Nonbacterial Pneumonia

Viral Pneumonia

Although viral infections of the upper respiratory tract are common, viral pneumonia is rare in patients who are not immunocompromised, except for children and the elderly. Four major groups of viruses account for most viral pneumonias in immunocompetent children (Table 28-1 ).

Table 28-1.

Respiratory Viruses That Cause Pneumonias in Nonimmunocompromised Hosts

	Influenza	Parainfluenza	Respiratory Syncytial Virus	Adenovirus
Family	Orthomyxoviridae	Paramyxoviridae	Paramyxoviridae	Adenoviridae
Genome	Single-stranded RNA	Single-stranded RNA	Single-stranded RNA	Double-stranded DNA
Envelope antigens	Hemagglutinin Sialidase	Hemagglutinin Sialidase Fusion Glycoprotein	Fusion glycoprotein Glycoprotein	250 capsomeres
Serotypes	Three (pathogenic in humans: A and B)	Four (pathogenic in humans: 1, 2, and 3)	Two (A and B)	50
Infected cells	Epithelial cells	Epithelial cells	Epithelial cells	Epithelial cells Lymphoid cells
Frequency among lower respiratory tract infections	Type A: 1–13% Type B: 1–9%	4–41%	6–63%	2–35%

Pneumonia accounts for 20–40% of viral lower respiratory tract infections in children. In adults, influenza is the most frequent cause of viral pneumonia, although respiratory syncytial virus (RSV) is also seen, and pneumonia may occur as part of systemic viral infections such as measles, chickenpox, and the hantaviruses. For each agent, epidemiology, risk factors, clinical features, diagnosis, treatment, clinical course, and prevention are considered.

Influenza Virus

Three types of influenza virus have been identified: A, B, and C. Type A is responsible for the most severe and widespread disease, and type C does not seem to be pathogenic. Major antigens of the virus envelope are hemagglutinin and neuraminidase (sialidase). In influenza A viruses, the former undergoes periodic changes, which may be major (resulting in antigenic shifts because of reassortments between strains, leading to an entirely new gene) or minor (resulting in antigenic drifts because of point mutations). Most of the host immune response is directed against hemagglutinin.

Influenza A and B viruses are responsible for at least 50% of the viral pneumonias encountered in immunocompetent adult subjects. Antigenic shifts are associated with pandemics when antigenic modifications lead to a decrease in the immunity of the community, whereas antigenic drifts are commonly associated with more limited epidemics. Outbreaks of severe disease occur every 10–30 years. During an outbreak, children are usually infected before adults (attack rates may reach 50–75%). The excess mortality caused by influenza may be as high as 10,000 patients per year, and the economic consequences of outbreaks are considerable.

The host immune response involves both cellular and humoral defenses, as well as local antibody responses caused by secretory immunoglobulin A (IgA). The result is mucosal inflammation that consists of hyperemia, edema, and, in severe cases, hemorrhage. Transmission is by respiratory secretions.

Pneumonia may occur directly after the acute illness (termed primary pneumonia, which is caused by the virus itself), or it may occur after a period of clinical improvement (secondary pneumonia, which results from bacterial superinfection, most commonly with Streptococcus pneumoniae, Haemophilus influenzae, or Staphylococcus aureus). Primary pneumonia seems to occur more commonly in association with conditions that result in increased left atrial pressure, whereas secondary pneumonia occurs mainly in older adults or in patients who have comorbid conditions, such as chronic cardiovascular or respiratory disease, diabetes mellitus, or chronic hepatic or renal failure.

A typical presentation includes the acute onset of cough, sore throat, conjunctival hyperemia, nasal discharge and congestion, fever, myalgia, headache, and malaise. Symptoms and findings of pneumonia are infrequent, and the disease is usually self-limited. Reappearance or worsening of respiratory symptoms and signs suggests pneumonia, but radiographic evidence of pneumonia may be found in the absence of such findings.

The typical radiographic findings of primary pneumonia are diffuse, interstitial, or patchy infiltrates. Secondary pneumonia may have a more segmental or lobar pattern. Primary and secondary pneumonia may occur in the same patient at the same time.

Indirect diagnosis is used primarily for epidemiologic purposes, because it requires two serologic assays performed 10–14 days apart. Direct diagnosis can be made by:

• •Culture of respiratory secretions or lung tissue, a process that takes 2–5 days (less if antigen detection techniques are used).
• •Immunofluorescence or enzyme-linked immunosorbent assay (ELISA) techniques on nasal or pharyngeal cells obtained by brushing or washing, a process that takes approximately 15 min.
• •Antigen detection in respiratory secretions, a less sensitive but more rapid technique.

In addition to supportive care, treatment with specific antiviral therapy such as amantadine (100 mg/kg per day for 5 days) or rimantadine may be beneficial if administered early in the course of the disease (within 48 h of symptom onset). Zanamivir and oseltamivir are related antiviral drugs with a similar mechanism of action and a similar rate of effectiveness against both influenza A and B viruses, whereas the M2 inhibitors, amantadine, and rimantadine are active only against influenza A. Both are neuraminidase inhibitors; zanamivir is inhaled, and oseltamivir is given orally. Both drugs are approved for the treatment of influenza only in persons who have been symptomatic for less than 2 days. Clinical studies showed that the symptoms of influenza disappeared 1–1.5 days sooner in the drug-treated groups than in the placebo groups. Antibiotics active against S. pneumoniae, H. influenzae, and S. aureus are needed to treat patients who have secondary pneumonia.

The morbidity and mortality of influenza pneumonia are high, and patients can deteriorate to the point of acute respiratory distress syndrome (ARDS) developing. In such cases, the likelihood of a secondary pneumonia developing is high.

Inactivated influenza vaccines are modified each year to follow the antigenic modifications of influenza A strains. They provide 50–80% protection against influenza-related illnesses and 30–65% protection against influenza-related hospital admissions and deaths in the elderly. Accordingly, vaccination is recommended for all patients older than 65 years, all patients who have chronic comorbid conditions (regardless of age), patients who reside in chronic care facilities, and health care workers (because of their increased risk of contacting patients who have influenza and spreading it to other noninfected patients). Preventive administration of amantadine or rimantadine for 2 weeks after vaccination has been recommended in very high-risk patients to provide protection during the period required to develop an effective immunologic response.

Pandemic Influenza

Recent human infections caused by avian influenza A (H5N1) in Vietnam, Thailand, Cambodia, China, Indonesia, Egypt, and Turkey raise the possibility of a pandemic in the near future. The severity of H5N1 infection in humans distinguishes it from that caused by routine seasonal influenza. Respiratory failure requiring hospitalization and intensive care has been seen in most of the 1140 recognized cases, and mortality is as high as 50%.

Early clinical features of H5N1 infection include persistent fever, cough, and respiratory difficulty progressing over 3–5 days, as well as lymphopenia on admission to the hospital. Exposure to sick and dying poultry in an area with known or suspected H5N1 activity has been reported by most patients, although the recognition of poultry outbreaks has sometimes followed the recognition of human cases. In patients with suspected H5N1 infection, droplet precautions and careful routine infection control measures should be used until an H5N1 infection is ruled out.

Patients with an illness compatible with influenza and with known exposure to poultry in areas with previous H5N1 infection should be tested for H5N1 infection. Direct fluorescent antibody tests are available for influenza and require approximately 2 h. They will detect animal subtypes such as H5N1. Rapid bedside tests to detect influenza A have been used as screening tools for avian influenza in some settings. Throat swabs tested by reverse transcriptase–polymerase chain reaction (RT-PCR) have been the most sensitive for confirming H5N1 infection to date, but nasopharyngeal swabs, washes, and aspirates; bronchoalveolar lavage (BAL) fluid; lung and other tissues; and stool have yielded positive results by RT-PCR and viral culture with varying sensitivity. Convalescent-phase serum can be tested by microneutralization for antibodies to H5 antigen in a small number of international reference laboratories. Specimens from suspected cases of H5N1 infection should be sent to public health laboratories with appropriate biocontainment facilities; the case should be discussed with health department officials to arrange the transfer of specimens and to initiate an epidemiologic evaluation. Recommendations for such testing will evolve on the basis of the features of the pandemic, and guidance should be sought from the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) Web sites (http://www.cdc.gov and http://www.who.int).

Patients with confirmed or suspected H5N1 influenza should be treated with oseltamivir. Most H5N1 isolates since 2004 have been susceptible to the neuraminidase inhibitors oseltamivir and zanamivir and resistant to the adamantines (amantadine and rimantadine). Patients with suspected H5N1 infection should be treated with oseltamivir and antibacterial agents targeting S. pneumoniae and S. aureus, the most common causes of secondary bacterial pneumonia in patients with influenza. The current recommendation is for a 5-day course of treatment at the standard dosage of 75 mg two times daily. Treatment recommendations may vary considerably with changes in the pandemic situation. More specific guidance can be found on the Infectious Disease Society of America (IDSA), American Thoracic Society (ATS), CDC, and WHO Web sites. In addition, droplet precautions should be used for patients with suspected H5N1 influenza, and they should be placed in respiratory isolation until that etiology is ruled out. Health care personnel should wear N-95 (or higher) respirators during medical procedures that have a high likelihood of generating infectious respiratory aerosols.

Parainfluenza Virus

Four serotypes have been identified, with types 1, 2, and 3 being responsible for most infections in humans. Parainfluenza viruses are responsible for up to 20% of the respiratory infections that occur in children but are found infrequently in immunocompetent adults. The epidemiologic and clinical characteristics depend on the serotype and are summarized in Table 28-2 .

Table 28-2.

Epidemiologic and Clinical Characteristics of Parainfluenza Infection Depending on the Serotype

	Serotypes
	1 and 2	3
Epidemiology	Epidemics during the fall	Endemic with increases during fall, winter, or spring
Clinical features	Croup (laryngotracheobronchitis); less severe with type 2	Bronchiolitis Pneumonia

As with influenza, parainfluenza viruses are transmitted between humans by respiratory secretions. The incubation period lasts 2–6 days, and humoral, local, and cellular immunities generate neutralizing circulating antibodies, local secretory IgA, and cytotoxic and helper T lymphocytes, respectively.

In adults, the disease may be completely asymptomatic or may present as a common upper respiratory tract infection with rhinitis and pharyngitis. Fever is unusual, as is the progression to pneumonia. When pneumonia does occur, the symptoms and signs are nonspecific, and the chest radiograph shows diffuse, interstitial infiltrates consistent with any type of atypical or viral pneumonia.

Although treatment with ribavirin (tribavirin) has some in vitro activity, it is only supportive. Corticosteroids have been reported anecdotally to accelerate recovery in patients who have severe involvement. No vaccine is yet available.

Respiratory Syncytial Virus

The leading cause of respiratory tract infection in young children, respiratory syncytial virus (RSV) is responsible for 25% of hospital admissions for pneumonia and 75% of bronchiolitis in children younger than 6 months old. The incubation period lasts 4–6 days; epidemics occur in the late fall and spring and usually last 1–5 months. Almost all children older than 5 years have anti-RSV antibodies.

Transmittal of RSV is by contaminated skin followed by autoinoculation in the conjunctiva or nose or by aerosols produced by coughing or sneezing.

Immunity involves mainly local and serum antibodies, but cell-mediated immunity also develops. Infection by RSV induces IgE production, the magnitude of which predicts the risk of subsequent wheezing episodes.

Usually, RSV infection begins in the upper respiratory tract with nasal congestion and pharyngitis and is associated with fever of variable intensity. The lower respiratory tract rapidly becomes involved in 25–40% of cases, which leads to worsening cough, dyspnea, wheezing, and rhonchi. Hypoxemia is common. Two types of lower respiratory tract involvement occur—pneumonia and bronchiolitis. Both are associated with interstitial infiltrates, the former from lung inflammation and the latter from peripheral atelectasis or hyperinflation. In older adults who have chronic cardiopulmonary disease, RSV may cause severe bronchitis, pneumonia, or both.

Serologic diagnosis can be made, but the tests may be less reliable in children younger than 4 months. Direct diagnosis requires cultures from respiratory secretions, nasopharyngeal washings, or throat swabs; virus detection is possible after 2–7 days. Immunofluorescence techniques are frequently used, and they allow a reliable and more rapid detection in nasal scrapings or washings. The ELISA assay is less sensitive.

Treatment with aerosolized ribavirin improves the clinical course and should be administered for 12–18 hours/day for 2–5 days to patients who have severe disease. Systemic corticosteroids are also given to those who suffer the most severe involvement.

Because RSV may spread among hospitalized children and hospital staff, prevention of nosocomial infection is recommended (Box 28-1 ). No vaccine is available.

Box 28-1. Preventive Measures Against Nosocomial Respiratory Syncytial Virus Infections.

• Isolation or cohorting of hospital-admitted infected infants in specific areas

• Surface decontamination of objects and furniture

• Isolation measures

• Handwashing

• Use of gowns, gloves, and eye–nose goggles

Adenovirus

Adenoviruses are responsible for up to 5% of respiratory infections in children but account for less than 2% of those in adults; an exception is military recruit populations, in which epidemics have been reported. Almost all adults have serum antibodies against adenoviruses (usually against several serotypes).

Adenovirus respiratory infection may be the consequence of airborne or of fecal-oral contamination. The incubation period lasts 4–7 days. Latent infection may develop and has even been implicated in the pathogenesis of chronic airway diseases such as asthma or chronic obstructive pulmonary disease. In children and military recruits, adenoviruses can cause bronchiolitis and pneumonia of variable severity.

Rapid diagnosis requires antigen detection or histopathologic examination of biopsy specimens (which show intranuclear basophilic inclusions). Virus isolation requires 3 days to several weeks, and serodiagnosis requires both acute and convalescent sera.

Treatment is supportive (e.g., analgesics, cough suppressants). Effective, enteric-coated live vaccines have been developed for military recruits, but they are not used in other settings.

Rubeola (Measles)

Measles virus belongs to the Paramyxoviridae family and is, therefore, similar to parainfluenza virus and RSV. Portals of entry are the respiratory tract and conjunctiva. Lower respiratory tract manifestations affect up to 50% of patients who have measles and include mainly bronchitis and pneumonia (which may be complicated by bacterial superinfection in up to 50% of cases). In the United States, pneumonia is the cause of 60% of measles-related deaths in children.

Patients who have measles show a typical viral prodrome that consists of fever, rhinitis, malaise, and anorexia and lasts for approximately 1 week before the onset of the rash. The maculopapular rash begins on the face and neck and progresses to the trunk and extremities. Leukopenia is seen early. Measles pneumonia can cause hilar lymphadenopathy and pleural effusions, in addition to reticulonodular parenchymal infiltrates. Secondary bacterial pneumonia also occurs.

Treatment is supportive, and antibiotics are required when bacterial secondary infection occurs. No consistent data are available on the effects of corticosteroids.

The measles vaccine has reduced the incidence of disease by 98% in developed countries and has shifted the median age of onset to the teenage years.

Varicella

Varicella causes pneumonia in adults, but this complication is unusual in immunocompetent children. Epidemics occur in the winter and spring, with infectivity rates that exceed 90% within the first 2–3 weeks after exposure.

Initially, a rash appears on the face and head, with subsequent spread to the thorax, abdomen, and extremities. The rash has a rather orderly progression, beginning with erythematous macules that progress to vesicles within hours to days. These subsequently become pustular and finally crust over. Lesions may also be found on mucosal surfaces (e.g., pharynx, vagina). When pneumonia occurs, it generally presents within the first 4–5 days after the onset of the rash. Cough is common, and pleuritic chest pain and hemoptysis may occur. Other organs such as the liver, kidney, heart, and brain may also be involved. Diffuse, small nodular infiltrates are the characteristic radiographic abnormality, and hilar adenopathy and effusions are common. With resolution, the nodules may calcify and persist for life (Figure 28-1 ).

Figure 28-1.

Calcific varicella nodules. Radiograph shows multiple 3- to 5-mm calcified nodules in the upper and lower lobes of a patient who had varicella pneumonia as a child.

Varicella infections can be diagnosed by a cytologic examination of scrapings from the lesions (e.g., the Tzanck smear, seeking multinucleated giant cells), although the sensitivity of this test is low. The virus may be cultured or found by polymerase chain reaction. A number of serologic tests are available, including the fluorescent antibody to membrane antigen test and ELISA.

Treatment with early administration of acyclovir (10–12.5 mg/kg intravenously every 8 h for 7 days) is recommended for immunocompromised hosts who have varicella and for immunocompetent patients who suffer pneumonia. Preventive administration of oral acyclovir in adults who have varicella may be prudent, especially in elderly subjects, pregnant women, or patients with chronic obstructive pulmonary disease. Zoster immune globulin is recommended to reduce the severity of illness in immunocompromised patients exposed to varicella.

The infection can spread readily in the hospital setting, so strict isolation must be instituted until all lesions have crusted over.

Hantavirus

The hantavirus pulmonary syndrome was first recognized in the United States in 1983, but the disease was retrospectively identified by use of serologic testing in patients who had a similar illness in 1959. The syndrome can result from several hantaviruses, such as Sin Nombre virus. Almost all cases have been reported in North and South America. Rodents (e.g., field mice, voles, chipmunks) serve as the reservoir, and transmission to humans results from aerosolization of viruses contained in their feces. Person-to-person spread rarely, if ever, occurs.

The initial presentation is that of a flulike syndrome of fever, myalgia, nausea, vomiting, and gastrointestinal pain suggestive of gastroenteritis. These are followed by a dry cough that portends diffuse noncardiogenic pulmonary edema (sometimes associated with bilateral pleural effusion), which may lead to ARDS and shock in severe cases. Hematologic examination usually demonstrates neutrophilic leukocytosis, hemoconcentration, thrombocytopenia, and circulating immunoblasts. Renal failure may occur but is uncommon.

The diagnosis can be made by serologic or immunohistochemical techniques.

Treatment is mainly supportive, but the results of controlled trials of intravenous ribavirin are pending. Although in vitro effects of ribavirin have been demonstrated, preliminary results from an open-label trial are not impressive.

Avoidance of areas in which infected rodents reside is the only recognized preventive measure.

Severe Acute Respiratory Syndrome (SARS)

An outbreak of SARS was recently reported, mainly in Asian countries and Canada. The origin of the epidemic was believed to be Guangdong province in China. None of the previously described respiratory pathogens was consistently identified, and a new coronavirus isolated from patients with SARS is thought to be the responsible pathogen.

The incubation period ranges from 2–11 days. The clinical presentation and radiologic features of SARS are those of atypical pneumonia.

No effective treatment is available, despite the use of antiviral therapy such as ribavirin or steroids in many cases.

SARS is a serious respiratory illness that can lead to significant morbidity, with 10–25% of patients requiring admission to an intensive care unit and a mortality rate of approximately 10%. Factors associated with a poor outcome are older than 60 years, significant comorbidities, diabetes mellitus, and initially elevated lactate dehydrogenase levels and elevated polymorphonuclear counts.

Because SARS is highly transmissible, it is recommended that patients be isolated in a single room (with negative pressure, if possible). Health care personnel should wear gloves, gown, mask, and eye protection and should wash their hands carefully after removing their gloves. The number of health care workers in contact with SARS patients should be limited. All suspected or confirmed cases should be reported to local health authorities and the World Health Organization.

Fungal Pneumonia

The most commonly encountered fungal and parasitic pulmonary infections are summarized in Table 28-3 . The differential diagnosis in any given patient depends on his or her immunologic status, geographic locale, and travel history. A number of the fungal pneumonias occur almost exclusively in North America (e.g., histoplasmosis, blastomycosis, coccidioidomycosis). Although fungal and parasitic pulmonary infections are frequently self-limited, recurrent or severe disease is common when cell-mediated immunity is impaired. Infections in immunocompromised patients are covered in Chapter 29. Although amphotericin B remains the most effective medication for most fungal infections, treatment is now facilitated by a number of new agents that are easier to administer and better tolerated. Therapeutic options are summarized in Table 28-4 .

Table 28-3.

Agents of Fungal and Parasitic Pneumonia, Classified According to the Immunologic Status of the Host

Type of Pathogen	Mainly in Normal Host	In Both Immunocompromised and Normal Host	Mainly in Immunocompromised Host
Fungi	Histoplasma capsulatum Blastomyces dermatitidis Coccidioides immitis Paracoccidioides braziliensis	Cryptococcus neoformans Aspergillus spp. Sporothrix schenckii Penicillium marneffei Geotrichum spp.	Zygomycetes Candida spp. Trichosporon spp. Fusarium spp. Penicillium spp. Hansenula spp. Mucor, Rhizopus, and Absidia genera (mucormycosis) Pseudoallescheria boydii Pneumocystis jiroveci
Parasites
Protozoa	Plasmodium spp. (malaria) Entamoeba histolytica (amebiasis)	—	Toxoplasma gondii Cryptosporidium spp. Babesia spp.
Nematodes	Ascaris spp. Hookworm Toxocara canis (visceral larva migrans) Dirofilaria immitis Wuchereria bancrofti, Brugia malayi (tropical eosinophilia)	Strongyloides stercoralis	—
Platyhelminths	Paragonimus spp. Schistosoma spp. Echinococcus spp.	—	—

Table 28-4.

Therapeutic Options in Fungal Pneumonias of the Nonimmunocompromised Host

Disease		First-Line Treatment	Alternatives
Allergic bronchopulmonary aspergillosis		Corticosteroids plus itraconazole	—
Aspergilloma		Surgical resection	Embolization Itraconazole Intracavitary instillation of amphotericin B
Histoplasmosis	Acute Chronic Disseminated	No treatment Itraconazole —	Itraconazole Ketoconazole Amphotericin B Amphotericin B
Blastomycosis	Acute Chronic	Itraconazole Itraconazole	— Amphotericin B
Coccidioidomycosis	Acute Chronic	Itraconazole Itraconazole	Ketoconazole Ketoconazole Amphotericin B
Paracoccidioidomycosis	Mild Chronic	Itraconazole Amphotericin B ± sulfadiazine	Itraconazole
Cryptococcosis		Fluconazole	Itraconazole Amphotericin B

Aspergillosis

Aspergillus species are ubiquitous saprophytic fungi that produce several toxic substances (e.g., endotoxin, proteases). Airway colonization by Aspergillus is usually seen in patients with chronic lung lesions, such as bronchiectatic cavities, pulmonary fibrosis, or tuberculosis sequelae, and local host defense impairment. Invasive aspergillosis is an unusual finding in nonneutropenic patients but has been described in patients with chronic obstructive pulmonary disease on long-term steroid therapy.

In nonimmunocompromised patients, Aspergillus species cause hypersensitivity pneumonitis (generally from Aspergillus fumigatus) and Löffler's syndrome (discussed in Chapters 45 and 52Chapter 45Chapter 52, respectively), allergic bronchopulmonary aspergillosis (covered in Chapter 45), and aspergillomas. Chronic necrotizing pneumonia has been described in nonneutropenic patients with preexisting lung disease or on chronic steroid therapy.

Amphotericin B is the most effective medication for most fungal infections. Treatment is now facilitated, however, by a number of new agents that are easier to administer and better tolerated, such as itraconazole, voriconazole, and caspofungin.

Histoplasmosis

Histoplasma capsulatum is frequently isolated from soil that has been contaminated by bird or bat feces, which provide the organic nitrogen necessary for its growth. The disease occurs in the central United States (where the estimated prevalence and incidence of infection are 50/10⁶ and 500/10³, respectively), Mexico, and Puerto Rico. The disease was initially seen only in rural communities but is now found in patients who reside in urban settings as well, particularly in association with construction projects that involve moving contaminated soil. Numerous occupations have an increased risk of exposure.

The inhaled spores are contained in infective particles 2–5 μm in diameter, an ideal size to reach the airways and alveoli. After inhalation, multiplication converts the spores into yeasts, which are phagocytosed by macrophages in which they are able to survive, proliferate, and disseminate to metastatic sites such as the liver and spleen. A lymphocyte-mediated, delayed-type hypersensitivity reaction occurs and results in the formation of granulomas that resemble those found in mycobacterial diseases; the necrotic material may become caseous and calcify. The granulomas may be found in the lung, as well as in a number of sites of metastatic infection. Patients affected by compromised cellular immunity (such as those who have AIDS or lymphoma) are more susceptible to histoplasmosis and may develop more severe disease.

Most patients who have acute primary infections are undiagnosed because histoplasmosis remains subclinical. Those who inhale larger numbers of spores (frequently as a result of exposure in a closed space) have a syndrome develop approximately 14 days later that has an abrupt onset and resembles influenza, bacterial pneumonia, or tuberculosis (Table 28-5 ). When the inoculum is particularly large, patients may have ARDS develop.

Table 28-5.

Clinical Presentations of Acute Histoplasmosis

	Mild Acute Pneumonitis	Pneumonic Histoplasmosis	Progressive Disseminating Primary Infection
Symptoms and physical signs	None or acute, influenza-like symptoms Arthralgia–erythema nodosum–erythema multiforme complex	Fever, chills, sweat, anorexia, weakness, cough with mucopurulent sputum, pleuritic chest pain Sometimes consolidation, rarely pleural effusion	Severe acute illness, often in immunocompromised patients Weight loss, low-grade fever, abdominal complaints, cough Sometimes mucosal ulcers, adrenal involvement
Chest radiography	Normal or consolidation 6 lymph node enlargement	Infiltrates of varying density, often with hilar lymph node enlargement, sometimes with pericarditis	Normal, or multiple nodules, linear opacities 6 lymph node involvement, or miliary aspect
Blood examination	—	—	In severe disease, leukopenia, thrombocytopenia, disseminated intravascular coagulation
Diagnosis	—	—	Few granulomas and many organisms in the most severe disease, the opposite in less severe forms
Clinical course	Spontaneous resolution; residual calcified nodules and lymph nodes	—	—

The growth of Histoplasma species is slow, such that several weeks are needed for cultures to become positive. Giemsa staining of blood or bone marrow smears may be diagnostic when the fungus load is high, but this is unusual in immunocompetent patients. Tissue samples can demonstrate the organisms with silver or periodic acid–Schiff (PAS) staining. Indirect diagnosis may be provided by several serologic techniques, including complement fixation, immunodiffusion, or radioimmunoassay, all of which may require several weeks to become positive.

Treatment is needed only for patients who have chronic, progressive histoplasmosis or for those who have dissemination. The use of amphotericin B is limited by the need for intravenous administration and the frequent development of renal toxicity, febrile reactions, and phlebitis. Renal toxicity may be reduced by the coadministration of large volumes of intravenous fluids. Side effects may also be reduced by use of the newly developed, but considerably more expensive, liposomal form of amphotericin. Ketoconazole has frequent gastrointestinal and antitestosterone effects. Fluconazole and itraconazole (200–400 mg/day) are as effective as amphotericin or ketoconazole in patients who have mild illness. Thus, amphotericin B should be reserved for patients who have more severe or disseminated disease.

Most acute primary infections are self-limited, require no treatment, and do not come to medical attention. Recurrent infiltrates may occur in some patients in association with eosinophilia, mimicking Löffler's syndrome. Evidence of calcified granulomas may be present in the lung (Figure 28-2 ) and the spleen. On occasion, marked hilar lymphadenopathy or focal or diffuse mediastinal fibrosis may compress the central structures (e.g., airways, arteries, veins, esophagus).

Figure 28-2.

Calcified granulomas in the lung of a patient who has histoplasmosis.

Chronic, progressive disease occurs rarely, with symptoms of cough, hemoptysis, dyspnea, and fever. Chest radiographs usually show upper lobe or peripheral areas of consolidation, which evolve into cavities that mimic healed tuberculosis. Empyemas may occur, as may broncholithiasis, which has been associated with hemoptysis and bronchial obstruction. Chronic infection of the meninges, brain, or heart may occur rarely.

Blastomycosis

Blastomycosis is found in North America (in areas largely overlapping those where histoplasmosis occurs), Mexico, the Middle East, Africa, and India and results from inhalation of Blastomyces dermatitidis. The fungus grows in the soil, and the spores become airborne and are inhaled before converting to the yeast form in the lung. B. dermatitidis infection may occur sporadically or in epidemics. The initial defense mechanism involves polymorphonuclear cells, followed by macrophages and giant cells; epithelioid granulomas often develop. Depending on the type of predominant inflammatory response (pyogenic or granulomatous), the histopathologic pattern can mimic that of a bacterial infection, sarcoidosis, or mycobacterial disease. After multiplication of the yeast in the lungs, it may spread to the skin, bones, brain, peripheral lymph nodes, or other organs, and extrapulmonary manifestations may occur many years after the initial infection.

The clinical manifestations of blastomycosis differ from one country to another. In North America, acute epidemic blastomycosis mimics bacterial pneumonia, with the abrupt onset of fever, chills, arthralgia and myalgia, cough with purulent sputum, and pleuritic chest pain. In milder cases, which are more frequent, the presentation is that of a more chronic disease, resembling tuberculosis; low-grade fever, cough, anorexia, and weight loss develop insidiously. Physical examination sometimes demonstrates erythema nodosum or findings of pulmonary consolidation, but it may be normal. The radiographic manifestations are nonspecific and include cavities, infiltrates, rounded densities, consolidation with air bronchograms, perihilar masses, or even a miliary pattern.

Mediastinal lymph node involvement is rare (<10% in most studies), and pleural effusions are quite uncommon. In the most severe cases, infection with B. dermatitidis can cause ARDS, even in immunocompetent hosts. Patients who have cutaneous blastomycosis frequently have a history of a self-limited pulmonary syndrome that occurred some years in the past.

The diagnosis of blastomycosis is made by microscopic examination of respiratory secretions digested by potassium hydroxide or by histopathologic examination of tissue samples after silver or PAS staining. In culture of respiratory samples, detectable growth takes up to 1 week.

Because blastomycosis is often self-limited, treatment is restricted to those who have chronic disease and those who have severe acute infections. Itraconazole has the best ratio of efficacy to side effects, but amphotericin B is preferred in the most severe cases. Ketoconazole is an alternative in slowly progressive disease.

Coccidioidomycosis

Coccidioidomycosis results from another soil-dwelling fungus, Coccidioides immitis. It is endemic in the southwestern United States and northern Mexico and occurs mainly during hot, dry summers. Inhalation of airborne spores leads to polymorphonuclear-mediated suppurative and cell-mediated granulomatous inflammatory responses. The incubation period is 10–16 days.

Patients who have coccidioidomycosis may complain of fever, chills, arthralgia, myalgia, and headache in addition to cough, pleuritic chest pain, dyspnea, and, on occasion, hemoptysis (which results from areas of lung necrosis manifested by cavitation). Physical examination may reveal a macular rash, erythema nodosum, or erythema multiforme, as well as rhonchi, wheezes, or signs of consolidation or pleural effusion. In many patients, the physical examination is normal. Chest radiographs initially show one or more areas of consolidation, which may cavitate. Hilar lymphadenopathy may be found. Cavities or multiple calcified nodules may persist for life. Occasionally, patients have progressive primary coccidioidomycosis develop, a condition in which the infiltrates and lymphadenopathy progress in association with fever, cough, and weight loss. Several months after the primary pulmonary infection, disseminated coccidioidomycosis may become manifest (affecting skin, bones, joints, genitourinary system, meninges), particularly but not exclusively in immunocompromised patients.

The diagnosis of coccidioidomycosis may be made by serologic or skin testing, both of which are most useful for epidemiologic purposes. Direct diagnosis can be made by microscopic examination of sputum or pus after potassium hydroxide digestion or Papanicolaou staining, by histopathologic examination of tissue biopsies after silver staining, or by cultures, which may demonstrate fungal growth after 5 days but pose an inhalation risk for laboratory personnel.

The treatment of coccidioidomycosis is similar to that of histoplasmosis and blastomycosis and relies on fluconazole and itraconazole, with amphotericin B and ketoconazole as alternatives. For most patients, no specific therapy is required.

Coccidioidomycosis is usually mild and self-limited, except in rare cases when it progresses or spreads hematogenously. Dissemination, which may be more common in dark-skinned races and in those who are immunocompromised, is associated with a high risk of meningitis and has a poor prognosis.

Paracoccidioidomycosis

Paracoccidioidomycosis results from inhalation of a soil fungus that is found mainly in South and Central America and in Mexico. In nonimmunocompromised patients, paracoccidioidomycosis presents as a chronic or subacute lung infection that is usually self-limited. In immunocompromised subjects, the clinical manifestations are those of an acute, severe disseminated infection.

The diagnosis of paracoccidioidomycosis relies on the same techniques used for coccidioidomycosis.

In severe or disseminated cases of paracoccidioidomycosis, treatment is similar to that of coccidioidomycosis but should be continued for up to 6 months.

Cryptococcosis

Cryptococcus neoformans is found throughout the world in bird guano. Cryptococcosis is a rare infection and is usually asymptomatic and self-limited in immunocompetent patients. In those who have impaired cell-mediated immunity, it may cause lung infection and meningitis. Symptoms of pulmonary infection include fever, malaise, cough, and chest pain. The chest radiograph may show large, nonspecific nodules (Figure 28-3 ) or infiltrates, sometimes associated with lymphadenopathy.

Figure 28-3.

Cryptococcal lung infection. Chest radiographs (A, posteroanterior and, B, lateral view) of an immunocompetent patient show bilateral, large nodular densities.

C. neoformans can colonize the airways of immunocompromised patients and those who have chronic bronchitis without causing illness. Accordingly, culture of fungus from sputum does not always indicate disease.

Because cryptococcosis resolves spontaneously in normal hosts, and because patients who have chronic mucopurulent pulmonary conditions may be colonized by Cryptococcus species, positive cultures do not, in and of themselves, denote a specific indication for treatment. For patients who have progressive disease, amphotericin B or ketoconazole, fluconazole, or itraconazole is recommended.

Parasitic Pneumonia

Pulmonary infections that result from parasites are infrequent in immunocompetent hosts but must be included in the differential diagnosis when patients have lived in endemic areas.

Amebiasis

Entamoeba histolytica is endemic in West and South Africa, South and Southeast Asia, South America, and Mexico. The disease is transmitted by ingestion of contaminated food or water, and sexual transmission has been reported in homosexual men.

The parasite disseminates from the intestine to the liver or, much less frequently, to the lung (in <5% of those with intestinal infection) or brain. Pleuropulmonary complications occur in up to 50% of patients who have liver abscesses as a result of either direct spread from the liver or hematogenous dissemination.

The main features of the disease are intestinal, ranging from diarrhea and abdominal cramps to dysentery or even intestinal perforation because of mucosal ulcerations. Pleuropulmonary symptoms include cough, dyspnea, and pleuritic pain (usually right-sided) associated with fever and chills, diaphoresis, and weight loss. The chest radiograph may show elevation of the right hemidiaphragm, pleural effusion, atelectasis, lung consolidation (which usually affects the right lower lobe), or lung abscess. Hepatobronchial fistulas have been reported in 47% of patients who have pleuropulmonary complications of amebiasis; this finding is associated with the production of copious volumes of chocolate-colored sputum. Pericardial involvement may be observed in up to 10% of such patients.

The diagnosis can be made by microscopic examination of stool, which has a sensitivity of less than 30%, or by serologic techniques, which have sensitivities and specificities as high as 95% in invasive disease. Antigen may be detected on pleural fluid or respiratory secretions. Needle aspiration of lung or of liver abscesses is seldom necessary.

The drug of choice for treating invasive amebiasis is metronidazole (750 mg every 8 h for 10 days), in addition to agents that are active against intraluminal protozoa such as iodoquinol, diloxanide, or paromomycin.

Malarial Lung

Pleuropulmonary complications result from Plasmodium falciparum, the agent of the most severe form of malaria. Mild respiratory involvement is probably underdiagnosed and may affect up to 20% of patients who have falciparum malaria. Pulmonary involvement is commonly associated with cerebral disease and marked parasitemia. Histopathologic features include capillary congestion, pulmonary edema, alveolar hemorrhage, and endothelial cell injury.

The pulmonary manifestations of malaria include mild cough associated with pleural effusion, lung consolidation, or interstitial infiltrates. Severe respiratory involvement can occur as a result of lung edema and pleural effusions, and patients may present with ARDS.

The diagnosis is made by examination of thin or thick blood smears stained with Giemsa or Wright stain.

Besides supportive and respiratory care, treatment of severe disease requires intravenous quinidine and exchange transfusion in the most severe cases. Depending on the region of origin, drug-resistant strains must be considered, and alternative treatments offered. Despite these measures, prognosis for the malarial lung remains poor.

Pulmonary Ascariasis

The estimated worldwide prevalence of infection with the nematode Ascaris lumbricoides is 25%. The normal habitat of the adult worm is the jejunum, and infection follows ingestion of embryonated eggs. Maturation occurs during pulmonary migration and may be responsible for ascaris pneumonia, a self-limited disease that occurs 4–16 days after ingestion and lasts for 10 days to several weeks.

Ascariasis is responsible for a Löffler-like syndrome in approximately 20% of cases. Symptoms are dominated by cough (sometimes with hemoptysis), wheezing, dyspnea, and high-grade fever. Abdominal pain, nausea and vomiting, and hepatomegaly may be present, as well as a variety of cutaneous reactions (e.g., urticaria, angioedema). The chest radiograph shows unilateral or bilateral patchy, migratory peribronchial infiltrates; eosinophilia may be present, and (on occasion) IgE elevation may be found.

Sputum analysis reveals eosinophils and Charcot–Leyden crystals. Stool examination may be negative at this early stage of ascariasis.

The pneumonia does not require any specific treatment, because it is usually self-limited. Bronchodilators and corticosteroids may be useful when bronchospasm is present. Antihelminthic therapy is necessary to eradicate intestinal adult worms (Table 28-6 ).

Table 28-6.

First-Choice Antihelminthic Drugs Active Against Ascaris lumbricoides and Hookworms

Drug	Dose and Duration	Common Side Effects
Pyrantel pamoate	11 mg/kg, single dose	Anorexia, nausea, abdominal pain, diarrhea
Mebendazole	100 mg q12h for 3 days	Abdominal pain, diarrhea
Albendazole	400 mg, single dose	Abdominal discomfort, diarrhea

Strongyloidiasis and Ancylostomiasis

Although Strongyloides stercoralis is endemic in tropical and subtropical areas, strongyloidiasis is less frequent than ascariasis and ancylostomiasis. The life cycle of the parasite is the same as that of ascaris and hookworm. Ancylostomiasis, or hookworm infection, may be caused by two nematodes: Ancylostoma duodenale and Necator americanus. The prevalence and life cycles are similar to those of Ascaris lumbricoides and Strongyloides stercoralis.

Patients may be asymptomatic or experience a Löffler-like syndrome after transient urticaria in association with abdominal symptoms. In some cases, massive invasion (which is favored by abnormal cell-mediated immunity and malnutrition-related immunosuppression) leads to a much more severe disease, termed the hyperinfection syndrome, which develops from disseminated disease (Table 28-7 ).

Table 28-7.

Clinical Presentation of the Hyperinfection Syndrome or Disseminated Strongyloidiasis

Manifestation	Presentation
Abdominal	Anorexia, nausea, vomiting, diarrhea, abdominal pain ileus
Pulmonary	Cough, hemoptysis, wheezing, dyspnea Adult respiratory distress syndrome Bacterial superinfection
Other	Invasion of liver, skin, central nervous system Bacterial meningitidis Sepsis caused by secondary bacterial infection (usually gram-negative bacilli)

The diagnosis can be made by sputum or stool examination or by duodenal or pleural aspiration. Serologic techniques may be of help in chronic cases.

The preferred treatment is thiabendazole 25 mg/kg every 12 h for 2 days (longer in disseminated disease), which may have to be repeated. Alternative agents are ivermectin and albendazole.

Visceral Larva Migrans

Human visceral larva migrans is caused by Toxocara canis or, less frequently, Toxocara catis. All canine species are hosts of the nematode, and the prevalence of the infection in dogs has been estimated at approximately 3%. Contamination of humans occurs after ingestion of eggs in contaminated food or soil. Larvae migrate to the liver and lungs through lymphatics and blood vessels and induce an IgE-mediated immune response. In rare cases, other organs may be involved, such as the heart or the central nervous system. Cells that infiltrate invaded tissues are mainly eosinophils and, to a lesser extent, lymphocytes.

Clinically apparent pulmonary involvement is common (20–85% of cases) and manifests as cough, wheezing, bronchiolitis, or pneumonia that may result in acute respiratory failure. Radiographic manifestations are usually mild migratory infiltrates, which are found in 50% of those who have respiratory symptoms. Systemic symptoms include weakness, malaise, anorexia, nausea, vomiting, weight loss, abdominal pain, or behavioral impairment. Overall, the severity of the clinical illness reflects the extent of the infestation.

Because Toxocara larvae do not mature in humans, the diagnosis can be made only by serologic or histologic examination of invaded tissues.

In mild cases, the disease is self-limited, so no treatment is required. In more severely affected patients, corticosteroids seem to improve the prognosis. Preventive measures are important to limit the spread of the disease (Table 28-8 ).

Table 28-8.

Preventive Measures to Limit Visceral Larva Migrans in Humans

Behavioral Measures	Veterinary Measures	Environmental Measures
Avoid geophagia Limit close contact between children and canine species	Deworming of cats and dogs	Keep children's sandbox dry

Dirofilariasis

Human dirofilariasis is the consequence of infestation by the nematode Dirofilaria immitis, which is a dog parasite transmitted by mosquitoes. In rare cases, larvae injected by mosquitoes into humans are transported by blood vessels to the pulmonary circulation, where they can cause thrombosis.

Clinical signs of cough, hemoptysis, chest pain, and fever are present in half of affected patients. Chest radiographs may show peripheral nodules of 1–5 cm in diameter, which may calcify. A minority of patients exhibit peripheral eosinophilia.

The diagnosis can be made by serology or histologic examination of lung tissues. No treatment is required.

Tropical Pulmonary Eosinophilia

Tropical pulmonary eosinophilia results from infection with Wuchereria bancrofti or Brugia malayi, which are lymphatic-dwelling filariae found in tropical and subtropical areas. Pulmonary manifestations are the consequence of a hypersensitivity reaction after the discharge of microfilariae into the circulation by gravid female filariae. Transmission is by mosquitoes that ingest the microfilariae and inject larvae when they bite humans. Of the patients who have tropical eosinophilia, 80% are men, and the lungs are involved in more than 90% of cases.

Clinical manifestations include fever, weakness, anorexia, weight loss, cough, wheezing, and dyspnea. Chest radiographs usually show bilateral basal, interstitial infiltrates, and increased bronchovascular markings. Lymph node involvement and consolidation are infrequent.

The parasites may be found on histologic examination of affected organs, but the diagnosis is generally made by finding high levels of IgE and high titers of antibodies to filariae and by clinical improvement after treatment.

Standard treatment is diethylcarbamazine, 6–12 mg/kg body weight for up to 3 weeks. Alternatives are mebendazole and levamisole. New agents such as ivermectin are being evaluated. Corticosteroids or antihistamines may be used when patients exhibit allergic reactions to dying filariae. Some patients (10–20%) require repeated courses of treatment because the adult parasites may be relatively resistant. Response to treatment is inversely related to the duration of symptoms.

Paragonimiasis

Paragonimus species (most frequently Paragonimus westermani) are hermaphroditic flukes that are endemic in Southeast Asia, South America, and South Africa and are transmitted to humans by ingestion of insufficiently cooked crabs or crayfish that contain the encysted parasite. These go to the lung through the intestinal wall, peritoneal cavity, diaphragm, and pleura.

The illness may occur during the first weeks of infection, during the parasite's migration from the intestine to the lung. When this occurs, symptoms may include abdominal pain, diarrhea, hypersensitivity reactions (urticaria, eosinophilia, fever), chest pain, cough, and hemoptysis. In most cases, however, no symptoms appear until the adult parasite begins to produce eggs in the lung, which induces cough and hemoptysis. Chest radiographs usually show patchy infiltrates, which may progress to cavities surrounded by a rim of infiltration (ring cysts). Areas of fibrosis or pleural thickening are common. Pleural effusions are infrequent, except in some series of South Asian patients. The chest radiograph may be normal in up to 20% of cases.

The diagnosis is based on demonstrating eggs in bronchial secretions, pleural fluid, or feces. A number of serologic tests are also available.

The preferred treatment is praziquantel (25 mg/kg every 8 h for 3 days), which is effective in more than 90% of cases. Bithionol (40 mg/kg every other day for 2 weeks) is a less effective alternative.

Schistosomiasis

Several Schistosoma species may be pathogenic for humans. The most frequently encountered are described in Table 28-9 . The parasite forms released by snails (in which asexual reproduction occurs) penetrate the skin and transform into immature parasites, which are transported in the blood, where they mature in venous plexuses (see Table 28-9) and reproduce. Eggs are deposited in the intestine or bladder, depending on the site of the infected venous plexus. The eggs, in turn, induce overwhelming granulomatous reactions; they may migrate to the liver and cause portal hypertension, with subsequent migration to the lung through portosystemic collaterals.

Table 28-9.

Pathogenic Schistosoma Species

Species	Area	Predominant Venous Plexuses in Which Mature Parasites Develop	Treatment: Doses of Praziquantel
Schistosoma mansoni	Arabia, South America, Caribbean	Inferior mesenteric veins	20 mg/kg body weight × 2, for 1 day
Schist. japonicum	China, Japan, Philippines	Superior mesenteric plexus	20 mg/kg body weight × 3, for 1 day
Schist. haematobium	Africa, Middle East	Vesical plexus	20 mg/kg body weight × 2, for 1 day

As shown in Table 28-10 , symptoms depend on the stage of the disease. The most frequent pulmonary manifestation is pulmonary hypertension, which occurs in the chronic stages of infection with Schistosoma mansoni or Schistosoma japonicum. Nodular lesions can also develop, and this infestation should be included in the differential diagnosis of pulmonary nodules (Figure 28-4 ).

Table 28-10.

Clinical Presentations of Schistosomiasis

Stage of Disease	Involved Species	Clinical Signs
Skin penetration	All	Transient cutaneous symptoms (“swimming itch”)
Tissue migration (immature parasite)	Mainly Schistosoma japonicum	Katayama fever: fever, chills, headache, myalgia, arthralgia, abdominal pain, diarrhea, weight loss, cough, wheezing, pulmonary infiltrates (sometimes with a miliary aspect), hepatosplenomegaly, lymphadenopathy, leukocytosis, eosinophilia, immune complexes
Chronic infection (mature reproducing parasites)	Schistosoma mansoni and S. japonicum	Abdominal pain, diarrhea, fatigue, portal hypertension, hepatic failure (presinusoidal hepatic fibrosis) Pulmonary hypertension Hypoxemia without pulmonary hypertension (intrapulmonary arteriovenous fistulas) Lung granulomas
	Schistosoma haematobium	Chronic bladder disease
Response to treatment	—	Transient and self-limited cough, wheezing, lung infiltrates, eosinophilia

Figure 28-4.

Multiple pulmonary nodules on the chest radiograph of a patient with schistosomiasis.

The direct diagnosis may be based on examination of the stool (Kato thick smear), urine, or rectal biopsies. Several serologic techniques have been developed.

The most effective treatment is praziquantel. Doses depend on the Schistosoma species (see Table 28-9).

Hydatidosis

Cystic hydatid disease (CHD) is caused by larvae of Echinococcus granulosus, and alveolar hydatid disease (AHD) is caused by Echinococcus multilocularis. Both are platyhelminths that infect humans through the ingestion of eggs. The parasite is transported by the blood or lymphatics to other sites, mainly the liver and lungs. Whereas CHD is the manifestation of the growth of larvae, which form spherical cysts, AHD results from persistent invasion by and destructive proliferation of the parasite. Of human hydatidosis cases, 90% of patients have CHD (with respiratory involvement in 25% of these), and 9% have AHD.

In CHD, symptoms occur in approximately 70% of cases and are related to compression of adjacent structures or to complications such as rupture or secondary infection. Accordingly, symptoms include chest pain, cough, expectoration of cyst contents (e.g., grape skins), dyspnea, hemoptysis, or even near drowning in cyst fluid. Rupture may also lead to dissemination of cysts within the lungs, hypersensitivity reactions, or pleural effusion. In rare instances (<10%), hydatid cysts may develop in the pleural space itself after the rupture of a pulmonary cyst. Chest radiographs typically show rounded opacities (called cannonballs), the borders of which can calcify. Sharply demarcated cysts, which may contain smaller daughter cysts, are shown by computed tomography scans. This finding allows CHD to be differentiated from AHD; in the latter, computed tomography shows less well-demarcated masses that have necrotic centers. Eosinophilia is frequent.

The diagnosis relies on the demonstration of associated hepatic cysts, serologic tests, and, in some cases, the presence of cyst material in sputum. Aspiration of the cyst should be avoided to limit the possibility of dissemination and hypersensitivity reactions.

The treatment of choice is surgical resection of the cysts. When surgery cannot be done, or when the cysts rupture and the parasite disseminates, the preferred treatment is albendazole 400 mg every 12 h (10–15 mg/kg per day) for 4 weeks. Treatment courses may be repeated.

Lipoid Pneumonia

Lipoid pneumonia results from the aspiration of exogenous lipids contained in orally administered laxatives or nasal decongestants. The histology is that of giant-cell inflammation with oil-containing vacuoles and phagocytes, type II cell metaplasia, degeneration of arteriolar or bronchial walls, necrosis, and fibrosis. Oil droplets or lipophages may be transported by lymphatics or through the blood to the liver, spleen, kidney, or other organs. Special stains allow exogenous lipoid pneumonia to be distinguished from conditions that arise from the accumulation of endogenous lipids, as occasionally occurs in the setting of chronic primary lung inflammation (Table 28-11 ).

Table 28-11.

Histopathologic Differences Between Exogenous and Endogenous Lipoid Pneumonias

Characteristic	Exogenous Lipids	Endogenous Lipids
Fat	Large droplets	Small droplets
Foreign body granulomas	Present	Absent
Birefringence under polarized light	Absent	Present
Special stainings
Periodic acid–Schiff	Negative	Positive
Sudan black	Light blue	Black
Sudan IV	Orange	Red
Oil red O	Orange	Red
Nile blue sulfate	Negative	Light violet
Osmium tetroxide	Negative	Positive

Symptoms include cough, dyspnea, fever, chest pain, and hemoptysis. The onset may be acute, but more commonly it is chronic and is accompanied by weight loss. In 50% of cases, the disease is clinically silent and is discovered on a chest radiograph. A number of radiologic presentations may be found (Box 28-2 ; Figure 28-5 ). Computed tomography or magnetic resonance imaging scans may be useful when they demonstrate attenuation values of −30 to −150 Hounsfield units or high-intensity T1 signals with a slow decrease on T2-weighted images, respectively, as a result of the low density of fat. Sputum, bronchoalveolar lavage fluid, or transbronchial biopsies can be examined for fat-containing macrophages after the application of special stains.

Box 28-2. Findings in Exogenous Lipoid Pneumonia on Chest Radiography.

• Dense consolidation with air bronchograms

• Ground glass infiltrates

• Cavitation

• Interstitial infiltrate

• Fibrotic infiltrates

• Nodules, masses

• Atelectasis

• Emphysema

• Pleural effusion

Figure 28-5.

Lipoid pneumonia. This series of radiographs demonstrates infiltration of the left lower lobe that progressed slowly over 19 years—from 1974 (A) to 1993 (D). The patient liberally applied a petrolatum-containing nasal grease each night before bed, and her husband documented that the patient routinely slept on her left side. The computed tomography scan shows low-density consolidation of the left lower lobe and a small left pleural effusion.

The most important intervention is to stop the administration of the causative agent. Corticosteroids do not seem to be beneficial.

Exogenous lipoid pneumonia usually follows a benign course. The most frequently encountered complications are bacterial, fungal, or mycobacterial superinfections. Respiratory insufficiency occurs infrequently, unless the condition is far advanced (e.g., years of chronic aspiration), and neoplasm is uncommon. The use of oil-containing laxatives and decongestants should be discouraged.