condition
Decreased airway clearance	General weakness, long-term bed rest
including expectoration	Chronic airway inflammatory disease
Decreased immune function	General weakness, long bed, malnutrition

Aspiration pneumonia reportedly has a poor prognosis in patients with CAP compared to patients with pneumonia other than aspiration pneumonia, with approximately 3.5 times higher mortality during hospitalization and 30 days after hospitalization (11). Furthermore, the presence of multiple risks of aspiration may additively worsen the prognosis. Possession of risk factors for aspiration is also linked to increased mortality from any cause, re-hospitalization, and recurrent hospitalizations for pneumonia within one year (12). This indicates that the risk of aspiration is correlated with the development of aspiration pneumonia and a poor prognosis. Furthermore, there is an aspect of senility wherein patients may succumb to various causes despite recovery from pneumonia.

Frequency of detected microorganism in patients with pneumonia

The JRS pneumonia guidelines for both 2017 and 2024 demonstrate comparable results regarding detected microorganisms, whether culture-based or identified through 16S ribosomal RNA detection in bronchoalveolar lavage fluid (BALF) directly obtained from pneumonia lesions in patients with pneumonia (7,9). Using culture-based methods, including antigen detection (such as S. pneumoniae and Legionella pneumophila), the most commonly detected bacterial species in patients with CAP was S. pneumoniae, which is also commonly found in patients with NHCAP.

However, significant differences existed between the data obtained from culture- or antigen detection-based methods and those obtained from molecular biology-based detection using directly collected samples. These disparities arise mainly due to differences in sampling techniques, culture processes, and reporting thresholds. Interestingly, the most frequently detected bacterial species in patients with CAP and NHCAP is S. pneumoniae when using culture-based methods; however, when utilizing molecular methods with BALF directly obtained from pneumonia lesions, oral streptococci emerge as the predominant bacterial species.

Furthermore, apart from oral streptococci, the most commonly detected bacterial species in both CAP and NHCAP, as identified by molecular methods, are Haemophilus influenzae rather than S. pneumoniae. In patients with HAP, there was also a significant disparity in the frequency of detected bacterial species between culture-based and molecular methods. The three bacterial species most frequently detected by culture-based methods were MRSA, P. aeruginosa, and methicillin-susceptible S. aureus. In contrast, molecular methods identify oral streptococci, Corynebacterium species, S. aureus, and H. influenzae as the most frequently detected bacterial species (9). In addition to oral streptococci, Corynebacterium species have emerged as the second-most commonly detected bacterial species by molecular methods, using samples directly obtained from pneumonia lesions. This bacterial species has recently been recognized as a pathogenic bacterial species of bacterial pneumonia with the increasing utilization of molecular biological methods (13). The clinical importance of Corynebacterium species in the diagnosis and treatment of pneumonia should be studied further.

Viral pneumonia

Viral pneumonia is now commonly detected owing to the widespread use of new devices for more precise diagnosis, particularly after the COVID-19 pandemic caused by infection with the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus. This has become a significant category of infectious pneumonia (9,14). In addition to SARS-CoV-2, other causative viruses of infectious pneumonia include human metapneumovirus, adenoviruses, coronaviruses other than SARS-CoV-2, and respiratory syncytial virus (15). Molecular methods capable of simultaneously detecting bacterial and viral microorganisms are now widely available in many facilities following the COVID-19 pandemic. The utilization of these detection devices may contribute to a more accurate identification of causative microorganisms. Further studies are necessary to elucidate the complete picture of causative microorganisms in patients with pneumonia, including an understanding of viral-bacterial relationships.

Treatment Strategy of Pneumonia in an Aging Society

After diagnosing and classifying pneumonia (CAP, NHCAP, and HAP), it is crucial to assess the patient's background to make informed decisions regarding treatment settings (inpatient vs. outpatient) as well as the route of antibiotic administration (oral vs. intravenous). In addition, considerations of oxygen supplementation and ventilatory support should be evaluated based on individual patient needs. Among older adults, CAP patients, particularly NHCAP patients, often include older individuals with compromised overall health conditions and low ADL. This encompasses those who are near or entirely bedridden or in terminal conditions, such as frailty, malignant diseases (e.g., cancer), chronic renal and/or heart diseases, or other significant comorbid illnesses. Although many patients with bacterial pneumonia generally show a good prognosis when treated with proper antibiotics, more complex and terminally ill patients frequently show recurrent pneumonia and/or a worsening of the overall health status, ADL, and QOL compared to those before pneumonia. Given these considerations, the JRS pneumonia guidelines 2024 emphasize the importance of respecting individual preferences and QOL in the management of pneumonia in terminally ill patients (9).

Antibiotic treatment (elderly CAP and NHCAP patients)

The process of prescribing specific antibiotics begins with diagnosing NHCAP/HAP and nursing home-acquired pneumonia (NHAP), followed by the assessment of pneumonia severity using the A-DROP criteria. Next, the antibiotic resistance risk was assessed (Table 3), based on which the treatment strategy was determined. This treatment may involve escalation therapy, de-escalation monotherapy, or de-escalation combination therapy. Appropriate antibiotics were selected based on these considerations (5,9). The identified risks for drug resistance in the NHCAP/HCAP/NHAP include enteral nutrition, hypoalbuminemia, a history of antibiotic use within the last 90 days, mechanical ventilation due to early intubation after hospitalization, a history of hospitalization within the past 90 days, and immunosuppression status (9). The selection of antibiotics for treating pneumonia was guided by the JRS pneumonia guidelines 2024 and the Japanese Association for Infectious Diseases/Japanese Society of Chemotherapy guidelines for clinical management of infectious diseases 2023. Aspiration pneumonia is often associated with older patients presenting with CAP and NHCAP, and oral bacteria are more likely to be causative pathogens. Respiratory quinolones, with fewer concerns about renal insufficiency, are promising treatment choices; however, tuberculosis must be carefully excluded.

Outpatient Treatment

For outpatient oral medications, when bacterial pneumonia is suspected, initial considerations include amoxicillin/clavulanic acid or sultamicillin, high-dose cefditoren pivoxil, and respiratory quinolones. In cases in which atypical pneumonia is suspected, minocycline, clarithromycin, azithromycin, and respiratory quinolones are administered. If it is challenging to differentiate between bacterial pneumonia and atypical pneumonia, when Legionella pneumonia is suspected, or in cases of complex concomitant chronic respiratory diseases, respiratory quinolones are considered. For intravenous medications, when bacterial pneumonia is suspected, ceftriaxone or lascufloxacin is preferred. If atypical pneumonia is suspected, lascufloxacin or azithromycin should be considered (9).

Inpatient Treatment

The recommended intravenous antimicrobial treatment for patients with suspected bacterial pneumonia includes sulbactam/ampicillin, ceftriaxone, cefotaxime, or lascufloxacin. When atypical pneumonia is suspected, minocycline, azithromycin, or lascufloxacin are preferred. Lascufloxacin or levofloxacin was considered when differentiating between bacterial and atypical pneumonia. Levofloxacin, lascufloxacin, and azithromycin are considered when Legionella pneumonia is suspected (9).

Corticosteroids in the Treatment of Pneumonia

The efficacy of adjunctive systemic corticosteroid therapy along with antibiotics in patients with pneumonia remains unclear. Nevertheless, systemic corticosteroids are sometimes used in cases of severe pneumonia. A meta-analysis focusing on CAP (16) indicated an enhanced short-term prognosis for severe-grade CAP with the addition of systemic corticosteroid therapy to the antibiotic treatment. However, conflicting results have been reported in other studies (17,18). A study that used the Japanese Diagnosis Procedure Combination (DPC) database revealed a decreased short-term (28-day) mortality rate among patients with severe CAP requiring mechanical ventilation with shock (defined as catecholamine use) when treated with low-dose systemic corticosteroid therapy (methylprednisolone ＜500 mg/day) (19). Conversely, a study investigating the long-term prognostic impact of systemic corticosteroids in patients with CAP did not demonstrate any beneficial effects (20). In addition, in a report utilizing nationwide inpatient data from the Japanese DPC system, the use of low-dose corticosteroids was relatively high (7.9%). This comprised 7.7% of mild and moderate patients (A-DROP 0-2) and 10.1% of those classified as “severe” or “extremely severe” pneumonia (A-DROP ≥3) according to the A-DROP system in Japanese patients with community-onset pneumonia (CAP and NHCAP) (21).

Comparing the prognoses among patients with or without the use of corticosteroids, the survival rates of pneumonia patients who used corticosteroids in cases of mild or moderate pneumonia were significantly lower. However, there was no significant difference between patients with and without corticosteroid use in cases of severe pneumonia severity (21), indicating that corticosteroids have no benefit. The different outcomes in the studies mentioned above may be attributed to the inclusion criteria for “severe” pneumonia. In studies demonstrating favorable outcomes, patients classified as having “severe” pneumonia were predominantly those who required intratracheal intubation. However, the category of “severe” or “extremely severe” in the A-DROP system might encompass a broader range of patients, potentially including those with less severe pneumonia. Based on these findings, systemic corticosteroid therapy may not correlate with an improved prognosis in patients with CAP and NHCAP classified as severe according to the A-DROP criteria but not requiring catecholamines or mechanical ventilation. Therefore, the use of corticosteroids should be carefully considered, particularly in older patients with pneumonia.

Oral Hygiene, Oral Care, and Vaccination in Preventing Pneumonia

Oral hygiene and care serve as the primary preventive strategies for pneumonia across all age groups, particularly among older adults. Pneumonia can occur due to aspiration of bacteria from the oral cavity, and this risk can be mitigated by maintaining oral hygiene and reducing bacterial presence through regular oral care practices. A randomized controlled trial conducted among residents of older adult-care facilities in Japan demonstrated that high-quality oral care resulted in a reduced incidence of pneumonia, fewer febrile days, and lower mortality rate associated with pneumonia (22). Efforts should be directed toward preventing aspiration, including adopting positions that minimize the risk of aspiration, and ensuring high-quality oral care. Ideally, oral care should be administered by dental and oral specialists, such as dentists and dental hygienists, to optimize its effectiveness.

Pneumococcal vaccines are broadly used to prevent pneumonia and are classified into two types: capsular polysaccharide and protein-bound. The capsular polysaccharide type is the 23-valent capsular polysaccharide-type pneumococcal vaccine [pneumococcal polysaccharide vaccine(PPSV)] 23, and the protein-conjugated type is the 13-valent protein-conjugated pneumococcal vaccine [pneumococcal conjugate vaccine (PCV)] 13 and PCV15. Japanese observational studies have shown that vaccine-capsular non-invasive pneumococcal pneumonia was reported in 33.5% of cases (23), and invasive pneumococcal disease (IPD) was reported in 42.2% of cases (24). Favorable preventive effects of PCV13 have been reported, including a 45% reduction in noninvasive pneumococcal pneumonia and a 75% reduction in IPD. In addition, PCV13 has been shown to reduce overall pneumococcal pneumonia by 30.6% and IPD by 51.8% for all capsular types (25). PCV15 showed superiority for serotype 3, a major capsular type in Japan, and no serious side effects were observed compared with PCV13 (26).

Vaccines are available for infections associated with pneumonia, such as influenza virus and respiratory syncytial virus (RSV). Influenza viral infections are known to cause both secondary bacterial and viral pneumonia. The effectiveness of the influenza vaccine varies depending on factors such as the age, underlying disease, and prevailing influenza strain. Nonetheless, vaccination has been shown to reduce the incidence of influenza by 54% in the United States (27). The effectiveness of this drug was also assessed among older adult individuals hospitalized in welfare facilities and hospitals in Japan, demonstrating its efficacy in preventing the onset of illness and being approximately 80% effective in preventing death. RSV is an RNA virus that is commonly associated with pneumonia in infants. However, RSV infection can also lead to viral pneumonia in older adults, with or without exacerbation of underlying diseases. An international phase III clinical trial of the RSV vaccine, specifically the RSV prefusion F protein vaccine, involved 24,966 adults ≥60 years old, including 1,038 Japanese participants. The trial demonstrated efficacy against all lower respiratory tract diseases caused by RSV infection, with reported rates of 82.6% for severe lower respiratory tract diseases and 94.1% for severe lower respiratory tract diseases (28).

Approach to managing patients with antibiotic treatment-resistant pneumonia

In patients diagnosed with bacterial pneumonia, de-escalation therapy is implemented when the causative pathogen can be accurately identified by culture or other diagnostic methods. This involves transitioning treatment to narrow-spectrum antibiotics. However, if there is no improvement in pneumonia or overall health despite initiating antimicrobial treatment, clinicians may consider escalation therapy. This can include switching to broad-spectrum antibiotics or adding antibiotics to target drug-resistant bacteria. When the initial antimicrobial treatment fails to produce a response, it is crucial to carefully differentiate between infectious and non-infectious conditions. Infectious diseases may include pulmonary infections that are ineffective, such as those caused by viruses, fungi, acid-fast bacteria, Mycoplasma pneumoniae, Legionella spp., MRSA, penicillin-resistant S. pneumoniae (PRSP), beta-lactamase-negative ampicillin resistance (BLNAR), P. aeruginosa, extended-spectrum beta-lactamase (ESBL)-producing bacteria, nocardiosis, actinomycetes septic shock, fulminant pneumonia (S. pneumoniae, Legionella sp., Klebsiella sp.), empyema thoracis, lung abscess, and bullous infections. Noninfectious conditions include congestive heart failure, uremic lung, pulmonary embolism, acute interstitial pneumonia, acute respiratory distress syndrome, eosinophilic pneumonia, organizing pneumonia, hypersensitivity lung inflammation, drug-induced lung injury, radiation pneumonitis, alveolar hemorrhaging, lung cancer, airway foreign body, repeated aspiration, expectoration deficiency, chronic respiratory diseases such as bronchiectasis and sinobronchial syndrome, immunosuppressive drug administration, lymphoproliferative disease, and hematological malignancy. In a report from the United States (29), the inappropriate diagnosis of CAP among hospitalized adults was prevalent, with 12.0% of patients with CAP being inappropriately diagnosed. This was particularly notable in the older population with dementia and an altered mental status. In addition, the duration of ineffective antibiotic treatment is associated with adverse events stemming from antibiotic use.

Instances are frequent where general symptoms, chest radiographic images, chest CT scans, and peripheral blood inflammation findings (WBC count and CRP level) do not improve following antibiotic administration. The JRS pneumonia guidelines recommend considering the ineffectiveness of antibiotics in distinguishing between infectious and noninfectious pathologies. In addition, infectious pathologies should be considered as factors related to bacteria, hosts, and drug/medical interventions (7,9) (Table 4).

Table 4.

Differential Diseases when Antibiotics Are Unresponsive.

Non infectious differential diseases			Examples
A. Identification is mainly based on techniques such as CT and echo.			Heart failure, uremic lung, pulmonary embolism
B. Identification is mainly based on bronchoscopy.			Acute interstitial pneumonia, acute respiratory distress syndrome, eosinophilic pneumonia, organizing pneumonia, hypersensitivity pneumonitis, drug-induced lung injury, radiation pneumonitis, pulmonary alveolar hemorrhage, lung cancer, lymphoproliferative disorders
Infectious differential diseases			Examples
A. Bacterial factors
	1. Pathogens that are not covered by antibiotics		Viruses, fungi, mycobacteria
	2. Pneumonia caused by common pathogens
		1) Atypical pathogens (β-lactam drugs are ineffective)	Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia spp.
		2) Antibiotic-resistant bacteria	MRSA, PRSP, BLNAR, Pseudomonas aeruginosa, ESBL-producing bacteria
		3) Infectious diseases caused by pathogens that take time to improve	Nocardia spp., actinobacteria
	3. Secondary infection after hospitalization due to opportunistic pathogens, etc.
	4. Rapid deterioration due to severe infection		Septic shock, fulminant pneumonia (Streptococcus pneumoniae, Legionella pneumophila, Klebsiella spp.)
B. Host factors
	1. Formation of lesions with poor antimicrobial penetration		Empyema, lung abscess, intrabullar infection
	2. Formation of extrapulmonary infection foci		Endocarditis, osteoarthritis, catheter infection, meningitis
	3. Impaired airway drainage		Central-type lung cancer, airway foreign bodies, repeated aspiration, expectorant failure, chronic respiratory diseases (bronchiectasis, sinobronchial syndrome)
	4. Immunocompromised host		HIV, immunosuppressants, hematological malignant tumors
	5. Aggravation due to delay in visiting a medical institution
C) Drug/medical factors
	1. Inappropriate administration of antibiotics		Insufficient dose, inappropriate route, or frequency of administration
	2. Increased severity due to delay in starting therapeutic intervention
	3. Adverse events derived from antibiotics		Drug fever

CT: computed tomography

Differential Diagnoses

Congestive heart failure (CHF)

CHF, the most common comorbidity associated with pneumonia, should be suspected if physical findings, such as edema, orthopnea, or cardiac enlargement, are present. Echocardiography, cardiac catheterization, and brain natriuretic peptide levels are useful for diagnosing CHF (30). Older patients with pneumonia are often dehydrated at the time of the diagnosis; however, they are also prone to CHF. Even if cardiac dysfunction is not evident during the initial visit, CHF may develop after initiating pneumonia treatment because of excessive intravenous sodium intake from fluids containing high amounts of sodium in antibiotics and infusion fluids. Therefore, the possibility of CHF should always be considered after the initiation of pneumonia treatment. In patients with CHF, chest radiographs typically reveal cardiac enlargement, cephalization, perivascular and peribronchial cuffing, Kerley lines (A-C), butterfly shadows, and pleural effusion with or without vanishing tumors. CT scans also demonstrated compatible features, including cardiac enlargement, bilateral pleural effusions, bilateral infiltrates (consolidations), ground-glass opacities, interlobular septal thickening, and thickening of the bronchovascular bundle (30) (Fig. 1).

Figure 1.

Chest high-resolution computed tomography findings in a patient with congestive heart failure. Interlobular septal thickening (red arrows), bronchovascular bundle thickening (red circles), and bilateral pleural effusion (blue arrows) are observed.

Pulmonary thromboembolism (PTE)

In cases of pneumonia unresponsive to antibiotics, worsening or unimproved oxygenation, along with signs such as pleural effusion, chest pain, and elevated serum D-dimer levels, PTE should be suspected. PTE can be diagnosed using contrast-enhanced CT (31), ventilation-perfusion scintigraphy (32), an electrocardiogram, and echocardiography, or by confirming the presence of deep vein thrombosis in the lower extremities. Older patients with pneumonia commonly exhibit dehydration and are more susceptible to PTE than those without pneumonia. However, they may not display typical symptoms, such as chest pain; hence, physicians should exercise caution in the early PTE diagnosis in these cases. On chest CT, wedge-shaped consolidations are sometimes observed in the lungs (33); however, diagnosing PTE based solely on imaging findings can be challenging. Confirming the presence of a thrombus within the pulmonary artery using contrast-enhanced imaging is often necessary (Fig. 2).

Figure 2.

A patient diagnosed with pneumonia at a nearby hospital was treated with carbapenem antibiotics with lack of improvement, so the patient was transferred to our hospital. Pulmonary consolidations in the lung fields (red circle) and pleural effusion (blue arrows) were observed, a thrombus in the pulmonary artery (red arrow) was confirmed by contrast-enhanced computed tomography, and the patient was diagnosed with pulmonary thromboembolism.

Lung cancer (especially invasive mucinous adenocarcinoma)

While lung cancer typically presents with nodular or mass-like shadows, invasive mucinous adenocarcinoma can manifest imaging findings similar to those observed in bacterial pneumonia (34) (Fig. 3). Invasive mucinous adenocarcinomas can be classified as acinar, papillary, bronchioloalveolar, or solid adenocarcinomas with mucus formation. Sufficient caution is warranted, especially in older adults with a history of smoking or comorbidities such as chronic obstructive pulmonary disease, and elevated serum tumor markers, such as carcinoembryonic antigen and cytokeratin 19 fragments, are occasionally helpful. Sputum cytology can be useful for the diagnosis, and a bronchoscopic examination should be performed if conclusive results are not obtained from sputum cytology.

Figure 3.

Chest computed tomography findings of a patient diagnosed with pneumonia upon admission, who was subsequently diagnosed with lung cancer. Pulmonary consolidations and partial ground-glass opacities were observed in the left lower lobe (red circle), and lung adenocarcinoma (invasive mucinous adenocarcinoma) was diagnosed based on sputum cytology.

Drug-induced lung injury

It is essential to consider that all medications and supplements have the potential to cause drug-induced lung injury. Known imaging patterns resemble those of diffuse alveolar damage, non-cardiogenic pulmonary edema, hypersensitivity pneumonia, organizing pneumonia, and acute/chronic eosinophilic pneumonia (35). Drug-induced lung injury manifesting as an organizing pneumonia pattern may be difficult to precisely differentiate from bacterial pneumonia, as secondary organizing pneumonia (SOP) due to bacterial pneumonia can also be present. Drug-induced lung injuries often present as a dry cough without purulent sputum production, and auscultation frequently reveals fine crackles. Chest imaging typically shows bilateral consolidations with air bronchograms or ground-glass opacities (Fig. 4). The most crucial step in diagnosing drug-induced lung injury is to suspect its occurrence with a thorough understanding of symptom progression and the clinical course of chest imaging after drug administration. Although the drug lymphocyte stimulation test can occasionally be helpful, it requires caution owing to potential false positives and negatives. Negative results do not definitively exclude the possibility of drug-induced lung injury.

Figure 4.

A case of amiodarone-induced lung injury. Chest computed tomography demonstrating pulmonary consolidations in both lung fields (red circles). Treatment with antibiotics for pneumonia did not improve the patient’s condition, and after visiting our hospital and undergoing a lung biopsy, pathological findings of organizing pneumonia were noted. The condition improved after discontinuation of amiodarone, leading to a diagnosis of amiodarone-induced lung injury.

Secondary organizing pneumonia (SOP)

When bacterial pneumonia is diagnosed and appropriate antibiotics with sufficient antimicrobial activity against the identified bacteria are initiated but the therapeutic effect is suboptimal, SOP should be considered. SOP resulting from infectious diseases are often attributed to bacteria, especially pneumococci; however, viruses, parasites, and fungi have also been reported as causative pathogens of SOP (36,37) (Fig. 5). Organizing pneumonia can be diagnosed by a transbronchial lung biopsy showing pathological organizing pneumonia and bronchoalveolar lavage (BAL) indicating lymphocyte predominance (37). Treatment includes oral corticosteroid administration, especially when symptoms such as worsening cough, dyspnea, or respiratory failure are present. Spontaneous recovery can also occur; hence, it may be appropriate to monitor whether or not pulmonary shadows are progressive without treatment if the patient is asymptomatic.

Figure 5.

A case of secondary organizing pneumonia following pneumococcal pneumonia. Chest computed tomography (CT) showed bilateral infiltrative shadows, and pneumococci were detected in the sputum, leading to a diagnosis of pneumococcal pneumonia (A). Treatment with SBT/ABPC improved the subjective symptoms and peripheral blood inflammatory findings; however, chest CT showed residual consolidation in both lung fields (B, red circles). A bronchoscopic lung biopsy confirmed organizing pneumonia, leading to the diagnosis of post-pneumonic organizing pneumonia.

COVID-19

Viral pneumonia characteristically produces bilateral ground-glass opacities and a crazy-paving appearance in lung fields (38) (Fig. 6). However, in COVID-19, the initial presentation of round multifocal ground-glass opacities can rapidly evolve into diffuse reticular shadows, consolidations, and volume loss (39,40) (Fig. 7). Although chest CT findings can be diagnostically useful in typical cases, relying solely on imaging findings to obtain negative COVID-19 results is challenging and may not be recommended. Furthermore, concurrent viral and bacterial infections are possible, particularly in older adults, and the differential diagnosis of COVID-19 should be carefully considered in all cases of pneumonia.

Figure 6.

A case of pneumonia due to varicella-zoster virus. High-resolution computed tomography of the chest showed ground-glass opacities distributed randomly in both lungs.

Figure 7.

A case of pneumonia associated with COVID-19. Chest computed tomography showing consolidation of the left lower lobe (A). Three days later, consolidation and ground-glass opacities expanded bilaterally in the lung fields (B).

Pulmonary mycoses

The primary fungal pathogens that cause pulmonary infections include Aspergillus, Candida, Cryptococcus, and Pneumocystis. Pulmonary aspergillosis can manifest in various forms, such as aspergilloma, chronic progressive pulmonary aspergillosis (CPPA), invasive pulmonary aspergillosis (IPA), and airway-invasive aspergillosis. Chest CT findings are distinctive: aspergilloma presents with a fungal ball within a cavity (41), CPPA with a cavity and surrounding consolidation (41,42), IPA with nodules or consolidations with a halo sign, and cavitated nodules with an air crescent sign (41,42), thereby making the differential diagnosis straightforward. In contrast, airway-invasive aspergillosis can present with patchy peribronchial consolidations and centrilobular nodular opacities (42) (Fig. 8), mimicking a CT appearance similar to that of bacterial pneumonia, which can complicate the proper diagnosis. Detection of Aspergillus spp. in respiratory specimens is important for the diagnosis, including the supplemental use of markers such as serum β-D-glucan and Aspergillus antigen and antibody detection.

Figure 8.

Case of airway-invasive pulmonary aspergillosis. Chest computed tomography shows consolidation in the entire right lung field (A), with a whitish exudate observed in the bronchial lumen (B). Grocott staining identified fungi resembling Aspergillus spp. (C) and Aspergillus fumigatus was cultured.

Cryptococcosis is mainly caused by Cryptococcus neoformans. In immunocompetent individuals, chest CT typically reveals subpleural-predominant nodules or localized consolidations (43) (Fig. 9A). However, consolidation, air bronchograms, and cavities have also been observed in immunosuppressed patients (44) (Fig. 9B). The diagnosis of pulmonary cryptococcosis necessitates microbiological and histopathological examinations of the fungus, typically using BALF or a transbronchial lung biopsy. Although the serum β-D-glucan test is typically negative for cryptococcosis, the Cryptococcus antigen test, which has high sensitivity and specificity, is useful (45).

Figure 9.

Pulmonary cryptococcosis in immunocompetent individuals. Peribronchial nodules are observed in the left upper lobe (A). Pulmonary cryptococcosis in a patient with rheumatoid arthritis treated with methotrexate. Consolidation was observed in the bronchiectatic region of the right middle lobe (B).

Pulmonary tuberculosis (TB)

Typical chest CT findings of pulmonary TB include cavitation predominantly in the upper (S¹, S²) and lower lobes (S⁶), centrilobular nodules, and bronchiolar lesions (46), and caseous pneumonia with consolidation, which can be challenging to distinguish from bacterial pneumonia, can also be seen (Fig. 10). This type of pneumonia is often observed in older individuals, and the first interferon-γ-releasing assay, acid-fast bacilli smear, and culture tests of sputum or gastric fluid can be useful for the diagnosis of pulmonary TB. If there is limited improvement after initiating antibiotics for pneumonia treatment, repeated sputum or gastric fluid tests can increase the TB diagnostic rate. A bronchoscopic examination should be performed aggressively if the diagnosis remains elusive. It is also important to note that the use of quinolone antibiotics before the diagnosis of TB can increase the mortality rate (47); respiratory quinolones should thus be used with special caution in older patients with pneumonia.

Figure 10.

A case of pulmonary tuberculosis misdiagnosed as bacterial pneumonia. Initially, the treatment for bacterial pneumonia failed to improve the patient’s condition, and Mycobacterium tuberculosis was detected in the sputum, leading to a diagnosis of pulmonary tuberculosis.

Pulmonary contusion due to chest trauma

Traumatic events, such as chest contusions or rib fractures, can lead to lung contusions, and ground-glass opacities, consolidations, and pneumothorax can be observed on chest CT (48). In cases of trauma, patients usually have an awareness or memory of the chest-blow event, thereby enabling a provisional diagnosis through relatively straightforward questioning. However, symptoms may be less noticeable in bedridden older individuals, in whom symptoms cannot be properly appealed, and if no episodes can be confirmed by healthcare providers, these patients may be treated for pneumonia. Identifying the location of rib fractures can facilitate the diagnosis of lung contusions (40) (Fig. 11).

Figure 11.

An older adult patient residing in a nursing home was transferred because of suspected pneumonia. Chest computed tomography showed pulmonary consolidations, and rib fracture was observed in the left lower lobe (A, red circle). Rib fracture sites were also identified in the bone image (B, red circle), leading to the diagnosis of pulmonary contusion due to chest trauma.

Conclusion

Careful consideration of the individual condition of each patient is important for pneumonia management in older adults. For pneumonia treatment, the JRS pneumonia guidelines 2024 describe helpful information regarding appropriate antibacterial therapy; enhanced maintenance of oral hygiene; nutritional interventions; and respiratory, swallowing, and physical rehabilitation. In addition, when encountering patients with pneumonia who are unresponsive to treatment, it is essential to re-evaluate and reconsider the diagnosis and treatment approaches.

Author’s disclosure of potential Conflicts of Interest (COI).

Kazuhiro Yatera: Honoraria, AstraZeneca, Nippon Boehringer Ingelheim, GlaxoSmithKline, KYORIN Pharmaceutical.