Cultures of blood, pleural fluid, material obtained by lung puncture, or lung biopsy specimens are usually considered conclusive.

Occasionally, one encounters statements about pneumonia that are not substantiated by any accurate data and in fact are examples of reverse logic. For example, the statement that 20% of patients with pneumococcal pneumonia have pneumococcal bacteremia requires some conclusive evidence that the other 80% without bacteremia had pneumococcal pneumonia. Such statistics are usually not supported by any conclusive tests such as lung puncture. However, it can be accurate to say that 20% of a group of patients with lobar pneumonia had pneumococcal bacteremia.

Material obtained from flexible fiberoptic bronchoscopy,^5,6 tracheostomy secretions,⁷ rigid bronchoscopy aspiration, and transtracheal aspirations may occasionally be useful in identifying the etiologic agent. Transtracheal aspiration, although used in adults, has rarely been used in children because of their small, growing tracheas. In one study of children, the correlation between the types of bacteria recovered from transtracheal aspiration and those recovered from lung puncture was only fair.⁸ Reported complications include transient hemoptysis, mediastinal or subcutaneous emphysema, and cardiac arrest, perhaps secondary to anoxia, vagal reflex, or vomiting with aspiration.⁹

Direct orotracheal aspirates sometimes are useful in newborns with pneumonia.¹⁰ Sputum culture is usually not useful, as children seldom produce sputum before about 6 years of age. After this age, specimen collection can sometimes be facilitated by techniques to induce sputum production, such as nebulized hypertonic saline. Occasionally, younger children do cough up and spit out tracheal secretions, especially if they have chronic pulmonary disease. However, sputum is an unreliable source for culture in children with acute pneumonia, because more than one potential pathogen can often be found even in normal individuals. In chronic pneumonias, even a 2-year-old may cough up purulent sputum, which may reveal budding yeasts (Fig. 8-1) or bacterial pathogens (as in cystic fibrosis).

Cultures of endotracheal tube secretions in patients on mechanical ventilators are similarly fraught with interpretational difficulties. One study suggests that endotracheal tube aspirates with negative Gram stains or with greater than 10 squamous epithelial cells per low-power field should be rejected.¹¹ Obtaining surveillance cultures from endotracheal tubes of all patients on mechanical ventilation does not predict the etiology of subsequent invasive disease.¹² Other than for epidemiologic purposes, this practice should be abandoned.

Nose or nasopharyngeal cultures usually yield a
high frequency of potential pathogens and are not useful in diagnosing bacterial pneumonia. They may occasionally be useful if a viral pathogen, such as respiratory syncytial virus (RSV) or influenza, is suspected. Throat cultures are not useful in the etiologic diagnosis of pneumonia.

A Gram stain of clinical material is often helpful. When the stain is done on material from a moderately significant culture source, it may help guide empiric therapy. The results of Gram staining may also aid interpretation of cultures obtained from sites that are often contaminated, such as the endotracheal tube, which may be cultured when ventilator-associated pneumonia is suspected. Endotracheal tubes are nearly always colonized with flora common to the intensive care unit, and therefore cultures are usually positive. If the Gram stain shows many neutrophils and a single bacterial morphology, the cultured organism is more likely to be a pathogen than if the Gram stain shows few white cells and mixed flora.

Assaying sputum, pleural fluid, or serum for antigens is neither useful nor approved for the diagnosis of pneumonia. In 1999, the Food and Drug Administration (FDA) approved a rapid assay for the detection of pneumococcal antigen in the urine. However, this assay lacks specificity in children and is not recommended for use in that population.¹³

Bronchoalveolar lavage (BAL) often is a useful procedure in immunocompromised hosts with pulmonary infiltrates. In non-neutropenic patients with diffuse pulmonary infiltrates, the sensitivity of BAL is 80–90% and is highest in detecting Pneumocystis jiroveci (formerly carinii) pneumonia (PCP) in patients with human immunodeficiency virus (HIV) infection.¹⁴ It is somewhat less sensitive in neutropenic cancer patients, and thus a negative result cannot rule out the possibility of an infectious cause of the infiltrates. For any patient population, the diagnostic yield in the case of focal infiltrates is relatively low.

Normal BAL cell counts in children have been published and are summarized in Box 8-2.¹⁵

Lung biopsy may be done thoracoscopically, by thoracotomy (open biopsy), or by needle. Open
lung biopsy is most useful for the diagnosis of tuberculosis (TB) or of opportunistic microorganisms such as Pneumocystis in an immunocompromised host¹⁶ or in chronic pneumonias (described later). It can be done using a limited thoracotomy (i.e., no rib resection).¹⁷ A small pilot study in 13 immunocompromised patients with pneumonia showed that open lung biopsy yielded superior diagnostic information compared with BAL 5 of the patients had diagnoses established by open lung biopsy only.¹⁸ However, we have occasionally seen patients in which the reverse was true (i.e., diagnosis was made by BAL with a negative lung biopsy).

Transbronchial lung biopsy using a flexible fiberoptic bronchoscope has been useful in distinguishing tumor from opportunistic infection in adults.¹⁹ The use of this technique in children is limited because of an increased risk of bleeding and pneumothorax compared with adults.¹⁴ In addition, transbronchial biopsy is contraindicated in patients receiving mechanical ventilation because of the risk of tension pneumothorax.²⁰

Percutaneous needle biopsy under fluoroscopic guidance for histologic diagnosis is sometimes done in adults,²¹ especially when malignancy is a consideration, but it is rarely done in children. Pleural biopsy is discussed in the section on pneumonia with effusion.

Thorascopy has been used in children to rule out PCP, usually using sedation and local anesthesia.²² It is also useful in evaluating intrathoracic tumors but is sometimes complicated by pneumothorax or bleeding. Its primary role is in decortication of loculated empyema and is discussed in the section on pneumonia with effusion.

The use of computed tomography (CT) and ultrasound procedures is discussed in the sections on the syndromes where they are helpful. For example, ultrasound is most useful in detecting pleural effusion and in guiding thoracentesis. CT scanning is certainly more sensitive than plain chest films in picking up pleural effusions;²³ typically, however, any effusion small enough to be detected only by CT scanning is probably too small to be clinically significant. CT scanning also improves visualization of abscesses, and affords the clinician a better view of the mediastinum and its structures.²⁴

Serologic diagnosis is usually retrospective, except for cold agglutinins, which usually appear after one week of illness, often at about the time the patient seeks medical attention. Testing of paired sera is most useful for the diagnosis of Chlamydia pneumoniae, Mycoplasma pneumoniae, Q fever, and psittacosis. Serologic methods can be used for the detection of respiratory syncytial virus (RSV), influenza virus, parainfluenza virus, and adenovirus infection, but rapid antigen testing or viral culture methods are preferable.

The intermediate-strength tuberculin test is very useful for the diagnosis of tuberculous pneumonia. However, serologic tests are better than skin tests for the diagnosis of current pneumonia caused by Histoplasma or Coccidioides species. Furthermore, skin tests for fungi may boost the antibody titer, resulting in a misleading rise.

The pneumococcus is almost always the cause of classic typical pneumonia as described earlier. However, the pneumococcus can also produce other forms of pneumonia, such as pneumonia that fails to respond promptly to antibiotics, pneumonia with effusion, and even interstitial pneumonia.²⁷ A retrospective review of 85 children between the ages of 5 months and 16 years with bacteremic pneumococcal pneumonia found that 70% of children had the “typical” illness described before, with high fever, leukocytosis (white blood cell [WBC] greater than 15,000/mcL), and lobar or segmental consolidation on chest x-ray.²⁸ Interestingly, however, one-fourth of the patients presented without any respiratory symptoms. Thirty-eight percent of patients had gastrointestinal tract symptomatology, but only 5 (6%) of the 85 children had gastrointestinal symptoms in the absence of respiratory symptoms.

Routine use of the conjugated heptavalent pneumococcal
vaccine will decrease the incidence of pneumococcal pneumonia, but it will not eliminate it. In a large, randomized controlled trial, the incidence of radiographically-confirmed pneumonia among vaccinees was decreased by 35%.²⁹

The prevalence of H. influenzae type b (Hib) as a cause of pneumonia in children has greatly decreased because of widespread use of conjugated Hib vaccine. It is still a possible cause of lobar or segmental pneumonia in the unvaccinated child and is frequently accompanied by pleural effusion.^30,31 The onset is usually gradual but can be acute. Otitis media is frequent.³⁰ Purulent conjunctivitis is occasionally present. Hib can produce lobar or segmental pneumonia in older children and adults. The response to amoxicillin in recognized cases is typically poor. H. influenzae non-type b is also an occasional cause of pneumonia, especially in children younger than 10 years.

Staphylococcus aureus is an uncommon cause of lobar pneumonia (see Box 8-3).³² It should be considered in young or debilitated infants or when there is effusion or pneumatoceles, as discussed in a later section.

Group A streptococcal pneumonia often is associated with pleuritic pain and marked leukocytosis.³³ Often the organism cannot be recovered from the throat culture. A scarlatiniform rash may be present. Empyema and pneumatoceles occasionally occur, and S. aureus infection may be suspected. Group A streptococcal pneumonia tends to occur following a viral infection (especially varicella) and to have a fairly severe and protracted course.³⁴ In stark contrast to pneumonia caused by the pneumococcus, fever in Group A streptococcal pneumonia persists for days to weeks even in the face of appropriate antimicrobial therapy. Pneumonia caused by toxin-producing strains of S. aureus or Group A streptococcus may result in toxic shock syndrome (see Chapter 11).

Mycoplasma pneumoniae has to be considered as a possible cause of lobar pneumonia.³⁵ It is discussed further in the section on atypical pneumonia syndromes.

Primary pulmonary TB occasionally causes an acute lobar pneumonia, and in such a case, the tuberculin test is almost always positive at the time the pneumonia occurs.³⁶ All children with acute lobar pneumonia that is poorly responsive to empiric antibacterial therapy should have a tuberculin skin test placed. Tuberculosis also can be the basis for a segmental bacterial pneumonia, particularly in the right middle lobe, or for obstruction of a major bronchus by a lymph node. Histoplasma or other systemic fungi also can do this and should be considered in endemic areas.

The right middle-lobe syndrome and other recurrent or chronic lobar pneumonias are discussed later in this chapter.

Klebsiella pneumoniae is rarely documented as a cause of pneumonia in children by blood culture or lung puncture except in association with neonatal sepsis, nosocomial infection, or in immunocompromised hosts.

Meningococcal pneumonia without meningitis has been documented by blood cultures but is uncommon in children.³⁷ It may be more frequent in military populations 16–30 years of age and may follow influenza or adenovirus pneumonia. Serogroup Y is more likely to be associated with pneumonia than are the other serotypes. Septic shock may occur, but the typical purpuric rash may be absent.

Francisella tularensis is also a possible cause of acute focal pneumonia.³⁸ Most cases of tularemia follow the bite of a tick or a deerfly, and cause a systemic disease plus local inflammation at the site of the bite. The pneumonic form of tularemia usually occurs after inhalation of airborne organisms.
Typically in these cases, there is an interesting exposure history; for example, beating a dead infected rabbit with sticks can be a cause of aerosolization. Pleuropulmonary involvement also occurs in typhoidal tularemia, which in children is sometimes acquired by ingestion of the agent.³⁹ Enteric bacteria such as E. coli, Enterobacter, and Pseudomonas aeruginosa are extremely rare causes of pneumonia unless there is an underlying disease or nosocomial acquisition in an intensive care unit.

Psittacosis with a lobar segmental pneumonia may present with an acute onset of chills and high fever. Patients with psittacosis usually do not have a leukocytosis.

Due to the ever-increasing numbers of penicillin-resistant pneumococci, therapy with ceftriaxone or cefotaxime should be instituted for an acute lobar pneumonia presumed to be due to the pneumococcus and requiring intravenous therapy (Table 8-2). If one is fortunate enough to isolate the organism from the blood, a pleural effusion, or another reliable sample (discussed earlier), sensitivity testing should be done, and therapy switched to penicillin for sensitive strains. For patients requiring intravenous therapy, administering penicillin by continuous infusion is an effective and cost-effective approach. The dose is generally 150,000–250,000 units/kg/day (with a maximum of 24 million units per day).⁴⁰ This provides constant serum levels that easily exceed the minimum inhibitory concentration (MIC) for all but highly penicillin resistant strains.⁴¹ The outcome in patients with pneumococcal pneumonia is similar whether the organism is sensitive or resistant to penicillin.⁴²

It is important to remember that resistance is relative and can often be overcome by higher doses of antibiotics. Success also depends on the ability of the antibiotic to achieve therapeutic levels at the site of infection (e.g., lung tissue or meninges). Confusion is compounded when some reports refer to both highly-resistant strains and intermediately-resistant strains as nonsusceptible, when in reality infections with intermediately-resistant strains are often easily treated by higher doses of penicillin or other beta-lactam antibiotics. The recent interpretive standards published by the National Committee for Clinical Laboratory Standards (NCCLS) address this issue by citing different MIC cutoffs depending on whether the isolate is from cerebro-spinal
fluid (CSF) or some other source (see Table 8-3).⁴³ In general, it is rarely necessary to add vancomycin for therapy of pneumococcal pneumonia. Poor response to therapy is more likely due to inadequate drainage of an empyema. In contrast, as discussed in Chapter 9, the addition of vancomycin is advocated for meningitis caused by strains that are intermediate or resistant to cephalosporins.

One study of 26 children with culture proven pneumococcal pneumonia and complicated parapneumonic effusions found that children with penicillin-resistant isolates were younger than those with susceptible organisms. Bacteremia was also more common.⁴⁴

Patients with presumed pneumococcal pneumonia who are well enough to be managed as outpatients can be given high-dose amoxicillin (80 mg/kg/day) or cefuroxime axetil, with close follow-up. Tetracycline should not be used for treatment of presumed pneumococcal pneumonia. Macrolides have relatively poor anti-pneumococcal activity as well. Fluoroquinolones are commonly used for community-acquired pneumonia in adults and adolescents. A report suggests that recent exposure to a fluoroquinolone antibiotic increases the risk of fluoroquinolone resistance and treatment failure of pneumococcal pneumonia.⁴⁵

Patients who have a late diagnosis, who are seriously ill, or who have underlying disease should not be treated as outpatients.

Moderately ill children of preschool age should be admitted and treated with a parenteral antibiotic effective against both S. pneumoniae and beta-lactamase producing strains of H. influenzae. The third-generation cephalosporins are stable against these beta-lactamases and are therefore a good choice.

Oxygen, bed rest, positioning, and other supportive therapies are discussed later. Chest physiotherapy is at best useless for the treatment of acute pneumonia in adults.^46,47

Persistent pneumonia is defined by persistence of consolidation on chest roentgenogram for more than 1 month. Pleural thickening, paralysis of the diaphragm, or atelectasis may explain some cases. Other causes of persistence of lobar or segmental densities are described in the section on chronic pneumonia.

Hemolytic-uremic syndrome (HUS) is an important, albeit uncommon, complication of pneumococcal pneumonia. Although occurring via a different mechanism, it presents similarly to other forms of HUS, with anemia, thrombocytopenia, and acute renal failure. Neuraminidase produced by S. pneumoniae removes N-acetylneuraminic acid from cell surface glycoproteins, exposing the T-antigen on red blood cells, platelets, and glomeruli. Immunoglobulin M (IgM) antibodies that are present in most human plasma react with the exposed T-antigen, resulting in hemolysis and damage to glomerular endothelial cells.⁴⁸

Typically, cases occur in young children (1–2 years old) with severe or even fulminant pneumococcal pneumonia. Most patients have a positive direct Coomb’s test.⁴⁹

Because plasma products contain IgM antibodies that can activate the T-antigen, their use is contraindicated. In addition, if transfusions are necessary,
the red blood cells should be washed to reduce the amount of IgM present.⁵⁰

This occasionally occurs in uncomplicated pneumococcal pneumonia. Patients with low white blood cell counts and multilobar involvement have the highest mortality rate. Poor clinical response may also occur in patients infected with highly penicillin-resistant strains of the pneumococcus. Occasionally, patients with pneumonia severe enough to require mechanical ventilation will have an initial response to therapy but then develop recrudescent fever. Such patients are often found to have secondary nosocomial pneumonia with a different organism (usually a gram negative).

Rare but serious complications include pericarditis, meningitis, endocarditis, arthritis, and peritonitis. Pleural effusion and empyema are described in the following section and should always be considered when there is failure of a lobar pneumonia to respond to adequate therapy (Fig. 8-3).

This question of the effect on lung function in adulthood was addressed by a prospective cohort study of 1392 British children followed from their births in 1958. Of these, 193 children had a history of pneumonia by the age of 7 years. At 35 years of age, pulmonary function testing was performed in all subjects. A history of pneumonia was associated with a small but significant decrease in forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC), even after controlling for a history of wheezing and multiple other confounding factors. The effect was no greater for the subjects who had pneumonia at younger than 2 years than for those who had pneumonia between ages 2 and 7. It remains unclear whether pneumonia causes the deficit in lung function or whether pneumonia is more common among children who have poorer lung function before the disease.⁵¹

Whenever there is radiologic evidence of pleural fluid in a patient with pneumonia, some of the fluid
should be removed for Gram stain and culture.⁶¹ Thoracentesis is rarely associated with complications.⁶² However, overly-rapid removal of large volumes may cause a sudden shift of the mediastinum with reflex changes in heart rate and, occasionally, cardiac arrest. Pneumothorax is rare.

The purpose of the procedure is to obtain enough fluid for diagnostic purposes, but occasionally respiratory excursions are improved by the removal of moderate volumes. Thoracentesis and exact bacteriologic diagnosis are especially needed in a severely ill patient. Even a small amount is useful for diagnostic study.

Thoracentesis is especially useful for culture of pus to determine the identity of the infecting organism so antibiotic therapy can be tailored. If the Gram stain is quickly available and reveals definite bacteria, the cell count, differential, protein measurement, glucose, and other studies add little. Both aerobic and anaerobic cultures should be ordered.

Type-specific antigens of pneumococci or H. influenzae can sometimes be detected in pleural fluid
using various techniques, although these tests are unavailable in many centers and their sensitivity and specificity are unknown.

Empyemas treated with closed chest tube drainage frequently loculate and then require a surgical procedure to remove the congealed pus. Several small trials have studied the idea of instilling fibrinolytic agents (such as urokinase) through the chest tube to prevent or even treat loculation.^64,65,66

In children, only case series are reported.⁶⁷ In adults, this practice seems to be safe and to have a modest effect in shortening hospital stay and decreasing the need for surgical intervention. A systematic review concluded that because of the small size of these randomized trials there was insufficient evidence to support the routine use of intrapleural fibrinolytic therapy in the management of empyema.⁶⁸ A large, multicenter trial is currently underway.

Percutaneous needle biopsy of the pleura is especially useful in the diagnosis of tuberculous pleurisy in adults. The procedure has also been used in children.⁶⁹

If the pleural fluid exudate is relatively clear, several etiologies are more likely (Box 8-5). Tuberculosis is a possibility if the fluid appears serous but the protein concentration is high. In tuberculous effusion, which reflects hypersensitivity, the tuberculin test is almost always positive.⁷¹ Partially treated bacterial pneumonia with effusion is also a frequent cause of exudate that is not grossly purulent.

Mycoplasma pneumoniae can cause small effusions in children.⁷² In a study of young adults with mycoplasmal and viral pneumonia, small pleural effusions were found in about 20% of the 59 patients with serologic evidence of nonbacterial pneumonia.⁷³ Pleural effusions were seen in 6 (21%) of 29 patients with Mycoplasma, 1 (14%) of 7 with adenovirus, 1 (25%) of 4 with influenza virus pneumonia, and in 4 (21%) of 19 patients with elevated titers to cold agglutinins ⁷³ Another study of 56
patients with moderately severe disease from M. pneumoniae revealed that pleural effusions were detectable in 8 (14)%.⁷⁴ However, other studies have indicated that the frequency of pleural effusions in Mycoplasma pneumoniae in young adults is closer to 5%.⁷⁵

Adenovirus, particularly type 7, can cause massive pleural effusions and disseminated disease, which may be fatal.⁷⁶ Epstein-Barr virus (EBV) is sometimes associated with a pleural effusion.⁷⁷ In infants and young children, the illness may not resemble infectious mononucleosis except for the presence of atypical lymphocytosis.⁷⁸ When a pleural effusion accompanies typical infectious mononucleosis in teenagers, a concurrent mycoplasmal pneumonia may be present.

A small pleural effusion can occur with viral hepatitis and may precede jaundice.⁷⁹ In an effusion secondary to hepatitis B, which is an immune-complex reaction, both blood and pleural fluid are positive for hepatitis B surface antigen, and serum transaminases are elevated even if jaundice has not yet appeared. Pleural effusion during the course of hepatitis A virus infection has been reported.⁸⁰ Cat scratch disease can produce a pleural effusion and anicteric hepatitis.⁸¹ Leptospirosis can be associated with a pleural effusion; other features of the disease may lead to the correct diagnosis.⁸² Yellow nail syndrome is an exceedingly rare lymphatic abnormality that may cause pleural, as well as pericardial, effusions.⁸³

Frankly purulent pleural fluid (empyema) is almost always caused by bacterial pneumonia. Before antibiotics were available, the pneumococcus or beta-hemolytic streptococci were the most common causes of empyema.^84,85,86 For a time thereafter, Staphylococcus aureus became the most common cause of empyema, but in recent years S. pneumoniae has again become prominent. The percentage of patients with pneumococcal pneumonia who have parapneumonic effusions is not as high as that seen with S. aureus (approximately 80% of children with S. aureus pneumonia have effusions);³² but cases of pneumococcal pneumonia outnumber those of staphylococcal pneumonia by a large margin. In one series, 88% of culture-positive cases of parapneumonic effusion were due to S. pneumoniae.⁸⁷ A more recent study suggest that S. aureus may once again be surpassing the pneumococcus as a cause of empyema.⁸⁸ As mentioned earlier, Group A streptococcus is an occasional cause. Rare causes include F. tularensis,⁸⁹ H. influenzae type b, and gram-negative enteric bacteria such as Pseudomonas or Salmonella.^90,91

The viridans group of streptococci and diphtheroids (which are normal mouth flora) are rare causes of empyema associated with aspiration pneumonia, particularly in adults. Pasteurella multocida has caused empyema in a child with underlying pulmonary disease and exposure to animals.⁹² Nocardia is a rare cause of pleural effusion, typically in compromised hosts. Other uncommon infectious causes of pleural effusions include Yersinia, Chlamydia trachomatis, and Listeria.^93,94,95

Bacteroides or Clostridium species, anaerobic actinomyces, and anaerobic streptococci are occasional causes of empyema (particularly in adults), so that any fluid removed should be cultured anaerobically.^96,97 Blastomycosis, histoplasmosis, and coccidioidomycosis can be associated with thin to moderately purulent pleural effusions.^98,99,100 These fungi and cryptococci are special risks for immunosuppressed patients.^{101,102,103,104} However, massive lung disease can sometimes occur in immunologically normal hosts who are exposed to a large inoculum of the fungus. Parasitic causes include paragonimiasis (in Far Eastern immigrants) and amebiasis.^105,106

Empyema is rarely the result of a perforated appendix.¹¹⁰ Sometimes it is difficult to determine whether fluid is above or below the diaphragm if CT scanning is not readily available. Usually, it is
better to do a thoracentesis and look for pleural fluid first, as removal of pleural fluid often results in the disappearance of radiologically apparent subdiaphragmatic fluid.

Pulmonary embolism (PE) is uncommon in children, and when it occurs the diagnosis is usually delayed. The symptoms of tachypnea, chest pain, dyspnea, and fever are easily confused with pneumonia, which is usually the initial diagnosis. Most children with PE have one of several well-described risk factors, such as recent surgery, immobilization, malignancy, pregnancy, obesity, heart disease, the presence of a central venous catheter, oral contraceptive use, nephrotic syndrome, and sickle cell anemia.^{111,112,113,114}

In children who develop PE without apparent risk factors, nearly all are found to have an antiphospholipid antibody or coagulation regulation protein abnormality (such as protein C or S deficiency).¹¹⁵

This subgroup is distinguished by a gradual onset over several days, usually with prominent extrapulmonary symptoms. The chest roentgenogram shows one or more patches of minimal foci of pneumonia. The most common causes are Mycoplasma pneumoniae, Chlamydia pneumoniae, and adenoviruses. Other causes are discussed in the following section on possible etiologies.

This subgroup is distinguished by a subacute onset and an unexpectedly dense focal infiltrate that is segmental or smaller. Most of the other features of acute focal pneumonias (typical pneumonia), such as fever, toxicity, marked leukocytosis, and focal chest signs, are absent. Tuberculosis is an important consideration to exclude.

This subgroup is distinguished by the absence of a solid focal or even minimal focal infiltrate. The infiltrate is sometimes described as reticular or patchy. There are many possible causes, most of which are viral and self-limited, but some of which are not viral or are progressive (Box 8-7).

Mycoplasmal pneumonia should not be used as a preliminary diagnosis without proof of etiology, because many atypical pneumonias are not caused by M. pneumoniae. Furthermore, it is not possible to distinguish mycoplasmal pneumonia from other atypical types on clinical grounds.¹³⁸

Nonbacterial pneumonia is a conclusion usually based on such observations as failure to respond to antimicrobial therapy, absence of leukocytosis, and sparse infiltrate. However, the term nonbacterial pneumonia should not be used, because it implies that bacterial causes have been excluded, when in fact this can rarely be done with certainty.

M. pneumoniae is probably the most frequent cause of atypical pneumonia, especially in school-age children and young adults.^139,140 Usually, the radiologic pattern is subacute with minimal densities, but occasionally it is an acute bilateral interstitial pneumonia.¹⁴¹
Rarely, it is lobar, as cited in the preceding section on focal pneumonias. The physician is often aware of an outbreak of atypical pneumonia syndrome (“walking pneumonia”) in the community. Typically, there is a long incubation period (2–3 weeks) between illnesses in the same family, a feature that helps with the diagnosis.¹³⁹ However, cases seen in association with outbreaks may have incubation periods as short as one week. Occasionally, a point-source outbreak occurs,^142,143 but usually the illnesses involve separate members of a family over a long period of time.¹³⁹

Otitis media with severe, painful, extremely red tympanic membranes is rarely caused by M. pneumoniae (as discussed previously). Urticarial or nonspecific maculopapular rashes are also associated in some cases.¹³⁹ Eosinophilia exceeding 5% is not unusual.¹⁴⁰ More severe complications are discussed at the end of this section.

It is often taught that mycoplasmal pneumonia has a classic radiographic appearance, which consists of bilateral reticular or interstitial infiltrates, with or without patchy infiltrates. However, almost any x-ray pattern is possible. Brolin and Wernstedt reported the radiographic findings of 56 patients with M. pneumoniae lower respiratory tract infection: 8 (14%) of patients had lobar findings and 21 (38%) had lobar or predominantly alveolar findings. Some had a combination of lobar/alveolar and interstitial infiltrates; if those are added, 36 (64%) of 56 patients had some component of lobar or alveolar infiltration. Twenty (36%) of the patients showed a purely interstitial pattern, and 33 (59%) had some component of interstitial infiltration. Interestingly, 22% had hilar adenopathy and 14% had a pleural effusion.⁷⁴

M. pneumoniae pneumonia occurs most frequently in individuals 5–12 years old.¹⁴⁴ Subclinical infection is probably common before 5 years of age, but the organism is a relatively unusual cause of pneumonia in this group.¹⁴⁵ Most young adults have serum antibodies, which suggests a past infection and indicates that past infection is apparently not protective against future reinfection.

There are three medically important species in this genus. C. trachomatis is a frequent cause of acute bilateral afebrile pneumonia in infants less than 4 months of age and a less-frequent cause of pneumonia in older children and adults. Because it is sometimes associated with peripheral eosinophilia, it is discussed in the section on pulmonary infiltrates with eosinophilia (PIE syndrome).

C. psittaci infection (psittacosis) is uncommon in the United States, with only about 50 cases reported annually. Nevertheless, it is important to recognize because it responds to tetracycline. There is typically an exposure to parakeets or other birds.¹⁴⁶ Large outbreaks have been reported from turkey processing plants.¹⁴⁷ Psittacine birds (those with a bent beak) are more likely to be infected, and most birds with psittacosis are ill. C. psittaci infection in humans usually produces fever, chills, and severe headache; arthralgia is sometimes present. Typically, there has been the gradual onset of cough, and there is a patchy infiltrate on chest x-ray. Usually there is no leukocytosis, but eosinophilia is sometimes present. Elevated serum transaminase and alkaline phosphatase can occur.

C. pneumoniae, originally classified as a strain of C. psittaci called the TWAR agent (named after the first two respiratory isolates, TW-183 and AR-39) is now recognized as a fairly common cause of respiratory disease in school-aged children, adolescents, and adults. Studies documenting its prevalence have been hampered by the lack of a diagnostic gold standard. The organism will not grow on cell-free media but is cultivatable in tissue culture. A nasopharyngeal swab is an appropriate specimen. The sample must be transported in culture transport media and processed within 24 hours of collection. The epidemiology of C. pneumoniae is similar to that of M. pneumoniae in that infection with this organism is rare in infancy, and becomes more common through childhood and peaks at adolescence. Most infections are probably asymptomatic.¹⁴⁸

At all age points it appears to be somewhat less common than M. pneumoniae.¹⁴⁹ Respiratory disease caused by C. pneumoniae is very similar to that caused by M. pneumoniae. A prospective study of 667 college students with acute respiratory disease found 20 patients (3%) with C. pneumoniae and 29 patients (4%) with M. pneumoniae infection; patients with C. pneumoniae were less likely to have a temperature greater than 100° F (37.8° C) and were more likely to present with sore throat as a prominent complaint (80% vs. 52%). Hoarseness was seen in 30% of patients with C. pneumoniae infection but only in 3% of patients with M. pneumoniae.¹⁵⁰ Finally, the time from onset of symptoms to presentation for medical care was longer in patients with C. pneumoniae infection.

A variety of serologic tests are available that make a retrospective diagnosis. It may take 3–4 weeks to mount a measurable response; when convalescent titers are ordered too soon the diagnosis may be missed. Polymerase chain reaction (PCR) has been done experimentally, but the results are not always concordant with culture and serology. From 10–90% of patients positive for C. pneumoniae infection by PCR do not mount appropriate serologic responses.^151,152

Some people harbor the organism for months after the acute infection. Such patients may be asymptomatic, or they may have problems with periodic wheezing and asthma. It has been suggested that some adults with severe, refractory wheezing may have chronic C. pneumoniae infection. In one study, resolution of infection correlated with improvement in asthma control.¹⁵³ Another study found that children with persistent C. pneumoniae PCR positivity suffered from more frequent asthma attacks.¹⁵⁴ C. pneumoniae-specific immunoglobulin E (IgE) was found in 12 (86%) of 14 culture-positive children with wheezing compared with only 1 (9%) of 11 culture-positive children without wheezing.¹⁵⁵ The precise relationship between C. pneumoniae infection and asthma is not understood.

Patients with cystic fibrosis can undergo pulmonary exacerbations in association with C. pneumoniae infection. In the one published study on this topic, M. pneumoniae, by contrast, was not found to be associated with exacerbations.¹⁵⁶

Some bacterial pneumonias are patchy or interstitial and do not respond to macrolides, the usual antibiotic therapy for M. pneumoniae. Tularemia is an example.¹⁵⁷

RSV is a frequent and important cause of atypical pneumonia, which is usually of the acute bilateral interstitial subgroup but can be patchy or even densely focal. The airway disease is more important than the alveolar involvement (Chapter 7).

A newly discovered virus, termed the human metapneumovirus (hMPV), was first isolated from nasopharyngeal aspirates of 28 children in the Netherlands who presented with respiratory tract symptoms and negative tests for known causes.¹³⁷ Like RSV, symptomatic infection appears to be most common in the first year of life. Symptoms ranged from mild respiratory problems to severe bronchiolitis or pneumonia, often accompanied by high fever and vomiting. Serologic testing suggests that infection within the first 5 years of life is nearly universal.

Adenoviruses, of which there are more than 40 serotypes, are a frequent cause of atypical pneumonia. Adenoviral pneumonia cannot be distinguished on clinical grounds from mycoplasmal pneumonia.¹³⁸ Occasionally, epidemics occur with severe disease, often with accompanying gastrointestinal signs.¹⁵⁸

Influenza viruses almost always are associated with epidemics or large outbreaks. They can cause an atypical pneumonia usually associated with prominent extrapulmonary manifestations.

Parainfluenza virus type 3 can cause atypical pneumonia, especially in young children. It usually produces bronchiolitis (discussed in Chapter 7),
possibly with minimal patchy pneumonitis, but occasionally produces bilateral interstitial pneumonia or perihilar pneumonia without bronchiolitis.

Rhinoviruses rarely cause atypical pneumonia.¹⁵⁹ Likewise, coxsackie A or B viruses are rarely associated. Coxsackievirus B has been recovered from the lungs of patients dying with pneumonia, and in the rare newborn or infantile case, the clinical syndrome is usually that of fulminant disease with concurrent myocarditis.

Measles virus is frequently associated with interstitial infiltrates when there is a classic measles illness.¹⁶⁰ It is not ordinarily considered a cause of atypical pneumonia, because the diagnosis is obvious in the classic case. However, pneumonitis is present before the eruption in about 20% of patients with classic measles.¹⁶⁰ Measles virus can cause fulminant pneumonia, as described in a later section.

Varicella-zoster virus can produce atypical pneumonia, especially in adults. The diagnosis should present no problem if the typical rash is present. The syndrome usually presents as chickenpox with pneumonia rather than as atypical pneumonia possibly caused by chickenpox virus. The virus can cause fulminating pneumonia in an immunosuppressed patient.

Cytomegalovirus (CMV) can produce an atypical pneumonia but more often produces an acute interstitial pneumonia in a patient with an immunologic problem (especially solid organ or stem cell transplant patients). In this population, CMV pneumonia is characterized by high fever, hypoxemia, and diffuse interstitial infiltrates. This is a serious disease with a high mortality rate. CMV also can cause interstitial pneumonia in very young infants, who appear to become colonized from their mother’s genitourinary tract just before or during delivery.^161,162

Herpes simplex can cause interstitial pneumonia, especially in immunosuppressed patients and newborns, that may become severe and extensive.^163,164

Late-onset rubella syndrome is a rare cause of bilateral interstitial pneumonia.¹⁶⁵ It is typically associated with diarrhea, a skin rash, and hypoglobulinemia. It usually occurs between 3 and 12 months of age, with cough, tachypnea, and cyanosis and is associated with circulating immune complexes.

Infectious mononucleosis can produce hilar adenopathy as a part of the generalized lymphadenopathy, and a few patients have small pulmonary infiltrates.¹⁶⁶ Concurrent infection with M. pneumoniae might explain some cases of infectious mononucleosis with pneumonia, as both diseases are common in young adults.¹⁶⁷

The recently discovered severe acute respiratory syndrome (SARS) coronavirus is discussed in the section on progressive or fulminating pneumonias.

Bordetella pertussis can be associated with an atypical pneumonia with subacute onset of cough, slight fever, and pulmonary infiltrates, especially linear lower-lobe interstitial infiltrates, perihilar infiltrates (shaggy heart border), or wedge-shaped upper-lobe infiltrates, perhaps with atelectasis. Lymphocytosis is usually present; when it is not, the clinical diagnosis is likely to be atypical pneumonia with perihilar infiltrate. Most children with pertussis have neither fever nor pulmonary infiltrates unless a secondary bacterial pneumonia (e.g., S. aureus) ensues. Pertussis-like illnesses are discussed in Chapter 7.

Other bacteria that can cause atypical pneumonia include the pneumococcus and H. influenzae. They are probably a more frequent cause of atypical pneumonia than are bacteria rarely causing human infection, such as F. tularensis. P. aeruginosa, acquired from water, can rarely cause atypical pneumonia.¹⁶⁸ Legionella is an important consideration, particularly in the immunocompromised host.

Mycobacterium tuberculosis is an uncommon but important cause of atypical pneumonia with a subacute onset, low-grade fever, and diffuse or linear infiltrates. Most often, the pneumonia is focal and dense, but the rest of the features are atypical, which would fit into the subgroup of a subacute dense focal pneumonia.

Occasionally other mycobacterium species are associated with an atypical pneumonia. Recently, nontuberculous mycobacteria (especially M. avium complex) have been associated with a diffuse pneumonia in patients exposed to hot tubs. Patients present subacutely with dyspnea, cough, hypoxia, and fever.¹⁶⁹ Some patients respond to corticosteroids alone, and thus the illness may be due to a hypersensitivity reaction to the organism.¹⁷⁰

Coxiella burnetii, the cause of Query fever (Q fever), is a rare cause of atypical pneumonia.¹⁷¹ The organism
is excreted in large numbers at the time farm animals, particularly sheep, give birth. Long after the fact, viable organisms remain in the soil, and can be blown about by the wind. Thus, the patient need not have been in attendance at a birth but usually lives in a rural area and has some farm animal exposure history. The condition usually responds to doxycycline or erythromycin, which may be given because of suspected mycoplasmal pneumonia.

In the past, this disease was very rare, and occurred primarily in those exposed to contaminated animal products (wool sorter’s disease). Although still rare, recent bioterrorism-related cases were well publicized.¹⁷² The illness presents in two stages. The first stage is that of an influenza-like illness with fever, cough, and chest pain. The second stage presents a few days later with abrupt onset of high fever, severe dyspnea, and shock. Chest x-ray classically demonstrates only a widened mediastinum, but progressive perihilar infiltrates can be present as well.¹⁷² At least two drugs active against B. anthracis are recommended for treatment, (such as a fluoroquinolone plus rifampin). Despite appropriate therapy, the mortality rate is more than 50%.

Histoplasma capsulatum and Coccidioides immitis are occasional causes of an atypical pneumonia. Patients may present with an acute interstitial pattern when there has been a single overwhelming exposure, but more often they present with a focal infiltrate of subacute onset.

Pneumocystis jiroveci can cause bilateral pulmonary infiltrates in immunocompetent infants 2–12 weeks of age.¹⁷³ Infants receiving high doses of systemic corticosteroids for prolonged periods of time are at increased risk,^173a as are children with HIV infection (Chapter 20), transplant recipients (Chapter 22), and patients with primary cellular immunodeficiency (Chapter 23). Cough, tachypnea, and apneic episodes may occur, but fever is unusual, so that the clinical pattern resembles that of pertussis or chlamydial pneumonia. Serum IgM is usually elevated. Treatment is with trimethoprim-sulfamethoxazole, which is now used as routine prophylaxis for immunocompromised patients.

Mycoplasma hominis and Ureaplasma urealyticum are uterine cervical flora that can colonize an infant just before or during delivery and lead to pneumonia.¹⁶¹ One case of pneumonia with pleural effusion in a postpartum adolescent that was due to M. hominis has been reported.¹⁷⁴

Congestive heart failure often resembles an atypical pneumonia. Pulmonary infarction or embolism is uncommon in children, as discussed in the section on pneumonia with effusion.

Allergies to Actinomyces species (which may contaminate air conditioners), to pigeons (pigeon breeder’s disease), and to maple bark also may cause noninfectious atypical pneumonia with diffuse interstitial infiltrates. These pneumonias are discussed in the sections on chronic and recurrent pneumonia and PIE syndrome.

Toxic causes include silo filler’s disease, caused by inhalation of nitrogen oxides, and other occupational inhalants. Medications such as phenytoin or nitrofurantoin are a rare cause of acute interstitial pneumonia.¹⁷⁵

Collagen diseases occasionally associated with atypical pneumonia include rheumatic fever (Chapter 18) or rheumatoid arthritis (Chapter 10).

Because the test is neither sensitive nor specific enough to establish a diagnosis, the use of cold agglutinins is in decline. In certain situations, however, the test may be helpful. If a specimen is desired, it may be obtained as soon as the pneumonia is recognized as “atypical,” as agglutinins are often present at this point in the illness. This specimen can also be used as an acute serum for mycoplasmal and viral antibody studies.

Cold agglutinins are found in low titers (about 1:10) in about 10% of normal adults.¹⁷⁶ A titer of 1:32 or higher has been regarded as abnormal. M. pneumoniae, C. pneumoniae, and adenoviruses are the most likely causes of cold-agglutinin positive atypical pneumonia. However, RSV, parainfluenza viruses, and coxsackieviruses may also be to blame.¹⁷⁷ Cold agglutinin titers greater than 1:10 are unusual in influenza-virus infection but can
occur in patients with pneumococcal pneumonia with bacteremia.¹⁷⁶

A rapid bedside screening test for cold agglutinins can be performed by placing a few drops of blood into an anticoagulant tube and cooling it on ice. After inserting the specimen in ice, agglutination of red blood cells is visible as clumps when the tube is held up to a light source and rolled slowly. Quantification of a titer of cold agglutinins is not possible at the bedside, although blood with large quantities agglutinates more than does blood with low titers. In one study, 50% of children with acute respiratory disease and 75% of children with pneumonia and serologic evidence of M. pneumoniae infection had a positive screening test for cold agglutinins.¹⁷⁸ If a cold agglutinin test is positive in a preschool child, the pneumonia is probably viral. If it is positive in a school-aged child, the pneumonia is probably mycoplasmal. Quantification of cold agglutinin titers is of less utility in children less than 10 years of age.

Some centers offer simultaneous fluorescent-antibody detection of the most common respiratory viruses, including RSV, influenza A and B, the parainfluenza viruses, and adenovirus. Enzyme-linked immunosorbent assay (ELISA) tests are also available for rapid detection of respiratory agents. Such rapid tests are especially useful if there is an established treatment, as for herpes simplex, varicella viruses, or M. pneumoniae, or a treatment that is possibly effective, as for influenza. Commercial ELISA tests for RSV and influenza A virus are readily available.

The serum tested for cold agglutinins can also be used as an acute-phase serum for a battery of antibody studies in comparison with a later serum specimen. Antibodies that may be studied in paired sera include M. pneumoniae, C. pneumoniae, adenovirus, psittacosis, Q fever, influenza virus, and RSV. Occasionally, other agents known by recent laboratory studies to be prevalent in the community will be sought by the reference laboratory.

Often, complement-fixing antibodies to M. pneumoniae are present in low to moderate concentrations in the first serum obtained, which often is a week or so after the onset of the illness. Such low to moderate titers can be regarded as presumptive evidence of current infection with this organism, because these antibodies are usually not detectable in healthy children or adolescents. In one study, an IgM-capture assay drawn in the convalescent phase of illness was the single most reliable test in the diagnosis of M. pneumoniae infection.¹⁷⁹ However, in our experience, infections with other organisms can sometimes result in a nonspecific rise in mycoplasma IgM antibodies.

Culture of M. pneumoniae is technically difficult, less sensitive than serology, and not readily available.

Culture for viral agents is generally slow. RSV may grow within 3–4 days. Herpes simplex virus, likewise, may be fairly rapidly grown in cell culture. Other respiratory viruses may take a week or two. When virus cultures are available and inexpensive, they may be useful in selected cases, especially to identify viruses prevalent in the community. Some laboratories are able to do a “shell vial” assay for adenovirus, which uses centrifugation and detection of early gene products to speed up the process, in which case results may be available within 48 hours.¹⁸⁰

PCR testing for M. pneumoniae and C. pneumoniae on throat swabs or nasopharyngeal aspirates are available on an experimental basis. The sensitivity of such tests is a matter of debate. Evaluation of these tests is ongoing. PCR testing of cerebrospinal fluid, when positive, can establish the diagnosis of M. pneumoniae encephalitis.¹⁸¹