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Respiratory tract infections are a major reason why children and the elderly seek medical care. These infections are more common in cold-weather months in locales with temperate climates. Respiratory tract infections are primarily spread by inhalation of aerosolized respiratory secretions from infected hosts. Some respiratory tract pathogens, such as rhinoviruses and respiratory syncytial virus (RSV), can also be spread by direct contact with mucous membranes, but this mode of transmission is much less common than inhalation. Organisms that are part of the endogenous microbiota of the oropharynx may, under certain conditions (such as aspiration of oropharyngeal secretions), be able to cause clinical disease. Animal exposure may result in some of the less common but more severe bacterial causes of respiratory infection, including inhalation anthrax, pneumonic plague, tularemia pneumonia, and hantavirus pulmonary syndrome. These zoonotic agents are also potential agents of bioterrorism. For the purposes of our discussions, we will divide these types of infections into two groups, upper tract and lower tract infection.

The most common form of upper respiratory tract infection is pharyngitis. Pharyngitis is seen most frequently in children from 2 years of age through adolescence. The most common etiologic agents of pharyngitis are viruses, particularly adenoviruses, coronaviruses, enteroviruses, and rhinoviruses, and group A streptococci. Pharyngitis due to group A streptococci predisposes individuals to the development of the poststreptococcal sequelae rheumatic fever and glomerulonephritis. Because rheumatic fever can be prevented by penicillin treatment of group A streptococcal pharyngitis, aggressive diagnosis and treatment of pharyngitis due to this organism is needed.

Otitis media is a common infectious problem in infants and young children. The most frequently encountered agents of this infection are the bacteria Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. These organisms, along with selected viruses and anaerobic bacteria from the oral cavity, are the most important pathogens in sinusitis.

S. pneumoniae, H. influenzae, M. catarrhalis, and adenoviruses are the common etiologic agents of conjunctivitis. Less commonly, Chlamydia trachomatis can cause conjunctivitis in neonates. External otitis, a common problem in swimmers, is more common in warm-weather months. Staphylococcus aureus and Pseudomonas aeruginosa are the most common agents of this relatively benign condition. Malignant external otitis is a serious medical condition seen primarily in diabetics, the elderly, and the immunocompromised. The infection can spread from the ear to the temporal bone. The most common etiology of malignant otitis externa is P. aeruginosa. Two other life-threatening infections of the upper respiratory tract are rhinocerebral mucormycosis (zygomycosis) and bacterial epiglottitis. Rhinocerebral mucormycosis is most common in diabetics, especially those with ketoacidosis. In this infection of the sinuses, fungi within the zygomycetes, such as Mucor and Rhizopus spp., invade blood vessels, resulting in necrosis of bone and thrombosis of the cavernous sinus and internal carotid artery. Treatment of this infection requires aggressive surgical debridement of the infected tissue in addition to antifungal therapy. Epiglottitis is most commonly caused by H. influenzae type b but can also be associated with S. pneumoniae, other streptococci, and staphylococci. In this disease, the airway may become compromised because of swelling of the epiglottis, with death due to respiratory arrest. With the widespread use of H. influenzae type b vaccine, the incidence of this disease has greatly decreased, but it is still occasionally seen in both children and adults.

Three childhood infections with respiratory manifestations or complications that were common in the early part of the 20th century—diphtheria, whooping cough, and measles—are now rare diseases in the developed world. This is due to the development and use of vaccines in children that are effective against the etiologic agents of these diseases, Corynebacterium diphtheriae, Bordetella pertussis, and measles virus, respectively.

Viruses play an important role in upper respiratory tract infections. The common syndrome of cough and “runny” nose is usually due to rhinoviruses, but enteroviruses and coronaviruses are frequent causes. More severe upper respiratory infections such as the “croup” are due to RSV, influenza viruses, parainfluenza viruses, and metapneumovirus. These viruses can also cause lower tract infection and are important causes of morbidity and mortality in the very young and very old.

When discussing lower respiratory tract infections, it is important to look at four different groups of patients: patients with community-acquired infections; patients with health care-associated infections; patients with underlying lung disease; and immunocompromised individuals, especially those with AIDS.

Common agents of community-acquired lower respiratory tract infections include S. pneumoniae; Klebsiella pneumoniae, especially in alcoholics; Mycoplasma pneumoniae, especially in school-age students through young adulthood; Mycobacterium tuberculosis, especially in individuals born in countries with a high prevalence of tuberculosis; RSV in infants and young children; and influenza A virus. The dimorphic fungi Histoplasma capsulatum and Coccidioides posadasii/immitis usually cause mild, self-limited diseases in patients residing in specific geographic locales. S. pneumoniae, H. influenzae, S. aureus, and M. catarrhalis may cause bronchitis and/or pneumonia in adults following viral pneumonia. Aspiration due to seizure disorders, semiconscious states from excessive consumption of alcohol or other drugs, or impairment of the gag reflex, as may occur following a stroke, may result in aspiration pneumonia or lung abscess caused by the organisms residing in the oral cavity. The anatomic location of the lung process depends on the patient’s position at the time of aspiration.

Health care-associated infections due to the organisms listed above certainly occur. Particular emphasis is placed on preventing the spread of M. tuberculosis in all patient populations and on preventing health care-associated spread of RSV in pediatric patients. Health care-associated pneumonia due to methicillin-resistant S. aureus and multidrug-resistant Gram-negative bacilli, such as P. aeruginosa and Acinetobacter baumannii, is a concern for intubated patients. Because of their ability to survive within hospital water and air conditioning systems, the potential for outbreaks of pneumonia due to Legionella spp. is a constant threat.

Patients with chronic obstructive pulmonary disease brought on by frequent smoking develop bronchitis. S. pneumoniae, M. catarrhalis, H. influenzae, and P. aeruginosa are common causes of this type of infection. Patients with cystic fibrosis have chronic airway infections that are primarily responsible for their premature death. S. aureus and mucoid strains of P. aeruginosa are the most important agents of such chronic airway disease. Both of these patient populations have an increased risk of developing allergic bronchopulmonary aspergillosis. Patients with cavitary lung disease, frequently due to prior M. tuberculosis infection, are at increased risk for another type of infection, an aspergilloma or fungus ball caused by Aspergillus spp. This fungus grows in the form of a ball in the preformed cavity. A distinction between actual tissue invasion with this fungus and noninvasive disease is clinically difficult but is important.

The diagnosis of the etiology of lung infection in immunocompromised patients is one of the most daunting in clinical microbiology and infectious disease. It has been greatly facilitated by the use of the flexible bronchoscope, which provides a relatively noninvasive means to sample the airways and alveoli. Immunocompromised patients are typically at risk for essentially all recognized respiratory tract pathogens. However, a distinction must be made between different types of immunosuppression—defects in cell-mediated immunity, humoral immunity, and neutrophil number or function—because different types of immunosuppression predispose patients to infection with different pathogens. The most common comorbidity for lower respiratory tract infections is cigarette smoking, which causes impaired removal of pathogens due to defective mucociliary clearance. Although smoking results in a significantly increased rate of both bronchitis and pneumonia, smokers are not normally described as immunosuppressed.

In AIDS patients, Pneumocystis jirovecii, Cryptococcus neoformans, S. pneumoniae, and multidrug-resistant M. tuberculosis are all seen more frequently than in other patient populations. Solid-organ transplant recipients have a greatly increased risk for pneumonia with cytomegalovirus, herpes simplex virus, Legionella spp., P. jirovecii, and Nocardia spp. Prophylactic antibiotics are frequently taken by these patients to prevent pulmonary infections with P. jirovecii. Prophylactic therapies are not as widely used for other agents for a variety of reasons, including expense, questionable efficacy of the prophylactic measures, or the rarity with which the organism is encountered. Profoundly neutropenic patients, especially those in whom the duration of neutropenia is prolonged, not only have a risk of infection with routine bacteria but have a very high risk of invasive aspergillosis and other invasive fungal infections.

TABLE II SELECTED RESPIRATORY TRACT PATHOGENS

ORGANISM	GENERAL CHARACTERISTICS	PATIENT POPULATION	DISEASE MANIFESTATION
Bacteria
Acinetobacter baumannii	Glucose-nonfermenting, Gram-negative bacillus	Hospitalized adults	Ventilator-associated pneumonia
Actinomyces spp.	Branching, Gram-positive bacilli, usually anaerobic	Adults with aspiration	Lung abscess
Bacillus anthracis	Spore-forming, Gram-positive bacillus	Victims of bioterrorism due to exposure to spores; woolsorters in endemic areas	Inhalation anthrax with widened mediastinum, high-grade bacteremia
Bordetella pertussis	Fastidious, Gram-negative bacillus	Children, adults	Whooping cough, chronic cough
Chlamydia trachomatis	Obligate intracellular bacterium; does not Gram stain	Neonatal	Conjunctivitis, pneumonia
Chlamydiophila pneumoniae	Obligate intracellular bacterium; does not Gram stain	Children, adults	Pneumonia, bronchitis
Chlamydiophila psittaci	Obligate intracellular bacterium; does not Gram stain	Children and adults with exposure to birds	Pneumonia, ornithosis (psittacosis)
Corynebacterium diphtheriae	Catalase-positive, Gram-positive, club-shaped bacillus	Unvaccinated adults and children, improperly vaccinated adults	Diphtheria
Enterobacter spp., Escherichia coli	Lactose-fermenting, Gram-negative bacilli	Hospitalized adults	Health care-associated pneumonia
Fusobacterium necrophorum	Anaerobic, Gram-negative bacillus	Adolescents, adults	Pharyngitis, Lemierre’s syndrome
Group A streptococci (Streptococcus pyogenes)	Catalase-negative, Gram-positive cocci in chains	Children >2 years, adults	Pharyngitis, pneumonia with empyema
Group B streptococci (Streptococcus agalactiae)	Catalase-negative, Gram-positive cocci in chains	Neonates	Pneumonia
Haemophilus influenzae	Pleomorphic, Gram-negative bacillus	Children; adults, especially with COPDa	Otitis media, conjunctivitis, epiglottitis, bronchitis, pneumonia
Klebsiella pneumoniae	Lactose-fermenting, Gram-negative bacillus	Adults	Community-acquired and health care-associated pneumonia
Legionella pneumophila	Poorly staining, fastidious, Gram-negative bacillus	Adults, especially immunocompromised	Pneumonia
Moraxella catarrhalis	Oxidase-positive, Gram-negative diplococcus	Children; adults with COPD	Otitis media, conjunctivitis, bronchitis
Mycobacterium tuberculosis	Acid-fast bacillus	Children and adults, especially HIV-infected	Tuberculosis
Mycoplasma pneumoniae	Fastidious; does not Gram stain	Children, adolescents, adults	Walking pneumonia
Neisseria gonorrhoeae	Oxidase-positive, Gram-negative diplococcus	Individuals with oral-genital contact, neonates	Pharyngitis, conjunctivitis
Neisseria meningitidis	Oxidase-positive, Gram-negative diplococcus	Adults	Pneumonia
Nocardia spp.	Partially acid-fast, aerobic, branching, Gram-positive bacilli	Adults, especially with defects in cell-mediated immunity	Pneumonia with brain abscess
Nontuberculous mycobacteria (many species)	Acid-fast bacilli	Adults with chronic lung disease, CFb patients	Granulomatous lung disease
Prevotella spp., Porphyromonas spp.	Anaerobic, Gram-negative bacilli	Adults with aspiration	Lung abscess
Pseudomonas aeruginosa	Glucose-nonfermenting, Gram-negative bacillus	Adults and children, diabetic adults, hospitalized patients, CF patients (mucoid variant)	External otitis (swimmer’s ear), malignant external otitis, ventilator-associated pneumonia, chronic bronchitis with mucoid strains
Staphylococcus aureus	Catalase-positive, Gram-positive cocci in clusters	Hospitalized patients	Pneumonia, pneumonia superinfections
Stenotrophomonas maltophilia	Glucose-nonfermenting, Gram-negative bacillus	Hospitalized patients	Ventilator-associated pneumonia
Streptococcus pneumoniae	Catalase-negative, Gram-positive diplococcus	Children, adults	Otitis media, sinusitis, conjunctivitis, pneumonia
Fungi
Aspergillus spp.	Acute-angle-branching, septate hyphae in tissue; molds	Children and adults with chronic lung disease, adults with cavitary lung lesions, neutropenic individuals	Allergic bronchopulmonary aspergillosis, aspergilloma (fungus ball), invasive pneumonia
Blastomyces dermatitidis	Broad-based budding yeast; dimorphic	Adults	Pneumonia
Coccidioides posadasii/immitis	Spherules in tissue; mold with arthroconidia at 30°C	Children and adults, especially in desert southwest of United States and northern Mexico	Flu-like illness with pneumonia; can disseminate
Cryptococcus neoformans	Encapsulated, round yeast	Adults with defects in cell-mediated immunity, especially with AIDS	Pneumonia, often asymptomatic, preceding meningitis
Histoplasma capsulatum	Very small, intracellular yeast; dimorphic	Adults, primarily with AIDS, especially in Missouri and Ohio River Valleys and Caribbean	Pneumonia, mediastinal fibrosis
Pneumocystis jirovecii	Clusters of 4- to 6-μm cysts in tissue and secretions	Immunocompromised individuals, especially with AIDS	Pneumonia
Rhizopus spp., Mucor spp.	Ribbon-like, nonseptate hyphae in tissue; rapidly growing molds	Diabetics, neutropenic individuals	Rhinocerebral zygomycosis, invasive pneumonia
Parasites
Ascaris lumbricoides	Larvae	Children, adults	Usually asymptomatic, incidental finding
Echinococcus granulosus	Tapeworm (cestode)	Exposure to dogs in areas with sheep	Cyst in lung growing over the course of years; rupture from liver may lead to pleural space
Entamoeba histolytica	Ameba	Children and adults with amebic liver abscess	Empyema, hepatobronchial fistula, lung abscess
Hookworm (Necator americanus, Ancylostoma duodenale)	Larvae	Children, adults	Usually asymptomatic, incidental finding
Paragonimus westermani	Fluke (trematode)	Children and adults in endemic areas	Hemoptysis, chronic bronchitis, bronchiectasis
Schistosoma spp.	Fluke (trematode); granulomas form around eggs	Children and adults in endemic areas	Pulmonary hypertension due to trapping of eggs in pulmonary capillaries
Strongyloides stercoralis	Rhabditiform larvae	Immunocompromised individuals	Wheezing, cough, pneumonia
Viruses
Adenovirus	Enveloped, dsDNAc	Children, adults	Pharyngitis, bronchiolitis, pneumonia, conjunctivitis (“pink eye”)
Coronaviruses (229E, HKU1, NL63, OC43)	Enveloped, ssRNAd	Children, adults	Common cold; pneumonia in immunocompromised individuals
Coronaviruses, novel (SARS-CoV,e MERS-CoVf)	Enveloped, ssRNA	Primarily adults	Acute respiratory distress syndrome
Cytomegalovirus	Enveloped, dsDNA	Immunocompromised individuals	Pneumonia
Enteroviruses	Nonenveloped, ssRNA	Children	Common cold, hand-foot-and-mouth disease, herpangina, pharyngitis, bronchiolitis, pneumonia
Hantaviruses	Enveloped, ssRNA	Children, adults	Acute respiratory distress syndrome, pneumonia
Herpes simplex virus	Enveloped, dsDNA	Immunocompromised individuals	Pneumonia
Influenza viruses	Enveloped, ssRNA	Children and adults, particularly elderly	Influenza, pneumonia
Metapneumovirus	Enveloped, ssRNA	Infants, young children, adults, immunocompromised individuals	Common cold, croup, bronchiolitis, pneumonia
Parainfluenza viruses (types 1, 2, 3, and 4)	Enveloped, ssRNA	Infants, young children	Croup, bronchiolitis, pneumonia, laryngitis
Respiratory syncytial virus	Enveloped, ssRNA	Infants, young children, elderly	Cough, wheezing, bronchiolitis, pneumonia
Rhinoviruses	Nonenveloped, ssRNA	Children, adults	Common cold; pneumonia in immunocompromised individuals
Varicella-zoster virus	Enveloped, dsDNA	Immunocompromised individuals, pregnant women	Pneumonia

^a COPD, chronic obstructive pulmonary disease.

^b CF, cystic fibrosis.

^c dsDNA, double-stranded DNA.

^d ssRNA, single-stranded RNA.

^e SARS-CoV, severe acute respiratory syndrome coronavirus.

^f MERS-CoV, Middle East respiratory syndrome coronavirus.