Pneumonia

Pneumonia or pulmonary inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation is an acute or chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of lung tissue. Causes include infection with bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, viruses, or fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Definition and Epidemiology

Types of pneumonia

  • Community-acquired pneumonia (CAP): pneumonia acquired outside of the hospital setting
  • Hospital-acquired pneumonia (HAP): pneumonia acquired 48 hours after admission into the hospital for another reason in a patient who does not meet the criteria for ventilator-associated pneumonia (VAP)
  • Ventilator-associated pneumonia: pneumonia acquired 48 hours after endotracheal intubation or within 48 hours after extubation
  • Nosocomial pneumonia: encompasses the definition of both HAP and VAP
  • Healthcare-associated pneumonia (HCAP): an inaccurate term based on low-quality evidence
  • Aspiration pneumonia: pneumonia in the setting of increased risk of aspiration such as poor gag reflex or a critically ill status
  • Atypical pneumonia: pneumonia caused by atypical organisms (e.g.,  Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or "walking" pneumonia. Mycoplasma pneumoniae Chlamydia Chlamydia Chlamydiae are obligate intracellular gram-negative bacteria. They lack a peptidoglycan layer and are best visualized using Giemsa stain. The family of Chlamydiaceae comprises 3 pathogens that can infect humans: Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae. Chlamydia pneumoniae, and respiratory viruses) and clinically characterized by milder symptoms with no lobar infiltrates on X-ray

Epidemiology

  • Most common cause of death due to infection in the United States
  • Higher mortality rates in developing countries
  • Leading cause of death in children under 5 years of age worldwide
  • More common in winter and in colder climates
  • Higher incidence and mortality rate in advanced age

Risk Factors and Pathophysiology

Risk factors for multidrug-resistant (MDR) pathogens

  • Too much emphasis on the management of pneumonia based on the above definitions has led to the inappropriate use of broad-spectrum antibiotics and worse outcomes.
  • More recently, the emphasis has been on the identification of risk factors that increase the likelihood of infection with drug-resistant pathogens including methicillin-resistant  Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus aureus (MRSA).
  • Identification of ≥ 2 of the risk factors outlined in Table 1 guides the choice of antibiotic therapy.
Table 1: Risk factors for infection with pathogens that are resistant to antibiotics for CAP
MDR gram-negative bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview and MRSA Nosocomial (HAP and VAP) MRSA Community-acquired MRSA
  • Hospitalization ≥ 2 days in recent 90 days
  • Antibiotic use in recent 90 days
  • Gastric acid suppression
  • Immunosuppression
  • Non-ambulatory status
  • Tube feeding
  • Severe chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD))/ bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis
  • Hospitalization ≥ 2 days in recent 90 days
  • Antibiotic use in recent 90 days
  • Gastric acid suppression
  • Current hospitalization ≥ 5 days
  • High frequency of antibiotic resistance in community/hospital setting
  • Immunosuppression
  • Chronic hemodialysis in recent 30 days
  • Established prior MRSA colonization
  • Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
  • Pulmonary cavitation
  • Hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis
  • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia
  • Erythematous rash
  • Concurrent influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza
  • Previously healthy status
  • Onset during summer

Pathophysiology

  • Main route: small-volume aspiration of pathogens such as bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview → access to and proliferation in alveolar space → immune response through alveolar macrophages → localized capillary leak and alveolar infiltration → symptoms and signs of pneumonia such as rales on auscultation and consolidation on X-ray
    • Respiratory defense mechanisms Defense mechanisms Defense mechanisms are normal subconscious means of resolving inner conflicts between an individual's subjective moral sense and their thoughts, feelings, or actions. Defense mechanisms serve to protect the self from unpleasant feelings (anxiety, shame, and/or guilt) and are divided into pathologic, immature, mature, neurotic, and other types. Defense Mechanisms that must be overcome: nasal hair and turbinates, the gag and cough reflex, the tracheobronchial tree and its mucociliary lining, and alveolar macrophages
  • Other routes:
    • Hematogenous (e.g., right heart endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis)
    • Contiguous spread (pleural or mediastinal infection)
  • Alternative pathogenesis: A defect in the normal defense mechanism of the airways facilitates overgrowth of the normal airway microbiota, causing pneumonia.
  • Typical pathologic phases for bacterial lobar pneumonia:
    • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema: alveolar exudate containing the pathogenic organism which transits quickly to the next phase
    • Red hepatization: predominant presence of erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes with neutrophils and occasional bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview in the exudate
    • Gray hepatization (successful control of infection): predominant presence of neutrophils and fibrin with few erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes and no bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
    • Resolution: predominant presence of macrophages with the clearing of neutrophils and fibrin

Community-Acquired Pneumonia

Etiology

Common pathogens that cause CAP to vary based on the severity of CAP (i.e., requiring treatment as an outpatient or as an inpatient outside or inside the ICU) (see Table 2):

Table 2: Microbial causes of community-acquired pneumonia
Outpatient Non-intensive care unit (ICU) Inpatient ICU
  • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumonia1
  • Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or "walking" pneumonia. Mycoplasma pneumonia2
  • Chlamydia Chlamydia Chlamydiae are obligate intracellular gram-negative bacteria. They lack a peptidoglycan layer and are best visualized using Giemsa stain. The family of Chlamydiaceae comprises 3 pathogens that can infect humans: Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae. Chlamydia pneumonia2
  • Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus pneumonia
  • Respiratory viruses2,3
  • S. pneumonia
  • M. pneumonia2
  • C. pneumonia2
  • H. pneumonia
  • Respiratory viruses2,3
  • Legionella Legionella Legionella is a facultative intracellular, gram-negative bacilli. Legionella does not grow on common culture media because it requires certain supplementation (cysteine and iron). Legionella pneumophila (L. pneumophila) accounts for the majority of human infections. Legionella/Legionellosis spp.2
  • S. pneumonia
  • Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus aureus
  • Gram-negative bacilli
  • H. pneumonia
  • Respiratory viruses2,3
  • Legionella Legionella Legionella is a facultative intracellular, gram-negative bacilli. Legionella does not grow on common culture media because it requires certain supplementation (cysteine and iron). Legionella pneumophila (L. pneumophila) accounts for the majority of human infections. Legionella/Legionellosis spp.2
Newly identified pathogens
  • Metapneumovirus
  • Severe acute respiratory syndrome coronavirus Coronavirus Coronaviruses are a group of related viruses that contain positive-sense, single-stranded RNA. Coronavirus derives its name from "κορώνη korṓnē" in Greek, which translates as "crown," after the small club-shaped proteins visible as a ring around the viral envelope in electron micrographs. Coronavirus (SARS-CoV): 2003 SARS epidemic
  • Middle East respiratory syndrome coronavirus Coronavirus Coronaviruses are a group of related viruses that contain positive-sense, single-stranded RNA. Coronavirus derives its name from "κορώνη korṓnē" in Greek, which translates as "crown," after the small club-shaped proteins visible as a ring around the viral envelope in electron micrographs. Coronavirus (MERS-CoV): 2012 MERS outbreak
  • Community-acquired methicillin-resistant S. aureus (CA-MRSA)
  • SARS-CoV-2: 2019-2020 COVID-19 pandemic
1Most common etiology
2Atypical pathogen (note: atypical pathogens are resistant to β-lactams, and must be treated with macrolides Macrolides Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides, fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones, or a tetracycline)
3Respiratory viruses include influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza viruses, adenoviruses, human metapneumovirus, and respiratory syncytial virus Respiratory Syncytial Virus Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus.

An anaerobic etiology is suggested only when a history of aspiration is present days to weeks before the diagnosis of pneumonia.

  • Major risk factor for aspiration pneumonia: unprotected airway (e.g., alcohol/drug overdose or seizure) + significant gingivitis
  • Common complications of aspiration pneumonia: abscess formation and empyema

Epidemiology

  • 80% of CAP cases are treated as outpatients.
  • Most common cause of death from infection in patients > 65 years
  • Almost 1 out of 5 CAP inpatients are rehospitalized within 1 month.
  • CAP mortality rate is highest at age extremes.

Risk factors

General

  • Age > 65 years and < 2 years
  • Immunosuppression
  • Chronic conditions (especially cardiopulmonary diseases, asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma)
  • Reduced gag reflex
  • Smoking
  • Institutionalization (e.g., hospital, nursing home)
  • Living in crowded conditions
  • Alcoholism
  • Asthma
  • Immunosuppression
  • Institutionalization (e.g., nursing homes)
  • Age ≥ 70 years (e.g., reduced gag/cough reflex)

Specific

  • Pneumococcal pneumonia: dementia, seizure disorders, heart failure, cerebrovascular disease, alcoholism, smoking, COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD), HIV
  • Legionella Legionella Legionella is a facultative intracellular, gram-negative bacilli. Legionella does not grow on common culture media because it requires certain supplementation (cysteine and iron). Legionella pneumophila (L. pneumophila) accounts for the majority of human infections. Legionella/Legionellosis infection: immunosuppression, diabetes, malignancy, HIV, smoking, male sex, and a recent hotel stay or ship cruise
  • P. aeruginosa: structural lung diseases such as severe COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD), bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis, or cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis
  • H. influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza: smoking, COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)
  • S. aureus: influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza infection
  • Gram-negative bacilli (e.g., Klebsiella Klebsiella Klebsiella are encapsulated gram-negative, lactose-fermenting bacilli. They form pink colonies on MacConkey agar due to lactose fermentation. The main virulence factor is a polysaccharide capsule. Klebsiella pneumoniae is the most important pathogenic species. Klebsiella pneumonia): increased risk of aspiration such as alcohol abuse

Clinical manifestations

  • Cough:
    • Productive (mucoid, purulent, or blood-tinged sputum)
    • Nonproductive (mostly with atypical pneumonias)
    • Gross hemoptysis suggests CA-MRSA
  • Dyspnea (mild to severe)
  • Pleuritic chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
  • Physical examination:
    • Increased respiratory rate and use of accessory muscles
    • Increased tactile fremitus and dull percussion: consolidation
    • Decreased tactile fremitus and flat percussion: pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion
    • Auscultation: crackles, bronchial sounds in the periphery, pleural friction rub
  • Nonspecific symptoms: fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, palpitations, chills, night sweats, fatigue, nausea, vomiting, headache, myalgia, arthralgia
  • Pneumonia in the elderly may present with confusion.
  • Severe cases may present with signs of septic shock Septic shock Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Septic shock is diagnosed during treatment when vasopressors are necessary to control hypotension. Sepsis and Septic Shock and multiorgan failure.
  • Cardiovascular complications including myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction and arrhythmias.

Clinical diagnosis

  • Most outpatients: symptoms and signs + chest X-ray (images 1–3)
  • Some patients may require lung CT to evaluate for suspected tumors, foreign bodies, cavitary lesions, etc.

Etiologic diagnosis

  • Sputum and blood cultures are recommended only in severe pneumonia or likely infection with MRSA or  Pseudomonas Pseudomonas Pseudomonas is a non-lactose-fermenting, gram-negative bacillus that produces pyocyanin, which gives it a characteristic blue-green color. Pseudomonas is found ubiquitously in the environment, as well as in moist reservoirs, such as hospital sinks and respiratory equipment. Pseudomonas aeruginosa.
  •  Polymerase chain reaction (PCR) of nasopharyngeal swabs:
    • During influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza season, testing for influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza is recommended.
    • Testing may be indicated for a specific virus during outbreaks based on local or regional health-care policies and availability of tests. For example, testing priorities for SARS-CoV-2 during the pandemic include:
      • Hospitalized patients
      • Symptomatic healthcare workers/first responders
      • Symptomatic patients who are in long-term care facilities, are ≥ 65 years old, or have comorbidities
      • Asymptomatic critical infrastructure workers, healthcare workers, or first responders
      • Symptomatic individuals who do not meet the above categories
      • Mildly symptomatic individuals in communities with high hospitalization rates for COVID-19
    • Can also detect bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview including  Legionella Legionella Legionella is a facultative intracellular, gram-negative bacilli. Legionella does not grow on common culture media because it requires certain supplementation (cysteine and iron). Legionella pneumophila (L. pneumophila) accounts for the majority of human infections. Legionella/Legionellosis species, M. pneumoniaeC. pneumoniae, and mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium
  • Urinary antigen test may detect Legionalla pneumophila or pneumococcus

Noninfectious differential diagnoses

  • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema: Bilateral infiltration with central predominance and abnormal ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) is suggestive.
  • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism: rarely presents with productive cough or infiltrations visible on chest X-ray
  • Lung carcinoma: A history of smoking, constitutional symptoms (e.g., significant weight loss), or chronic cough may be suggestive.
  • Radiation
  • Hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis: diagnostic criteria including a compatible exposure history
  • Connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue disease involving the lung: Most often, a prior diagnosis or symptoms of underlying disease is already present.

Infectious differential diagnoses

  • Acute bronchitis Acute Bronchitis Acute bronchitis is an infection of the mucous membrane of the bronchi without evidence of pneumonia. Due to its pathogenesis, acute bronchitis is frequently accompanied by an upper respiratory tract infection. Cases in which the trachea is also involved are referred to as tracheobronchitis. Acute Bronchitis
  • Exacerbation of COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)
  • Tuberculosis
  • Lung abscess

Risk assessment

In addition to clinical judgment, a validated prediction tool is recommended to determine the need for hospitalization:

  • Preferred tool: Pneumonia Severity Index (PSI) (based on a combination of patient demographics, comorbidities, physical examination findings, and laboratory and imaging studies including arterial pH, blood urea nitrogen, serum sodium and glucose, hematocrit, partial pressure of oxygen, and pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion)
    • Risk class 1 or 2 is sent home on oral antibiotics.
    • Risk class 3 may be sent home on oral antibiotics or admitted for short-term monitoring and antibiotic therapy based on home environment and follow-up.
    • Risk class 4 or 5 is hospitalized.
  • Alternative tool: CURB-65 (1 point for each of the following: confusion, blood urea nitrogen ≥ 20 mg/dL, respirations ≥ 30/min, systolic blood pressure < 90 mm Hg or diastolic blood pressure < 60 mm Hg, age ≥ 65 years):
    • 0–1 (mortality rate < 1%–3%): Patient should be sent home on oral antibiotics.
    • 2 (mortality rate 7%): Patient may be sent home on oral antibiotics or admitted for short-term monitoring and antibiotic therapy based on home environment and follow-up.
    • 3–5 (mortality rate 14%–28%): Hospitalize the patient.

Severe CAP or CAP requiring ICU admission is defined by CAP plus at least 1 of the following:

  • Septic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock requiring vasopressors
  • Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure requiring mechanical ventilation
  • 3 or more of the following: respirations ≥ 30/min, PaO2/FiO2 ≤ 250, multilobar pneumonia, confusion, blood urea nitrogen ≥ 20 mg/dL, WBC < 4,000 cells/µL, platelet < 100,000/µL, hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension requiring aggressive fluid management)

Management

  • Serum procalcitonin levels should not influence the decision to treat pneumonia with antibiotics.
  • Initial antibiotic treatment for outpatients with CAP:
    • No comorbidities or risk factors for MRSA or P. aeruginosa:
      • Amoxicillin OR
      • Doxycycline OR
      • Macrolide (azithromycin, clarithromycin)
    • With comorbidities (e.g., congestive heart disease, chronic lung disease, malignancy, cerebrovascular disease, renal disease, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease):
      • Amoxicillin/clavulanate (or cephalosporin) AND macrolide (or doxycycline) OR
      • Respiratory fluoroquinolone (levofloxacin, moxifloxacin, gemifloxacin)
  • Initial antibiotic treatment for inpatients with CAP:
    • Nonsevere:
      • Β-lactam and macrolide OR
      • Respiratory fluoroquinolone
      • If ≥ 2 risk factors for MRSA or P. aeruginosa are present, add coverage (see below) only if culture/PCR is positive.
      • If lung abscess or empyema is suspected, add anaerobic coverage. (Note: suspected aspiration pneumonia is not an indication for anaerobic coverage.)
    • Severe:
      • Β-lactam and macrolide (preferred) OR
      • Β-lactam and respiratory fluoroquinolone
      • If ≥ 2 risk factors for MRSA or P. aeruginosa are present, add coverage
      • If lung abscess or empyema is suspected, add anaerobic coverage. (Note: suspected aspiration pneumonia is not an indication for anaerobic coverage.)
  • Empiric coverage for MRSA includes vancomycin or linezolid.
  • Empiric coverage for P. aeruginosa includes piperacillin-tazobactam, cefepime, ceftazidime, aztreonam Aztreonam The carbapenems and aztreonam are both members of the bactericidal beta-lactam family of antibiotics (similar to penicillins). They work by preventing bacteria from producing their cell wall, ultimately leading to bacterial cell death. Carbapenems and Aztreonam, meropenem, or imipenem.
  • Outpatients and inpatients with CAP who test positive for influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza should receive anti- influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza treatment (e.g., oseltamivir) in addition to standard therapy for CAP.
  • Adjunctive measures in the treatment of CAP:
    • Hydration, oxygen therapy for hypoxemia, vasopressors for shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock, and mechanical ventilation for respiratory failure
    • Corticosteroids are only used in refractory septic shock Septic shock Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Septic shock is diagnosed during treatment when vasopressors are necessary to control hypotension. Sepsis and Septic Shock.
  • Duration of antibiotic therapy in outpatients and inpatients with CAP is at least 5 days and based on improvement of vital signs, mentation, ability to eat, and the patient’s overall clinical condition.
  • Follow-up chest imaging is not routinely recommended in patients with resolution of CAP within 1 week.
  • If no improvement by day 3 or progressively worsening condition despite receiving antibiotics, evaluate:
    • Noninfectious differential diagnosis
    • Infections other than pneumonia
    • Nosocomial superinfection
    • Focus such as lung abscess or empyema blocking antibiotic access to pathogen
    • Resistance to or wrong dose of antibiotic(s)
    • Presence of unsuspected pathogens such as CA-MRSA, tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, or fungus

Complications

  • General:
    • Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure
    • Shock and multiorgan failure
    • Coagulopathy
  • Specific:
    • Metastatic infection (rare) such as brain abscess Brain abscess Brain abscess is a life-threatening condition that involves the collection of pus in the brain parenchyma caused by infection from bacteria, fungi, parasites, or protozoa. The most common presentation is headache, fever with chills, seizures, and neurological deficits. Brain Abscess or left side endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis
    • Lung abscess: suggests aspiration pneumonia (mixed anaerobic-aerobic infection), CA-MRSA, or P. aeruginosa
    • Complicated pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion (pus, pH < 7, glucose < 2.2 mmol/L, lactate dehydrogenase > 1,000 U/L, or positive culture for bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview): complete drainage usually with a chest tube ± delayed video-assisted thoracoscopy
    • Relapse or recurrence in same lung segment: evaluate for underlying neoplasm

Prevention

  • Vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination:
    • Pneumococcal vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination (e.g., PCV13) is recommended in children, the elderly, and immunocompromised patients
    • Inactive or recombinant form of influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination is recommended.
      • During outbreaks, patients without prior immunization and at risk for complications should receive the vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination + antiviral chemoprophylaxis (oseltamivir or zanamivir) for 2 weeks until the vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination induces sufficient protection
  • Smokers should be encouraged to quit smoking.

Ventilator-Associated Pneumonia and Hospital-Acquired Pneumonia

Etiology

  • Hospital/ICU dependent
  • Common non-MDR pathogens: S. pneumoniaH. influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza, methicillin-sensitive S. aureus (MSSA), antibiotic-sensitive Enterobacteriaceae
    • More common in HAP than in VAP
    • More common in VAP developing in the first week of admission
  • Common MDR pathogens: P. aeruginosa, MRSA, antibiotic-resistant EnterobacteriaceaeL. pneumophilaAspergillus spp., etc.
    • More common in VAP than in HAP
    • More common in VAP developing after 1st week of admission
  • Anaerobes are more common in HAP than in VAP

Epidemiology

Approximately 10% of ICU patients have pneumonia, mostly VAP.

Pathogenesis of VAP

  • Oropharyngeal colonization with pathogenic organism
  • Aspiration of the pathogen
  • Compromise of the normal host defense mechanism

Risk factors

  • Risk factors for CAP
  • Endotracheal tube: increases risk of microaspiration
  • Endotracheal tube: allows pathogenic bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview to form a layer of resistant biofilm
  • Suctioning: damages the endotracheal mucosa and dislodges bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview in biofilm
  • Poor hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand hygiene: increases risk of cross-infection from other patients
  • Antibiotic exposure: increases risk of MDR pathogens
  • Severely ill state with sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock, trauma, and/or hyperglycemia: causes immunoparalysis

Clinical manifestations and diagnosis

  • Similarities with CAP: tachypnea and increased minute ventilation, tachycardia, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, increased sputum, leukocytosis, worsening oxygenation, and signs of consolidation
  • VAP is more difficult to diagnose:
    • Prior infiltrates are common in ventilated patients
    • Anterior-posterior view on chest X-ray is more difficult to interpret
    • Signs and symptoms such as fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and leukocytosis could be due to a variety of other causes such as sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock, other infections, and medication
  • Cultures from tracheal aspirates or more distal bronchial aspirates are used for etiologic diagnosis
  • Absence of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview in gram stains of endotracheal aspirates suggests an alternative diagnosis for symptoms of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and pulmonary infiltrates
  • Culture-based diagnosis is more difficult in HAP because cultures are more difficult to obtain

Differential diagnosis

  • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema
  • Pulmonary contusion
  • Alveolar hemorrhage
  • Hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis
  • Acute respiratory distress syndrome Acute Respiratory Distress Syndrome Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome
  • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism

Treatment

  • Empiric broad-spectrum antibiotics in patients with risk factors for MDR pathogens (most patients with VAP and HAP, especially VAP)
  • Specific antibiotic therapy: once the etiologic diagnosis is known; usually a single agent
  • Appropriate clinical response is expected within 48–72 hours.

Complications

  • Shock, multiorgan failure, coagulopathy, complicated pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion, lung abscess, metastatic infection, etc.

Prognosis

  • Due to frequent presence of comorbidities, VAP mortality rate is 50%–70%.
  • VAP with MDR pathogens has higher mortality.
  • HAP has a better prognosis due to better host immunity and lower prevalence of MDR pathogens.

Prevention

  • Consistent infection-control measures and hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand washing
  • Avoiding unnecessary intubation
  • Appropriate use of noninvasive ventilation
  • Minimizing duration of intubation
  • Judicious use of antibiotics
  • Head elevation (30°–45°)
  • Endotracheal tubes with special cuffs that reduce microaspiration
  • Reducing patient transportation outside the ICU

References

  1. Metlay JPWaterer GWLong AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67. doi: 10.1164/rccm.201908-1581ST. Retrieved from https://pubmed.ncbi.nlm.nih.gov/31573350/#
  2. Kasper DL, Fausi AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill Education; 2018.

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