Atypical pathogens are now responsible for almost 50% of pneumonia cases.

Pneumonia is a leading cause of morbidity and mortality. Roughly 4 million cases of community-acquired pneumonia occur in the United States each year,^1-3 resulting in approximately 1 million hospitalizations and more than $9 billion in health care costs.⁴ Pneumonia is the number-one cause of infection-associated mortality, and is the sixth leading cause of death in the United States.¹

In recent years, both the causes and the treatment of pneumonia have undergone changes. Community-acquired pneumonia is increasingly common among older people and those with coexisting illnesses. Such illnesses include chronic obstructive lung disease, diabetes, kidney failure, and congestive heart failure. Patients with these and other illnesses may be infected by a variety of atypical organisms, which are being isolated with increasing frequency from patients with pneumonia.

The terminology of atypical pneumonia can be confusing. Atypical pneumonia, first used as a term in 1938,⁵ originally described a type of pneumonia in which systemic symptoms are more prominent than respiratory symptoms. When penicillin and ampicillin (once almost universally effective antibiotics for Streptococcus pneumoniae infection) were widely used, a significant proportion of cases failed to respond to treatment and were labeled primary atypical pneumonia. Primary referred to pneumonia occurring as a new event and atypical to the fact that S. pneumoniae was not isolated.

The pathogens that cause atypical pneumonia are themselves considered atypical, in that they are not the classic bacterial cause of acute community-acquired pneumonia. In the past, up to 90% of cases of community-acquired pneumonia were caused by S. pneumoniae; recently, however, the relative importance of this pathogen has diminished. Today, S. pneumoniae is isolated only in about 25% to 60% of sputum cultures,^6-8 and up to 40% of cases of community-acquired pneumonia are due to atypical pathogens.⁹

The usual causes of atypical pneumonia include Mycoplasma pneumoniae, Chlamydophila (formerly Chlamydia) pneumoniae, Chlamydophila psittaci, Legionella pneumophila, and Coxiella burnetii.^10,11

M. pneumoniae Infection
Mycoplasmas are the smallest prokaryotic organisms that can grow in cell-free culture media. These free-living, pleomorphic organisms lack cell walls and multiply by binary fission. They are found in humans and other animals (including insects), plants, soil, and sewage. M. pneumoniae was isolated in the early 1960s and was found to produce a pneumonia-like illness.

Unlike other organisms that inhabit the respiratory tract, M. pneumoniae can attach to the respiratory epithelium; its tip binds to cell membrane receptors. The organism neither enters host cells nor penetrates beneath the epithelial surface, but its attachment can lead to direct damage of the respiratory epithelium, to loss of cilia, and, eventually, to cell death. Mycoplasma-induced cell damage may be caused by the hydrogen peroxide released by the organism, because there is no evidence that this organism produces an exotoxin. An inflammatory response, characterized by infiltration of lymphocytes and macrophages, causes the walls of the bronchial tubes and alveoli to thicken.

M. pneumoniae infection occurs worldwide. Although it is endemic in most areas, increased infections occur in late summer and early fall in temperate climates. The incubation period is relatively long (2 to 3 weeks), and the peak incidence is in individuals 5 to 15 years of age.¹² M. pneumoniae accounts for 15% to 20% of all pneumonias observed among school-age children and young adults.¹³ Intensive exposure to infected people appears to be required for transmission; spread of the organism from person to person is quite slow, and generally occurs only within closely associated groups (such as families and military recruits), rather than through casual contact. The organism is generally introduced into a household by a school-age child.

Mycoplasma infections typically have an insidious onset, with malaise, myalgia, sore throat, or headache overshadowing and preceding chest symptoms by 1 to 5 days. Cough, which starts around the third day, is characteristically dry, troublesome, and sometimes paroxysmal, and becomes a prominent feature. Patients usually do not appear seriously ill, and few are admitted to hospitals. Physical signs such as rales may become apparent, frequently after radiographic evidence of pneumonia. Diagnostic tests include cold agglutinins, complement fixation, culture, and enzyme immunoassay. A fourfold rise in M. pneumoniae–specific antibody in serum from acutely ill and convalescent patients remains the reference standard for diagnosing the infection. Chest radiographs may indicate patchy opacities, usually of one of the lower or middle lobes. About 20% of patients suffer bilateral pneumonia, but pleurisy and pleural effusions are unusual.¹⁴ The course of the disease is variable, but cough, abnormal chest signs, and radiographic changes may extend over several weeks and relapse may occur. A prolonged paroxysmal cough (simulating whooping cough) may occur in children. Very severe infections have been reported in adults, usually in those with immunodeficiency or sickle-cell anemia.^15,16

Disease caused by M. pneumoniae is typically limited to the respiratory tract. Tetracycline and erythromycin are usually effective in treating Mycoplasma pneumonia. Elimination of symptoms, however, is not always accompanied by eradication of the organism. Immunity after recovery is not permanent, and repeated attacks have occurred within 5 years.

C. pneumoniae Infection
The members of the genus Chlamydophila are obligate intracellular bacterial pathogens of eukaryotic cells, with a characteristic growth cycle different from that of other bacterial organisms. Infections are initiated by environmentally resistant, metabolically inert infectious structures called elementary bodies. These organisms are small, with a rigid, spore-like body that attaches to, and is ingested by, a susceptible host cell. In the host cell, the bacteria enlarge and become a noninfectious form called a reticulate body. The reticulate body divides repeatedly by binary fission, resulting in numerous elementary bodies that are released from the host cell and infect nearby cells.

Comparatively little is known about how Chlamydophila produces disease, but C. pneumoniae is known to cause pneumonia, pharyngitis, bronchitis, otitis, and sinusitis, and has an incubation period of about 21 days. This organism is also suspected to be a significant cause of acute exacerbations of asthma. C. pneumoniae is uncommon in childhood. The main route of infection is via aerosol droplets. C. pneumoniae is believed to be the most frequent cause of community-acquired pneumonia, but is seldom identified as the infectious agent because laboratory tests for its identification are not widely used. A new microimmunofluorescence test for the detection of C. pneumoniae–specific antibodies has been developed, however.¹⁷

C. pneumoniae is a chronic, and often insidious, respiratory pathogen to which there appears to be little immunity. Clinical reactivation of existing infection and reinfection are probably common, although the two are difficult to distinguish. Seroepidemiological studies¹⁸ indicate that some 60% to 80% of people worldwide become infected with C. pneumoniae during their lifetimes, at an incidence of 1% to 2% per year. Severe—even fatal—pneumonias have been seen in compromised adults and young children. These organisms are usually susceptible to tetracyclines and erythromycins.

C. psittaci Infection
Avian strains of C. psittaci cause psittacosis (formerly called ornithosis), a flu-like syndrome, in humans. The organism is ubiquitous among avian species. Infected birds may be totally asymptomatic or may be severely ill. Infected birds often have diarrhea and shed the organism in copious amounts. They may also have respiratory tract infections and conjunctivitis. Asymptomatic shedders can still provide sufficient environmental contamination to cause transmission to humans. C. psittaci can remain viable in dust and cage litter for months.

Human infections usually occur in either a respiratory or a typhoidal form. The incubation period for respiratory disease is about 10 days, and the illness ranges from a flu-like syndrome with general malaise, fever, anorexia, sore throat, headache, and photophobia to a severe illness characterized by delirium and pneumonia. The illness may resemble bronchopneumonia, but the bronchioles and larger bronchi are involved as a secondary event, and sputum is scanty. The organism is blood-borne throughout the body, and there may be other complications such as meningoencephalitis, arthritis, pericarditis, and/or myocarditis. Hepatomegaly, splenomegaly, and a rash resembling that of enteric fever have also been described.^19,20

The typhoidal form of the disease involves a general toxic febrile state without respiratory involvement. Person-to-person transmission is uncommon, but has occurred. This infection usually can be treated using a regimen of tetracycline or erythromycin.

L. pneumophila Infection
The Legionellaceae are gram-negative rods whose natural habitat is water. There are more than 40 genetically defined species; however, L. pneumophila serogroup 1 is the most infectious.

L. pneumophila infection is acquired by breathing aerosolized water contaminated by the organism. Healthy people are quite resistant to infection, but smokers and those with impaired host defenses due to chronic diseases are more susceptible. The disease is most common in those over the age of 40, with peak incidence in those 60 to 70 years old.^21,22

The incubation period for this organism is 2 to 10 days. During this time, the inhaled organisms lodge in and near the alveoli, and cell-surface proteins adhere to macrophages, thereby enhancing phagocytosis. The bacteria are not killed by the phagocytes, but multiply within them and are released upon the death of the macrophages to infect other tissues. Necrosis of alveolar cells and an inflammatory response result, causing multiple small abscesses, pneumonia, and pleurisy. Bacteremia is often present. The illness, called legionnaire’s disease, is characterized by high fever, respiratory distress, confusion, hallucinations, and, occasionally, focal neurological signs. The severity of the disease may range from a rapidly progressing fatal pneumonia to a relatively mild pneumonic illness. Fatal respiratory failure occurs in about 15% of hospitalized cases.²³

High-dose intravenous erythromycin is the standard therapy for Legionella pneumonia. Azithromycin exhibits better antimicrobial activity than erythromycin in vitro and penetrates well into cells and lung tissue.²⁴ It is emerging as a drug of choice, based on efficacy observed in clinical trials.²⁵ In severe cases, treatment may be supported by rifampin.²⁶ Like many other pathogens, L. pneumophila produces the enzyme b-lactamase, which makes it resistant to many penicillins and cephalosporins.

Unlike most forms of bacterial pneumonia, Legionella pneumonia may be prevented by the eradication of Legionella species in the various water sources that give rise to aerosol production. Methods to control or eradicate this organism from its water sources include heat (above 60°C) and disinfection using chlorine or other biocides, including chlorine dioxide and copper-silver ionization.

C. burnetii Infection
Q fever is a disease caused by the rickettsia C. burnetii, which is propagated in sheep and cattle, where it produces no symptoms. Human infections occur as a result of contact not only with such animals but also with other infected humans, air and dust, wild reservoir hosts, and other sources. Q stands for query, and the diseases is so named because the etiologic agent was unknown in the mid 1930s, when the illness was first described.

C. burnetii is an obligate intracellular parasite. A pleomorphic, gram-negative bacterium, this organism typically reproduces within the phagolysosome of macrophages. Observations of this organism’s growth suggest that it has a developmental cycle and that it needs acidic conditions to accomplish significant levels of macromolecular synthesis.²⁷ Unlike other rickettsiae, C. burnetii produces a small, dense, highly resistant spore-like form whose stability in the environment is important for transmission.²⁸

Although C. burnetii is globally ubiquitous, infections caused by this organism often go unreported or are misdiagnosed. C. burnetii may, in fact, be the most infectious of all bacteria. Human infections generally follow inhalation or direct contact with the organism in the milk, urine, feces, or birth products of infected animals. This organism can survive on wool for 7 to 10 months, in milk for up to 40 months, and in tick feces for at least a year.^29-31 Most individuals acquire the disease as an occupational hazard.

Q-fever pneumonia usually follows inhalation of aerosols containing C. burnetii. Entry into the lungs results in infection of the alveolar macrophages. Most infections are subclinical.^32,33 The incubation period for the acute form of the disease is usually about 2 weeks, but it can be longer. In addition to a nonspecific febrile illness, the patient may develop a severe headache, respiratory symptoms, and an atypical pneumonia. The rickettsia can also spread to the liver and cause hepatitis. The spectrum of manifestations of infection due to C. burnetii continues to expand. Some of the more recently described findings are acalculous cholecystitis, rhabdomyolysis, long-term persistence of Coxiella, post–Q-fever fatigue syndrome, and hemolytic uremic syndrome.³⁴

After about 2 weeks, most C. burnetii infections resolve without antibiotic treatment, but the disease may become chronic. Q-fever pneumonia generally responds to treatment with doxycycline, quinolones, or macrolides. Administration of these antibiotics may reduce the duration of fever in acute infection and is recommended in cases of chronic infection. Alkalinization of the acidic phagolysosome with chloroquine or hydroxychloroquine has been suggested to achieve better bacterial killing, particularly in cases of Q-fever endocarditis.^35,36 C. burnetii may be recovered from some patients after months or even years of continuous treatment. The complete genome of C. burnetii has recently been sequenced,³¹ which may eventually lead to easier diagnostic methods and new treatment modalities.

Principles of Treatment
Factors in the treatment of atypical pneumonia include initial assessment of the severity of the pneumonia, which dictates the site of treatment (home, hospital, or intensive care unit); appropriate supportive care (fluids and oxygenation); investigation and treatment of comorbid conditions (chronic obstructive lung disease or ischemic heart disease); end-of-life decisions (resuscitation status and the initiation and termination of ventilator support); and discharge.

One of the first steps in the management of patients with pneumonia is deciding whether they need to be hospitalized. Once pneumonia is suggested by chest-radiography findings, it may be a challenge to determine which patients can be treated as outpatients and which should be hospitalized.

Treatment for atypical pneumonia is usually initiated empirically because, in many cases, specific pathogens have not yet been identified. Several classes of antibiotics are effective against atypical pathogens, but b-lactam antibiotics are generally ineffective because C. pneumoniae and Legionella species are intracellular organisms and M. pneumoniae lacks a cell wall.

Erythromycin and (in some cases) tetracycline have been traditional choices for the treatment of atypical pneumonia. Erythromycin and tetracycline are effective against M. pneumoniae, and have been shown to reduce symptom duration in C. pneumoniae infection.^37,38 Newer macrolides such as azithromycin and clarithromycin have good activity against M. pneumoniae, C. pneumoniae, and Legionella species, and generally are better tolerated than erythromycin.^39-43 Doxycycline also is effective,⁴⁴ and typically is associated with fewer gastrointestinal adverse effects. Fluoroquinolones have also demonstrated excellent activity against M. pneumoniae, C. pneumoniae, and Legionella species.^45-48 Specific empiric recommendations are based on whether the patient is hospitalized or treated as an outpatient.

Conclusion
Atypical pathogens are now responsible for almost 50% of pneumonia cases, so whether the term atypical really applies any longer is questionable. Given the prevalence of atypical pathogens and the morbidity with which they are associated, the Infectious Diseases Society of America⁴⁹ recommends an empiric treatment approach that includes agents with good activity against both typical and atypical pathogens.

Phyllis C. Braun, PhD, is a professor, Department of Biology, Fairfield University, Fairfield, Conn. John D. Zoidis, MD, is a contributing writer for RT.

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