Maida V. Soghikian
Historically, the term atypical pneumonia was applied to pulmonary infections that were without identifiable causative organisms on routine culture and did not respond to standard antimicrobial therapy. They had unusual clinical and radiographic presentations compared with classic bacterial pneumonias. Subsequently, a variety of causative organisms were identified that are often considered synonymous with the term atypical pneumonia, including Mycoplasma pneumoniae, Chlamydophila psittaci (psittacosis), Chlamydophila pneumoniae (formerly C. psittaci, strain TWAR), Coxiella burnetii (Q fever), Legionella species, and various viruses. This group of organisms is responsible for at least 25% of all community-acquired pneumonias (CAP) worldwide. The illnesses caused by these organisms differ in their epidemiology and natural history, but they are all thought to be transmitted via particle or droplet inhalation and all are resistant to beta lactam antibiotics. CAP empiric therapy guidelines specifically address atypical pathogens, and some scoring systems have been developed in an attempt to differentiate typical from atypical CAP. Because laboratory identification of these infections remains difficult, much effort has gone into developing newer diagnostic techniques such as polymerase chain reaction (PCR). Mortality with these pathogens is characteristically less than with other common causes of CAP and many, including Legionella, are frequently managed as outpatients. The enhanced ability to identify these infectious agents and their relative frequency leads some to argue that atypical is now a misnomer.
M. pneumoniae is a free-living organism without a cell wall that readily attaches to mucosal surfaces. It was first described in 1938, and at that time it was believed to be caused by a nonfilterable virus. It was later found to be associated with a rise in cold agglutinins and to be a bacterial infection. It is the most common cause of atypical pneumonia, accounting for 10% to 30% of pneumonias in ambulatory patients (some reports suggest even higher). It had previously been called “walking pneumonia” due to the discordance between radiographic infiltrates and relative paucity of symptoms. M. pneumoniae is the most common cause of pneumonia in young adults and teenagers, though the frequency is also increased in the elderly. Hospitalization is rarely required except in individuals who are chronically ill or develop complications. M. pneumoniae has an incubation period averaging 2 to 3 weeks. The infection is usually endemic, occurring most frequently in the fall and winter months. The rate of infection is greatest in areas of close personal contact (e.g., military bases, households). M. pneumoniae infection most commonly presents as tracheobronchitis with intractable cough and low-grade fever. Relatively few infected persons develop frank pneumonia (3%–6%). Pulmonary exam may be normal but often demonstrates diffuse inspiratory rales that correspond to unilateral or bilateral infiltrates on radiographs. Lobar consolidation is rare. Small pleural effusions occur in up to 25% of patients. Leucocytosis is often absent. In addition to respiratory illness, M. pneumoniae can cause a myriad of extrapulmonary illnesses either by direct invasion or by immune mechanisms, such as non-exudative pharyngitis, bullous myringitis, diarrhea, and erythema multiforme. Rarely, patients may present with central nervous system (CNS) manifestations (meningoencephalitis, transverse myelitis) or cardiac manifestations (pericarditis, myocarditis). A potentially serious extrapulmonary manifestation is cold agglutinin-induced hemolysis, which results from IgM antibodies that cross-react with the erythrocyte I antigen. A nonspecific elevation in cold agglutinin titers occurs in 75% of patients by the first to second week of the illness, but may be mild and without associated complications. Diagnosis by a 4-fold rise in antibody titers by enzyme-linked immunosorbent assay (EIA) is both sensitive and specific. PCR is not yet standardized or available for routine use. It is recommended to treat empirically, while using paired EIA serology and rapid PCR assays if available. M. pneumoniae infection is self-limited in most cases; in one large series, it represented only 5% of patients hospitalized with pneumonia. The overall mortality rate is extremely low and generally attributed to neurologic and cardiac sequelae. M. pneumoniae can be treated with azithromycin 500 mg initially followed by 250 QD mg daily for 4 days or with doxycycline 200 mg initially, then 100 mg Q12H for 10 to 14 days, although macrolide resistance is an increasing problem. The respiratory fluoroquinolones, moxifloxacin or levofloxacin, are effective alternatives and given for 5 days.
The Chlamydophila species are obligate intracellular bacteria and include two species associated with human pneumonia in adults: C. psittaci and C. pneumoniae. Chlamydia trachomatis causes conjunctivitis and pneumonia in newborn infants but has not been implicated as a cause of adult respiratory disease. C. psittaci is primarily an avian pathogen but also causes infection in humans (psittacosis) after contaminated droppings from diseased birds are inhaled. Parrots and parakeets (psittacine birds) are the most common sources of human infection, but domestic (chickens, ducks, and turkeys) and urban (pigeons) fowl also have been described as a source of infection. Infected birds are commonly asymptomatic but can develop an illness of ruffled feathers, respiratory symptoms, conjunctivitis, or diarrhea. Psittacosis occurs sporadically but frequently is seen in association with avian outbreaks. It is a serious occupational hazard in poultry-processing plants, with turkeys being the most commonly involved bird in the United States and ducks in Europe. After the organism gains access to the upper respiratory tract, it spreads hematogenously to the lungs and to the reticuloendothelia system. The incubation period is 5 to 21 days. Human-to-human transmission is unusual, although infection of health-care workers by patients has been described. The reported incidence is 0.01/100,000 in the United States, but this is likely an underrepresentation since clinical disease is often mild and likely underdiagnosed. Psittacosis is responsible for less than 5% of hospitalized pneumonia cases. It can affect any age, but is more common in young and middle-aged adults. The clinical spectrum of psittacosis is protean and ranges from a mild, flulike illness with fever, dry cough, and headache (the majority) to fulminant sepsis with multiorgan failure. Pneumonia, although generally mild, can present as a severe, multilobar, consolidative process associated with splenomegaly and relative bradycardia. Many extrapulmonary manifestations have been described, including severe headache, photophobia, myalgias, arthralgias, nausea and vomiting, lymphadenopathy, hepatosplenomegaly, and thyroiditis. Serious manifestations such as meningoencephalitis, endocarditis, myocarditis, and nephritis can be seen. Dermatologic manifestations include erythema nodosum, erythema marginatum, and a pink, roselike, macular rash (Horder spots). The chest radiograph is abnormal in 80% of patients, most often with lobar consolidation. Labs are nonspecific. Fulminant psittacosis is an infrequent but important complication manifested by hypoxic respiratory failure, septic shock, impaired cognition, and renal, hepatic, and hematologic failure. Poor prognostic signs include increased age, confusion, leukopenia, severe hypoxemia, and renal and multilobar pulmonary involvement. The mortality rate was 20% in the preantibiotic era and now is about 1% with appropriate treatment.
C. pneumoniae occurs most commonly in elderly. In contrast to C. psittaci, no animal vector (other than humans) has been discovered. Transmission is likely from person to person through respiratory secretions. Serologic evidence indicates that infection is common throughout the world. About 5% to 15% of community-acquired pneumonia is attributed to this organism, although serologic tests used to make such estimates have suffered from poor specificity. Repeated infection and persistent infection can occur. Dual infections in combination with Streptococcus pneumoniae or M. pneumoniae have been reported. Often the patient has a brief prodrome of headache and myalgias and then high fever and shaking chills, but they may be asymptomatic. Cough and pharyngitis are frequently present. Other clinical manifestations include sinusitis and delirium. Extrapulmonary signs and symptoms are less common but can include arthritis, myocarditis, Guillian-Barre syndrome, and meningoencephalitis. In addition to causing pneumonia, C. pneumoniae has been identified as an etiologic factor in acute exacerbations of chronic obstructive pulmonary disease and coronary artery disease. Laboratory data are not specific, and radiographs generally have patchy subsegmental infiltrates. Diagnosis is most commonly made by demonstrating a 4-fold rise in complement fixation (CF) titers drawn 2 weeks apart. The clinical utility of serial titer measurement is limited by lack of specificity (with significant cross-reactivity between C. psittaci and C. pneumoniae) and by the delay incurred while waiting for a second sample. Microimmunofluorescence (MIF) is a specific assay that can be positive on the basis of a single IgM titer of 16 or greater; however, it is less readily available than other tests. PCR of sputum and bronchoalveolar lavage (BAL) samples is a rapid and specific diagnostic test, but it is not routinely available outside of reference laboratories. Cell culture techniques are not generally available except in specialized labs (C. psittaci is classified as a dangerous pathogen).
The antibiotic of choice for Chlamydophila pneumonias is doxycycline for 10 to 14 days for C. pneumoniae and 14 days for C. psittaci. Tigecycline and fluoroquinolones have in vitro activity, but clinical treatment data are limited. Newer macrolides have in vitro activity against Chlamydophila species and are an appropriate choice in pregnancy and childhood. Birds infected with C. psittaci should be treated with doxycycline to cure or at least suppress any major ongoing exposure risk.
Q fever is a zoonosis, named “Query fever” in 1936 following an outbreak in Australia of a febrile illness characterized by headache, malaise, anorexia, and myalgia in abattoir workers. Coxiella burnetii, the etiologic agent of Q fever, is an obligate intracellular bacterium with a large natural reservoir that includes rodents, cattle, sheep, and goats. In nature, a tick vector maintains the disease. C. burnetii
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