Pneumonia is the inflammation of the terminal airways, alveoli, and lung interstitium, and can be caused by pathogens, physical and chemical factors, immune damage, allergies, and medications. Bacterial pneumonia is the most common type and one of the most prevalent infectious diseases. Before the use of antibiotics, bacterial pneumonia posed a significant health threat to children and older adults. The advent and development of antibiotics once significantly reduced the mortality rate of pneumonia. However, in recent years, despite the use of potent antibiotics and effective vaccines, the mortality rate from pneumonia has not decreased further and has even risen.
Epidemiology
The annual incidence of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) is approximately (5 - 11)/1,000 and (5 - 10)/1,000, respectively. The mortality rate is less than 1% - 5% in CAP outpatients, averagely 12% in inpatients, and about 40% in patients in intensive care units. The mortality rate in HAP is 15.5% - 38.2%. The high incidence and mortality are associated with an aging population, smoking, underlying diseases, and immunosuppression, such as COPD, heart failure, cancer, diabetes, uremia, neurological diseases, drug addiction, alcoholism, AIDS, weak constitution, major surgery, use of immunosuppressants, and organ transplants. Additionally, they are linked to changes in pathogens, the emergence of new pathogens, difficulties in etiological diagnosis, and the irrational use of antibiotics leading to increased bacterial resistance, particularly the rise of multidrug-resistant (MDR) pathogens.
Etiology, pathogenesis, and pathology
Normal respiratory immune defense mechanisms, such as the bronchial mucus-ciliary transport system and the integrity of alveolar macrophages, protect the lower respiratory tract from infections by bacteria and other pathogens. The occurrence of pneumonia depends on pathogens and hosts. Pneumonia can occur if there are numerous pathogens, strong virulence, and/or damage to the host's local and systemic immune defense systems.
Pathogens can cause community-acquired pneumonia through the following routes:
- Inhalation of airborne particles
- Hematogenous dissemination
- Spread from adjacent infected areas
- Aspiration of colonized bacteria from the upper respiratory tract
Hospital-acquired pneumonia is more often caused by the aspiration of colonized bacteria from the gastrointestinal tract (gastroesophageal reflux) and/or inhalation of environmental pathogens through artificial airways.
Once pathogens reach the lower respiratory tract, they multiply, causing congestion and edema in the alveolar capillaries, fibrin exudation, and cellular infiltration in the alveoli. Except for pathogens like Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, which can cause necrotizing lesions and cavitation in lung tissue, pneumonia generally does not leave scars after healing, and lung structure and function can be restored.
Classification
Pneumonia can be classified by anatomy, etiology, and environment.
Anatomical classification
Lobar (alveolar) pneumonia
Pathogens initially cause inflammation in the alveoli and spread to other alveoli through the pores of Kohn, affecting partial or entire lung segment or lobe. Typical manifestations are parenchymal inflammation without involving the bronchi. The pathogen is mostly Streptococcus pneumoniae. Chest x-ray shows consolidation in the lobe or segment.
Lobular (bronchial) pneumonia
Pathogens invade through the bronchi, causing inflammation of the bronchioles, terminal bronchioles, and alveoli. This condition is often secondary to other diseases, such as bronchitis, bronchiectasis, and upper respiratory viral infections, and can occur in critically ill bedridden patients. Pathogens include Streptococcus pneumoniae, Staphylococcus, viruses, Mycoplasma pneumoniae, and Legionella. Chest x-ray shows irregular patchy opacities along lung markings, with hazy, hypodense edges, often involving the lower lobes.
Interstitial pneumonia
Inflammation primarily involves the lung interstitium, affecting bronchial walls, peribronchial tissue, and alveolar walls. Symptoms are mild due to only interstitial involvement, but widespread lesions can cause significant dyspnea. This condition can be caused by bacteria, mycoplasma, chlamydia, viruses, and pneumocystis. Chest x-ray shows irregular, ground-glass, reticular opacities in one or both lower lung fields, with or without small areas of atelectasis.
Etiological classification
Bacterial pneumonia
This condition can be caused by pathogens such as Streptococcus pneumoniae, Staphylococcus aureus, α-hemolytic streptococcus, Klebsiella pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Acinetobacter baumannii.
Pneumonia caused by atypical pathogens
This condition can be caused by Legionella, Mycoplasma, and Chlamydia.
Viral pneumonia
This condition can be caused by coronaviruses, adenoviruses, respiratory syncytial virus, influenza virus, measles virus, cytomegalovirus, and herpes simplex virus.
Fungal pneumonia
This condition can be caused by Candida, Aspergillus, Cryptococcus, Pneumocystis, and Mucor.
Pneumonia caused by other pathogens
This condition can be caused by Rickettsia (Coxiella burnetii), Toxoplasma (Toxoplasma gondii), and parasites (Echinococcus, Paragonimus, Schistosoma).
Pneumonia caused by physical and chemical factors
This condition includes radiation-induced pneumonia, chemical pneumonia caused by gastric acid aspiration, and lipoid pneumonia caused by inflammatory reactions to inhaled or endogenous lipid substances.
Environmental classification
Due to the low positive rate of bacteriological tests and delayed culture results, etiological classification is challenging in clinical practice. Currently, pneumonia is often classified based on the environment in which it is acquired, as the etiology differs depending on the setting, aiding empirical treatment.
Community-acquired pneumonia (CAP)
CAP is infectious inflammation of the lung parenchyma (including the alveolar walls) acquired outside hospital, including pneumonia that develops during the incubation period after hospital admission.
Clinical diagnosis is based on:
- Community onset
- Pneumonia-related clinical manifestations, including (a), new onset of cough, expectoration, and exacerbation of existing respiratory symptoms with purulent expectoration, with or without thoracodynia, dyspnea, and hemoptysis; (b), fever; (c), signs of lung consolidation and/or the presence of moist crackles; (d), white blood cell count >10×109/L or <4×109/L, with or without left shift of neutrophils
- Chest imaging showing patchy infiltration or interstitial changes, with or without pleural effusion
A clinical diagnosis can be established if criteria 1 and 3, and any one of criteria 2 are met, after excluding tuberculosis, lung tumors, non-infectious interstitial lung diseases, pulmonary edema, atelectasis, pulmonary embolism, eosinophilic pneumonia, and vasculitis. Common pathogens include Streptococcus pneumoniae, Mycoplasma, Chlamydia, Haemophilus influenzae, and respiratory viruses (influenza A and B, adenovirus, respiratory syncytial virus, and parainfluenza virus).
Hospital-acquired pneumonia (HAP)
HAP occurs in patients who have not received invasive mechanical ventilation, are not in the incubation period of an infection, and develop pneumonia 48 hours or more after hospital admission. Ventilator-associated pneumonia (VAP) is pneumonia occurring within 48 hours after endotracheal intubation or tracheostomy, and within 48 hours after extubation.
Diagnosis is based on new or progressive infiltrates, consolidation, or ground-glass opacities on chest x-ray or CT, along with two or more of the following:
- Fever > 38°C
- Purulent airway secretions
- Peripheral white blood cell count >10×109/L or <4×109/L
The accuracy of clinical diagnosis is directly proportional to the satisfied diagnostic criteria. The clinical features, laboratory test, and imaging in HAP lack specificity and should be differentiated from atelectasis, heart failure, pulmonary edema, underlying lung disease, drug-induced lung injury, pulmonary embolism, and acute respiratory distress syndrome. After diagnosing HAP/VAP, microbiological specimens should be collected. In non-immunocompromised patients, HAP/VAP is usually bacterial, with common pathogens and resistance patterns varying by region, hospital level, patient population, and antibiotic exposure, and changing over time. Common pathogens include Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus. It is crucial to consider local hospital microbiological data for empirical treatment, tailoring antibiotic choice to local patterns and patient factors.
Clinical manifestations
The symptoms of bacterial pneumonia range from mild to severe, depending on the pathogen and host condition. Common symptoms include cough, expectoration, and exacerbation of existing respiratory symptoms with purulent or bloody expectoration, with or without thoracodynia. Extensive lesions may cause dyspnea and respiratory distress. Most patients have fever. Early lung signs may be inapparent, but severe cases may show increased respiratory rate, nasal flaring, and cyanosis. Lung consolidation presents with typical signs such as dull percussion, increased vocal fremitus, and bronchial breath sounds, as well as moist crackles. Concurrent pleural effusion may reveal dull percussion, decreased vocal fremitus, and reduced breath sounds on the affected side.
Diagnosis and differential diagnosis
The diagnostic procedure for pneumonia is as follows.
Definite diagnosis of pneumonia
Based on the previously mentioned diagnostic criteria, pneumonia can be diagnosed, and community-acquired pneumonia or hospital-acquired pneumonia can be classified. It is important to differentiate pneumonia from the following conditions.
Acute upper respiratory tract infection and tracheobronchitis
These conditions typically present with cough, expectoration, and fever, but lack pulmonary infiltrates, which can be distinguished via chest x-ray.
Pulmonary tuberculosis
Pulmonary tuberculosis often presents with systemic symptoms such as afternoon fever, diaphoresis, fatigue, emaciation, insomnia, and palpitations. Female patients may experience menstrual irregularities or amenorrhea. Chest x-ray typically shows lesions in the lung apex or above or below the clavicle, with inhomogeneous density, slow resolution, and possible cavitation or intrapulmonary dissemination. Mycobacterium tuberculosis may be found in the sputum, and response to general antibacterial treatment is poor.
Lung cancer
Lung cancer usually lacks acute infection symptoms. Sputum may occasionally contain blood, and white blood cell count is not elevated. Lung cancer may be concurrent with obstructive pneumonia, and tumor opacities become more apparent after inflammation resolves with antibiotic treatment, possibly with hilar lymphadenopathy or atelectasis. Persistent or recurrent pneumonia in the same site after antibiotic treatment warrants close follow-up. In smokers or older patients, CT, MRI, bronchoscopy, and sputum cytology may be necessary to avoid misdiagnosis.
Pulmonary embolism
Pulmonary embolism is often associated with risk factors for venous thrombosis, such as thrombotic phlebitis, cardiopulmonary diseases, trauma, surgery, and cancer. Symptoms include significant dyspnea, hemoptysis, and syncope. Chest x-ray may show localized reduction in pulmonary vascular markings or wedgy opacity pointing to the hilum. Arterial blood gas analysis often reveals hypoxemia and hypocapnia. D-dimer testing, CT pulmonary angiography, ventilation/perfusion scintigraphy, and MRI can aid in differentiation.
Noninfectious pulmonary infiltration
Noninfectious pulmonary infiltration must be differentiated from interstitial pneumonia, pulmonary edema, atelectasis, and vasculitis.
Assessment of severity
Once pneumonia is diagnosed, evaluating the severity is crucial for deciding on outpatient, inpatient, or ICU treatment. The severity depends on the extent of local lung inflammation, the spread of lung inflammation, and the severity of systemic inflammatory response. There is no universally accepted standard for diagnosing severe pneumonia. However, if respiratory support (acute respiratory failure, severe gas exchange impairment with hypercapnia or persistent hypoxemia), circulatory support (hemodynamic instability, inadequate peripheral perfusion), and intensive monitoring and treatment are required, the condition is considered severe pneumonia. The CURB-65 score is recommended for determining if a CAP patient requires hospitalization.
CURB-65 consists of five criteria, with one point for each:
- Confusion (C)
- Uremia (U) >7 mmol/L
- Respiratory rate (R) ≥30 breaths/min
- Blood pressure (B) with systolic <90 mmHg or diastolic ≤60 mmHg
- Age ≥65
A score of 0 - 1 suggests outpatient treatment; 2 suggests hospitalization or close outpatient follow-up; 3 - 5 indicates hospitalization. Other factors such as age, comorbidities, socioeconomic status, gastrointestinal function, and treatment adherence should also be considered. CAP can be diagnosed as severe pneumonia if one major criterion or at least three minor criteria are met, requiring close observation and proper treatment, with ICU admission if possible.
Major Criteria:
Need for mechanical ventilation via intubation
Septic shock requiring vasopressors after fluid resuscitation
Minor Criteria:
- Respiratory rate ≥30 breaths/min
- PaO2/FiO2 ≤250 mmHg
- Multilobar infiltration
- Confusion or disorientation
- Blood urea nitrogen ≥7.14 mmol/L (20 mg/dL)
- Systolic blood pressure <90 mmHg requiring aggressive fluid resuscitation
Identification of pathogens
Due to the presence of numerous microorganisms on the mucosal surfaces and in the secretions of the upper respiratory tract, known as normal flora, lower respiratory tract secretions or sputum passing through the oropharynx are easily contaminated. This issue is more pronounced in individuals with chronic airway diseases, older adults, and critically ill patients, as their respiratory tracts have increased colonization, affecting the isolation and identification of pathogens in sputum. Additionally, the use of antibiotics can influence bacterial culture results. Therefore, when collecting respiratory specimens for bacterial culture, it is crucial to collect them before antibiotic administration to avoid contamination and ensure timely submission for testing, so that the results can guide treatment.
Sputum
Sputum is easy to collect and is the most common specimen for lower respiratory tract pathogens. It should be submitted for testing within 2 hours at room temperature. A direct smear is first prepared to observe cell counts in microscopy. If there are less than 10 squamous epithelial cells and more than 25 white blood cells per low-power field, or a squamous epithelial cell to white blood cell ratio of less than 1:2.5, the specimen can be considered qualified with relatively less contamination for culture. Pathogenic or opportunistic bacteria isolated at concentrations ≥107 cfu/ml can be considered as pathogens causing lung infection; ≤104 cfu/ml indicates contaminants; between these values suggests repeated sputum culture. If the same bacteria are isolated consecutively at 105 - 106 cfu/ml more than twice, they can also be considered pathogens.
Bronchoscopy or artificial airway aspiration
Bronchoscopy or artificial airway aspiration is less likely to be contaminated by oropharyngeal bacteria compared to expectorated sputum. If bacteria are cultured at concentrations ≥105 cfu/ml, they can be considered pathogens; below this concentration suggests contaminants.
Protected specimen brush
Bacteria at concentrations ≥103 cfu/ml can be considered pathogens.
Bronchoalveolar lavage (BAL)
Bacteria at concentrations ≥104 cfu/ml, or ≥103 cfu/ml in protected BAL specimens can be considered pathogens.
Percutaneous needle aspiration and open lung biopsy
They are highly sensitive and specific but invasive, with risks of complications such as pneumothorax or hemorrhage. They are generally used when empirical antibiotic treatment is ineffective or other tests are inconclusive.
Blood and pleural effusion culture
If the same bacteria are isolated from both blood and sputum in pneumonia patients, they can be identified as pathogens. Bacteria cultured from pleural effusion are generally considered pathogens. Since blood or pleural effusion samples are collected through the skin, results must exclude contamination by skin bacteria during the procedure.
Urinary antigen test
Urinary antigen test includes tests for Legionella and Streptococcus pneumoniae urinary antigens.
Serological tests
Serological tests measure specific IgM antibody titers. A fourfold increase between the acute and convalescent phases can diagnose infections such as Mycoplasma, Chlamydia, Legionella, and viral infections, often used for retrospective diagnosis.
Molecular diagnostic techniques
Nucleic acid detection methods include real-time PCR, digital PCR, isothermal amplification, and point-of-care nucleic acid tests. Real-time PCR is mainly for outpatient, inpatient, and large-scale screenings. Digital PCR can directly quantify pathogens in respiratory specimens. Isothermal amplification and point-of-care tests are suitable for rapid pathogen screening in respiratory infections at outpatient and fever clinics. Metagenomic next-generation sequencing (mNGS) is mainly used for severe respiratory infections, suspected special pathogen infections, and cluster respiratory infections, especially when traditional microbiological tests are inconclusive or rapid identification is needed. For community-acquired pneumonia, nucleic acid detection improves pathogen detection rates. Hospital-acquired and ventilator-associated pneumonia primarily rely on traditional culture methods, with mNGS considered when patients have immune deficiencies, pathogens remain unidentified after 3 days of traditional tests, and empirical treatment fails.
Despite many diagnostic methods, 40% - 50% of pneumonia cases still cannot identify the pathogen. The low detection rate and delayed etiological and serological diagnosis mean most lung infections, especially initial antibiotic treatments, are empirical. However, for hospital-acquired pneumonia, pneumonia in immunocompromised hosts, and severe pneumonia unresponsive to treatment, various methods should be actively used to identify pathogens and guide antibiotic treatment. Possible pathogens can be estimated based on clinical and radiological features of different types of pneumonia.
Table 1 Symptoms, signs, and x-ray features of common pneumonia
Treatment
Antimicrobial therapy is a key aspect of pneumonia treatment, including empirical and pathogen-targeted therapy. The former is based primarily on the epidemiological data of pneumonia pathogens in the region or institution, selecting antibiotics that likely cover the pathogens. The latter involves choosing antibiotics that are sensitive in vitro based on etiological culture results or lung tissue specimen cultures, pathology results, and antibiotic sensitivity tests. Additionally, factors such as age, presence of underlying diseases, aspiration risk, patients in general ward or ICU, duration of hospitalization, and severity of pneumonia should be considered in selecting antibiotics and administration routes.
In young and middle-aged patients with community-acquired pneumonia without underlying diseases, penicillins and first-generation cephalosporins are commonly used. Due to the high resistance of Streptococcus pneumoniae to macrolides, macrolides should not be used alone for treating pneumonia caused by this bacterium. For resistant Streptococcus pneumoniae, respiratory fluoroquinolones (moxifloxacin, gemifloxacin, and levofloxacin) can be used. For older patients, patients with underlying diseases, or hospitalized CAP patients, respiratory fluoroquinolones, second- or third-generation cephalosporins, β-lactam/β-lactamase inhibitors, or ertapenem are commonly used, possibly in combination with macrolides. Hospital-acquired pneumonia is often treated with second- or third-generation cephalosporins, β-lactam/β-lactamase inhibitors, fluoroquinolones, or carbapenems.
Severe pneumonia should initially be treated with broad-spectrum, potent antibiotics in adequate doses and combinations. Inadequate or inappropriate initial empirical treatment, or adjustments based on etiological culture results, result in significantly higher mortality than correct initial treatment. Severe CAP is treated with β-lactams in combination with macrolides or fluoroquinolones; in penicillin-allergic patients, respiratory fluoroquinolones and aztreonam are used. For HAP, β-lactam with antipseudomonal activity, broad-spectrum penicillin/β-lactamase inhibitors, or carbapenems can be in combination with respiratory fluoroquinolones or aminoglycosides. If multidrug-resistant (MDR) bacteria are suspected, vancomycin, teicoplanin, or linezolid can be added.
Antimicrobial therapy should be initiated as early as possible; once pneumonia is suspected, the first dose of antibiotics should be administered promptly. The earlier the treatment, the better the prognosis. Once the condition stabilizes, intravenous administration can be switched to oral therapy. Antimicrobial treatment can generally be stopped 2 - 3 days after fever subsides and major respiratory symptoms improve, but the duration should vary based on the severity of the condition, speed of resolution, complications, and different pathogens, rather than the resorption of pulmonary opacities. Typically, mild to moderate CAP patients have a course of 5 - 7 days, while severe cases with extrapulmonary complications may have an extended course. For atypical pathogens with slower treatment responses, the course can be extended to 10 - 14 days. Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella species, and anaerobes can cause lung tissue necrosis, requiring a course of 14 - 21 days.
Most CAP patients show clinical improvement within 72 hours after initial treatment, with lowered temperature, symptom improvement, stabilized clinical status, and gradual normalization of white blood cells, C-reactive protein, and procalcitonin, although radiological improvement lags behind clinical symptoms. The condition should be evaluated 72 hours after initial treatment. Some patients may respond slowly to treatment; as long as there is no clinical deterioration, observation can continue without rushing to change antimicrobials. Clinical stability after treatment indicates effective initial treatment.
Clinical stability criteria include meeting all five indicators:
- Temperature ≤37.8°C
- Heart rate ≤100 beats/min
- Respiratory rate ≤24 breaths/min
- Systolic blood pressure ≥90 mmHg
- Blood oxygen saturation ≥90% (or arterial oxygen partial pressure ≥60 mmHg in room air)
In patients who achieve clinical stability and can take oral medications, oral formulations of the same or similar antimicrobial spectrum that are sensitive to the pathogen for sequential therapy can be administered.
If symptoms do not improve in 72 hours, possible reasons include:
- Pathogen not covered by drugs or resistant
- Infection with special pathogens, such as Mycobacterium tuberculosis, fungi, or viruses
- Complications or host factors affecting efficacy (immunosuppression)
- Misdiagnosis of noninfectious disease as pneumonia
- Drug fever
Careful analysis and necessary examinations should be conducted for appropriate management.
Prevention
Physical exercise to improve fitness should be strengthened. Risk factors such as smoking and excessive alcohol consumption should be reduced. Individuals over age 65 can receive influenza vaccines. Individuals over age 65, or under age 65 with cardiovascular disease, lung disease, diabetes, alcoholism, cirrhosis, or immunosuppression can receive pneumonia vaccines.