Definition and Classification of Respiratory Tract Infection

Introduction

Pneumonia has challenged clinicians since ancient times. While the lay public often believes that the problem of pneumonia has been solved by antibiotics, epidemiologists continue to report increasing mortality in specific populations. Between 1980 and 1992, the mortality rate of pneumonia increased 20%, from 25 to 30 per 100,000 population. More recent information has indicated a rising incidence of hospital admission, more marked in older individuals and in men. Mortality remains high for patients with pneumonia who require intensive care (15-50%). Elderly individuals show disproportionately high mortality, with more than half of all deaths from infection occurring in those over age 65 years. Nine of ten deaths attributable to pneumonia occur in the elderly, while rates in children and young adults continue to decrease. While the incidence of community-acquired pneumonia (CAP) requiring hospitalization has been reported at 89-1,138 cases per 100,000 population for adults <65 years of age, it increases to 847-3,500 cases per 100,000 population in those age 65 years and above.

It has been estimated that 5.6 million Americans develop pneumonia annually, with nearly 1.7 million hospital admissions and ~8 million bed days (based on an average length of stay of 4.4-4.9 days). There are 20 million patient-physician interactions due to pneumonia. Inpatient care costs on average >20 times that of outpatient care, with additional expenses incurred through loss of work, catastrophic disability and prolonged recuperation. Healthcare-associated pneumonia (HCAP), formerly called hospital-acquired pneumonia (HAP) and nosocomial pneumonia, remains the leading cause of death due to infectious disease in inpatients, with the incidence highest in the intensive-care unit (ICU). Outside the ICU, patients with altered mental status and those who are recovering from abdominal and thoracic surgery are at highest risk. While crude mortality in patients with skin and urinary tract infections is <5%, HAP results in death in 25-50% of those affected and approaches 75% in cases of virulent infections due to pathogens such as Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA).

Attributable mortality is a concept that accounts for the role of HAP in adding to the likelihood that an already ill or compromised patient will die from lower respiratory tract infection (LRTI); this has been estimated as one third to one half of the overall mortality. The development of pneumonia after a procedure such as cardiac surgery results in prolonged length of hospital stay with concomitantly increased resource consumption.

It is estimated that 5 hospital days and approximately $1,200 are added to the cost of care for each episode of respiratory infection. Once a patient is hospitalized with pneumonia, mortality takes a quantum jump from <1% in low-risk outpatients to 14-20% in hospitalized patients to 50% in critically ill pneumonia patients. It must be remembered that respiratory tract infection is an even greater problem in the developing world, where prevalence of and mortality due to chronic obstructive pulmonary disease (COPD), an important pneumonia risk factor, is increasing at an even greater rate than in the United States.

Pneumonia-related challenges for clinicians include:

• Altered demographics
• New and resistant pathogens, most recently, gram-positive and viral as well as multidrug-resistant Streptococcus pneumoniae (MDRSP), MRSA and influenza A virus (H1N1)
• Economic pressure
• Diagnostic confusion.

Altered Demographics

The number of elderly and immunologically impaired individuals living in the community is increasing. There remains a high reservoir of human immunodeficiency virus (HIV)- positive patients in the community along with an increasing population of transplanted patients. There is a higher incidence of respiratory tract infection in association with lower socioeconomic status and homelessness.

New and Resistant Pathogens

The rising problem of resistant pathogens has been recognized even in the lay press, with hospitals and businesses coming together to develop a strategy to deal with this problem. Among the most problematic are multiple MDRSP, MRSA and numerous multiresistant enteric gram-negative rods, including P aeruginosa. In 2017, the World Health Organization (WHO) gave 7 bacterial pathogens the highest
“priority status” because of their threat to public health; these include Enterococcus faecium, S aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P aeruginosa, and Enterobacter spp, collectively know by the acronym ESKAPE. Emerging viral pathogens, such as H1N1, Hantavirus, Ebola virus, “bird flu”, and, most notably severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) – the cause of the most recent viral pandemic – have also become significant health risks.

Economic Pressure

Insurers and health care providers are under increasing pressure to deliver quality health care at lower cost. Patients generally prefer outpatient care, with which costs are at least 20 times lower. The threat to quality of care brought about by limiting resources challenges clinicians to provide cost-effective care.

Diagnostic Confusion

Treatment of pneumonia today relies on empiric therapy based on epidemiologic studies of groups of patients. This is because prompt initiation of treatment is of paramount importance and culture-based tests for specific pathogens typically take 48-72 hours to perform; however, as molecular (ie, PCR-based) pathogen identification techniques, which can identify pathogens in just minutes to hours, become more widespread, we are entering an era where targeted antibiotic therapy can commence earlier and inappropriate antibiotic use can be reduced.

Historical Perspective

Pneumonia is a complex pathologic process that includes the accumulation of edematous fluid and inflammatory cells in the alveoli in response to proliferation of microorganisms in normally sterile lung parenchyma. The relatively defined clinical response (i.e., the inflammatory process) is the clinical illness of pneumonia.

Classifications, including typical and atypical pneumonia and, more recently, CAP and HAP, have been utilized in an attempt to improve clinical relevance. The term “atypical pneumonia” was originally applied to cases with mild symptomatology and a more prolonged prodrome. Initially closely associated with Mycoplasma pneumoniae (as differentiated from typical pneumococcal pneumonia), the term has been applied to a variety of pathogens, including Chlamydia, Legionella and viral pathogens. These organisms (with the exception of Legionella) are usually associated with a more benign prognosis and offer the possibility of outpatient treatment in most cases. More recent data indicate that atypical organisms may coinfect or superinfect along with the pneumococcus, resulting in illness that is multietiologic in origin and usually not benign.

In contrast, the increasing use of the hospital for treatment and the employment of immunosuppressive therapy have fostered the development of a new class of patients with HAP, which has associated unique syndromes, timing of onset, prognosis and treatment. While these classifications (Table 1-1) are still relevant, the blurring of inpatient and outpatient therapy and the increasing number of immunocompromised patients in the community have reduced the utility of these paradigms.

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Community-Acquired Pneumonia (CAP)

Lower respiratory tract infections acquired out of the hospital (or other residential health care facilities) are labeled “community-acquired.” Traditionally, typical pneumonia referred to the constellation of signs and symptoms of acute onset associated with S pneumoniae, Haemophilus influenzae, S aureus and other gram-negative and anaerobic bacteria. Atypical pneumonia referred to the more subacute prodrome associated with M pneumoniae, Chlamydia pneumoniae (also known as Chlamydophila) and occasionally Legionella spp. There is, however, significant variability in the definition applied to pneumonia. Overlap exists such that utilization of clinical examination to determine microbial cause of pneumonia has not been possible. Both classic and atypical pneumonia syndromes may develop in the setting of viral pneumonia; this has been observed in the H1N1 epidemic and the COVID pandemic.

The greatest challenge to the clinician is differentiating pneumonia from upper respiratory tract infection and other conditions (e.g., pulmonary embolism [PE], heart failure [HF]) that may share clinical features. Few clinical signs are reliably predictive of pneumonia. However, given the ramifications of antimicrobial overuse, diagnostic refinement is increasingly a concern. Whenever feasible, diagnosis of pneumonia should be confirmed with a chest radiograph. In particular, use of antibiotics to treat acute viral bronchitis is a source of antimicrobial overuse and adds to increasing rates of drug-resistant organisms. Once pneumonia is diagnosed, it is important to stratify these patients based on risk of complications and outcome (Figure 4-1). Physician judgment and vital sign abnormalities are the best independent predictors, with likelihood ratios >2.5. With a respiratory rate <10 breaths per minute, a heart rate <100 beats per minute and a temperature <37.8°C (100°F), the likelihood of pneumonia is reduced by 80%. Reproducibility of physical findings is poor. There are no uniformly established diagnostic criteria, and the expression of pneumonia varies considerably depending on the age and immunocompetence of the host, even if the causative organism is the same.

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Symptoms and Signs

Signs and symptoms of CAP include:

• Fever present in younger individuals (≥37.8°C [100°F]); less common in patients >76 years of age
• Increased sputum production or change in color with associated cough
• Less-sensitive criteria include:
  • Pleuritic chest pain
  • Dyspnea
  • Altered mentation, especially in the elderly
  • Increased or decreased white blood cell (WBC) count (<4000 or >12,000 cells/mm³).

While signs of pulmonary consolidation may also be present, rales are more common. Dullness to percussion, bronchial breathing and broncho/egophony are not present in 65% of inpatients and 85% of outpatients with pneumonia. Elderly patients or those with significant immune deficiency are likely to incompletely express the signs and symptoms of pneumonia.

Nonclassic Symptoms/Clinical Signs in Elderly CAP Patients

Some elderly CAP patients will present with the following nonclassic signs and symptoms:

• Cough, dyspnea, fever less with increasing age
• Less sputum production, pleuritic chest pain
• Tachypnea
• Confusion due to hypoxia, a hallmark sign
• Malnutrition
• WBC count response not mounted.

Chest Radiographs

While consolidation, infiltration and cavitation on chest radiographs have traditionally been considered the gold standard for radiologic diagnosis, there is a significant lack of standardization of interpretation. Some studies have pointed out a lack of concordance of interpretation of radiologic signs. The clinician must be cognizant of the lack of reliability of any radiologic pattern, including lobar, interstitial, or cavitary. In addition, standard chest radiography may be significantly less sensitive than computerized tomography (CT).

The requirement of either multiple segmental involvement or new onset of infiltration may exclude mild pneumonia or infection in those with chronic underlying lung disease, such as cancer. Lobar consolidation has been classically associated with pneumococcal pneumonia (Figure 1-1), but more recently has been reported to be more common than bronchopneumonia in this condition. Diffuse interstitial infiltration has been associated with atypical pneumonia, especially M pneumoniae (Figure 1-2). Involvement of multiple lobes has been consistently identified as a marker of poor prognosis in CAP and should prompt consideration of admission to the ICU for observation. In the absence of altered vital signs, it is unlikely that a chest radiograph will be abnormal. Elevation of pulse, respiratory rate and temperature or decreased blood pressure (BP) in the setting of respiratory symptoms should trigger a confirmatory chest radiograph.

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HCAP, HAP and VAP

HCAP is the umbrella term for the spectrum of acute lung infections contracted in a health care institution, including rehabilitation and skilled nursing facilities. HAP is defined as an infection that develops after at least 48 hours of hospitalization. Ventilator-associated pneumonia (VAP) is a subset of HAP pneumonias that occur at least 48 hours after intubation and up to 48 hours after extubation.

Infection developing within the first 2 days of hospitalization is presumed to be acquired prior to admission. The overall incidence of HAP in the United States is estimated at 3.6 cases per 1,000 patient-days; the greatest risk is to patients requiring mechanical ventilation. The incidence of VAP is estimated at 2-6 cases per 1,000 ventilator-days, with the rate of acquisition declining with duration of ventilation; patients are at highest risk for infection at the time nearest to intubation. Gram-negative bacilli have been most often associated with VAP, accounting for the vast majority of the most common pathogens. MRSA is increasingly recognized as an important ventilator-associated pathogen.

HAP may also be classified according to the time of onset. This classification permits the clinician to initiate treatment based on likely pathogens. Early-onset pneumonia develops within 4 days of admission and probably results from pathogens already colonizing the upper airway prior to hospitalization. Such infections usually are associated with community organisms, such as pneumococcus or H influenzae. Pneumonia developing after 4 days of hospitalization is referred to as late-onset pneumonia and results from organisms that colonize the gut, upper airway, or trachea after admission. Organisms that replace normal endogenous flora include P aeruginosa, Enterobacter and MRSA species. Criteria for diagnosis of HAP include the following:

• Fever >38°C (100.4°F)
• Leukocytosis
• Purulent tracheal secretions (usually requires positive Gram’s stain of >25 leukocytes and <10 squamous cells per low-power field)
• New or progressive infiltrate or abscess formation on chest radiograph
• Deterioration of gas exchange.

While the above criteria are sensitive, there are many causes of fever and pulmonary infiltrates that are not of infectious etiology (Table 1-2). A large body of literature has confirmed the limitation of clinical diagnosis in the cases of VAP. There has been significant variance when clinical diagnosis was compared with either histologic criteria or quantitative culture, with reported error rates of 30%-40% error rates reported, leading to significant prescription of incorrect treatment plans, including failure to:

• Diagnose pneumonia
• Recognize polymicrobial pneumonia
• Appreciate antibiotic resistance
• Eliminate unnecessary prescription of antibiotics.

This makes the diagnosis of HAP in the ICU particularly difficult. The presence of all criteria increases specificity, but it still remains <50%. The wide differential of diagnostic possibilities has led to increasing use of quantitation of bacterial cultures obtained either by aspiration or bronchoscopic sampling (protected specimen brush [PSB], bronchoalveolar lavage [BAL]) to improve diagnostic accuracy.

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Summary

The physician confronted with a patient with suspected pneumonia should be aware of the following caveats:

• Pneumonia may be present in patients who appear to have only an upper respiratory tract infection.
• The chest radiograph is unlikely to be abnormal in the absence of vital signs abnormalities. Pneumonia is uncommon when the chest radiograph is normal.
• There should be a high index of suspicion for the diagnosis of pneumonia in elderly or immunocompromised patients in whom signs and symptoms may be incompletely expressed.
• While clinical findings are unlikely to define specific microbial etiology, they are helpful in identifying potential lower respiratory tract infection and in stratifying risk so that appropriate decisions regarding pharmacotherapy and treatment setting can be made.
• Mortality in patients with pneumonia is low overall but increases dramatically in those who require hospitalization, especially in ICUs.
• Pneumonia in ventilated patients is a particularly challenging diagnostic problem. The diagnosis is often inaccurate on clinical grounds alone. Quantitative microbiologic diagnostic studies are often required.
• VAP adds to morbidity, mortality and resource consumption in patients who are already compromised.