0025-7125/01 $15.00 RESPIRATORY INFECTIONS + .OO NONRESOLVING PNEUMONIA AND MIMICS OF PNEUMONIA Lauren Rome, MD, Ganesan Murali, MD, and Michael Li...

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NONRESOLVING PNEUMONIA AND MIMICS OF PNEUMONIA Lauren Rome, MD, Ganesan Murali, MD, and Michael Lippmann, MD

Pneumonia is the sixth leading cause of death and tends to be more prevalent and severe in the elderly.17,28It is estimated that there are more than 3 million episodes of pneumonia in the United States per year, with more than half of patients being treated as outpatients, resulting in annual costs of $23 billion. The death rate has remained constant at about 30 per 100,000 episodes.2s Using conventional culture techniques, the cause of communityacquired pneumonia (CAP) is determined in only approximately 50% of cases." A more recent prospective study using transthoracic needle aspiration to obtain a microbiologic diagnosis found Streptococcus pneumoniae to be the most common cause of CAP, accounting for 25% of all cases, with failure of conventional microbiologic techniques in one third of cases.56The appropriate resolution rate for CAP depends to a great degree on age; comorbid factors, particularly the presence of underlying lung disease; and factors such as alcohol abuse and social Occasionally the radiograph may show progression despite clinical improvement as exemplified by defervescence and reduction in leukocytosis.42 The virulence of the infecting organism plays an important role in resolution rates, with Staphylococcus aureus, enteric gram-negative pathogens, and Legionella taking the longest to resolve, occasionally months; Mycoplasma resolving the fastest, at 2 to 4 weeks; and Chlamydia having an intermediate resolution rate.=, It is useful to determine if one is dealing with a slowly resolving process (i.e., <50% resolution in 1 month), the emergence of resistance, or treatment of the wrong pathogen or process. HOST FACTORS

A multitude of host factors may adversely affect the resolution rates of pneumonia, many of which are more prevalent in the elderly (Table 1).Age From the Division of Pulmonary and Critical Care, Albert Einstein Medical Center; and Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania




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Comorbid factors Age-related Congestive heart failure Ineffective cough Diabetes mellitus Loss of lung elasticity Chronic obstructive pulmonary disease Decreased mucociliary clearance Renal failure Increase in functional residual capacity Cerebrovascular disease Flattening of diaphragms Ethanol abuse Decreased T-cell function Corticosteroids Decreased IL-1, IL-2, and IgM levels Smoking-related Immunosuppression Malignancy Impaired mucociliary clearance IL



produces physiologic alterations in lung function, including loss of elasticity and mucociliary clearance, increase in functional residual capacity, and flattening of the diaphragms, all of which may contribute to an ineffective cough.l0 These changes may contribute to the tendency to aspirate in the elderly. Aging is associated with a decrease in T-cell function, with a decrease in interleukin-1 and interleukin-'2 levels (potent cytokines that combat infection) as well as a decline in antibody levels (particularlyIgM). Smoking influences resolution rates of pneumonia principally by interfering with mucociliary clearance. Data suggest that cigarette smoking is the strongest independent risk factor for invasive (often bacteremic) pneumococcal pneumonia.52 Congestive heart failure, a significant factor particularly in the elderly, may cause depletion of antibacterial surfactant and impaired lymphatic drainage, providing a fluid medium for bacterial growth. Chronic obstructive lung diseases, such as emphysema, bronchitis, and bronchiectasis, are associated with impaired mucociliary clearance mechanisms, ineffective cough, and pooling of secretions, all of which promote and delay clearance of bacterial pneumonia. Renal failure, with impaired phagocytic activity (alveolar macrophages and neutrophils) and reductions in complement and humoral activity, is associated with a high incidence of infection. Diabetics suffer from impaired neutrophil function as well as a decrease in cell-mediated immunity. Malnutrition may impair cell-mediated and humoral immunity and increase the colonization rates for many bacteria, all serving to delay resolution of the pneumonic process. Patients who have sustained cerebrovascular accidents may have a tendency to aspirate and be unable to clear their secretions. Alcohol impairs phagocytic activity, particularly of encapsulated organisms, and is associated with a greater severity and slower resolution of pneumonia. The immune status of the patient, often impaired by corticosteroids and other immunosuppressive agents, and cancer are important considerations in the incidence, severity, and resolution of pneumonia.21, 42,51 Patients on immunosuppressive agents may have an incidence of complicated pneumonia 12 times that of a normal The absence of chills, fever, and pleuritic chest pain may lead to delay in recognition and in seeking medical attention for pneumonia. This situation is of particular concern in the elderly and may lead to a more virulent course with delay in resolution. Similarly, altered mental status and delirium may delay therapeutic 23 Other factors that have been associated with increased mortality in patients with pneumonia include hyperthermia or hypothermia, hypotension, tachypnea, excessive leukocytosis, and multilobar involve-



ment. S. aureus and gram-negative pneumonias are associated with the highest mortality.26


Physicians caring for patients with CAP often are faced with the dilemma of how to approach a patient with slowly resolving or nonresolving pneumonia. The term nonresolving pneumonia has not been defined clearly but may be considered when the radiograph has failed to resolve by 50%in 2 weeks or completely in 4 weeks, although it may require longer in certain clinical settings.18Reports vary in what is the expected time for complete radiographic resolution (range, 6 to 12 weeks).16Complete radiographic clearing of pneumonia occurs in 50%at 2 weeks and 66.7%at 4 weeks." Other studies have shown complete resolution at 2 weeks in only 12.5%and at 4 weeks in only 41% of cases.30This discrepancy may be explained by the nature of the study group, which comprised hospitalized patients with bacteremic pneumococcal pneumonia. To assess whether a patient's pneumonia is not resolving or slowly resolving, several factors require consideration. Resolution times may vary among different infectious agents causing pneumonia. Pneumococcal pneumonia should resolve radiographically within 6 weeks in an otherwise healthy adult. In comparison, the expected resolution time for Legionella pneumonia may be 2 to 6 months. Mycoplasma infections generally resolve quicker than pneumococcal pneumonia.**Emerging resistance to frequently used antibiotic therapy may be a reason for nonresolution. Attention should be paid to the use of the appropriate drug, dosing, and compliance. Access of the drug to the site of infection should be ensured by excluding the presence of a sequestered focus of infection, such as an empyema.3 Occasionally, noninfectious diseases can mimic pneumonia, accounting for lack of expected response to antimicrobial therapy.

Resolution Rates According to Pathogen Streptococcus pneumoniae

S. pneumoniae is the most common pathogen, accounting for about two thirdsz4of cases of bacteremic CAP, and causes significant mortality. Extremes of age, poor functional status, and comorbid illnesses are associated with a worse prognosis. Bacteremia= and multilobar involvemenP predict higher mortality rates and longer rates of resolution. Potential complications are parapneumonic effusion, empyema, necrotizing pneumonia, and lung abscess. Although lobar consolidation is suggestive of a bacterial pneumonia, radiologists cannot differentiate between bacterial versus nonbacterial on the basis of radiographic appearance. Israel et alZ8reported that by 4 weeks, 87% showed radiographic clearing. At 8 weeks, only 1 in 139 patients had incomplete radiographic clearing. Jay et a130 studied bacteremic infection and showed that at 4 weeks only 41% had complete clearing, which increased to 72% at 8 weeks. At week 4, 10% of patients younger than age 50 had persistent radiographic abnormalities compared with 67% in the older than age 50 group. Most studies have shown that 90%of patients with pneumococcal pneumonia achieved radiographic resolution at 4 months.3°,46,66 Six weeks is the appropriate time interval for follow-up radiographs.


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Legionnaires’ Disease

Legionella species account for 1% to 8% of all cases of CAP.46,60,61 This figure is much higher (11%to 24%)in patients requiring intensive care unit admission. Legionnaires‘ disease often is classified as an atypical pneumonia because the chest radiographic findings are neither lobar nor consolidating, as in the classic pyogenic pneumonias. Clinical presentation may be that of a fulminant pneumonia, often progressing to respiratory failure (20% to 40%) and associated with significant mortality. Risk factors for developing legionnaires’ disease are underlying chronic lung disease, cigarette smoking, and immunos~ppression.~ Corticosteroids are an important risk factor for nosocomial legionnaires’ disease. Contaminated water towers are an important source of infection.&Tan et a1,62in a study evaluating radiographic manifestations of legionnaires’ disease found that most cases showed worsening of infiltrates in the first week despite appropriate antibiotic therapy, with small effusions being seen in at least 50% of cases. The chest radiograph cannot distinguish legionnaires’ pneumonia from other bacterial pneumonias. In immunosuppressed patients, especially patients receiving corticosteroids, distinctive bilateral nodular opacities may be seen, which may cavitate.13 Radiographic improvement lags behind clinical improvement. The radiographic resolution rates are variable but definitely slower than with other causes of CAP. At 12 weeks, at least half the patients have been found to have persistent radiographic abnormalities,” with full resolution sometimes taking 4 months.6oThe urinary Legionella antigen is a useful diagnostic test for legionnaires‘ disease, but it can detect only Legionella serotype 1. Mycoplasma pneumoniae and Other Atypical Pathogens

The term atypical pathogens is limited to include only Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species. The 1993 American Thoracic Society guidelines for CAP stated that one cannot accurately predict microbial cause by classifying patients with CAP into typical and atypical pneumonia M . pneumoniae and C. pneumoniae CAP are usually relatively mild diseases, which cannot be distinguished clinically or radiographically from other causes of CAP. One study has suggested that the nature of the infiltrate may be determined more by the host’s immunologic response than by the causative agent itself.63Mycoplasma pneumonia usually resolves completely in 2 to 4 weeks, which is shorter than the resolution time of other bacterial pneumonias. Residual scarring and fibrosis are rare sequelae.6, Tuberculosis and Nontuberculous Mycobacterial Diseases

Tuberculosis may be a consideration in patients with pneumonia who fail to respond to conventional antibiotic therapy. When tuberculosis is treated with antibiotics, the course of illness may wax and wane, further obscuring the accurate diagnosis.36The radiographic manifestations of tuberculosis depend on several host factors, including prior exposure to Mycobacterium tuberculosis and the underlying immune status. In immunocompetent adults with primary tuberculosis, segmental or lobar consolidation typically occurs in association with hilar or mediastinal lymphadenopathyR Pleural effusion occurs in approximately one third of affected adults with primary tuberculosis? In postprimary tuberculosis, parenchymal opacities are situated in the apical and posterior segments of the upper lobes and superior segment of the lower lobes, usually involving multiple segments, and commonly these can cavitate.” Endobronchial



spread manifests as multiple, ill-defined 5- to 10-mm nodules distributed in a segmental or lobar distribution typically involving the dependent lung zones. Miliary or hematogenous spread is characterized by a millet seed appearance on chest radiograph. Vigilance for tuberculosis should be highest in the immigrant (particularly Asian), poor, and drug-abusing populations. In patients with pulmonary tuberculosis and human immunodeficiency virus (HIV) infection, a normal chest radiograph is found more commonly than in immunocompetent hosts.MWith advanced HIV disease, the radiographic findings are more atypical: Cavitation is uncommon; lower lung zone or diffuse infiltrates and intrathoracic adenopathy predominate. The most common nontuberculous mycobacterial diseases are caused by Mycobacteriurn avium complex and Mycobacteriurn kansasii, both of which are more common in the presence of underlying lung disease. Symptoms and radiographic findings of these infections are indistinguishable from tuberculosis (Fig. 1). Fungal Pneumonias

The presentation of fungal pneumonias depends largely on the host’s immune status as well as the size of the inoculum. A comprehensive residential, travel, and occupational history is important in considering the diagnosis of fungal infections. Histoplasmosis and blastomycosis are more common in the Mississippi and Ohio River valleys. Chest radiographs show apical infiltrates that eventually cavitate, mimicking chronic active tuberculosis. Extrapulmonary

Figure 1. Posteroanterior (PA) chest radiograph of a 70-year-old man with chronic obstructive lung disease with a right lower lobe infiltrate unresponsive to conventional antibiotics. Fiberoptic bronchoscopy confirmed Mycobacterium Kansasii as the cause of his pneumonia.


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manifestations, involving skin, bone, and genitourinary tract, are common in blastomycosis. Coccidioidomycosis may present after the initial primary infection as benign residual nodules or cavities, persistent pneumonia, or a chronic progressive pneumonia. This indolent form may mimic chronic tuberculosis. In the immunocompetent host, Cyptococcus neoformans may colonize the tracheobronchial tree or produce a pulmonary nodule without tissue invasion. Progressive pulmonary cryptococcosis, which occurs infrequently, presents with indolent symptoms, alveolar and interstitial infiltrates, nodules, and consolidation. Occasionally, hilar adenopathy and pleural effusions may be present. Chronic necrotizing aspergillosis may occur in patients with severe underlying lung disease, usually with some degree of immunosuppression (e.g., lowdose steroids). Aspergillosis is a locally invasive and slowly progressive illness associated with upper lobe cavitation, which may resemble tuberculosis. The mortality rate is fairly high, h o ~ e v e r .Intracavitary ~,~~ mycetomas may be present but often are not prominent. The predominant features of the disease are severe cough, productive of mucopurulent sputum, and fever. Therapeutic options include systemic therapy with intravenous amphotericin B, prolonged oral itraconazole therapy, and sometimes surgical re~ection.~~ Allergic bronchopulmonary aspergillosis is characterized by asthma, peripheral blood eosinophilia, positive skin test for Aspergillus antigen, the presence of serum Aspergillus precipitating antibodies, elevated IgE, migrating pulmonary infiltrates, and central bronchiectasis. Oral itraconazole together with the standard systemic corticosteroids has been advocated for treatment of allergic bronchopulmonary aspergillo~is.5~ Viral Pneumonias

Viral upper respiratory tract infections in adults usually are mild and selflimited, rarely causing pneumonia. Pneumonia is a more frequent complication in immunocompromised hosts and in the elderly. A viral cause for pneumonia may be suspected when there is failure to respond to antibiotics. The most frequent causes of viral pneumonias in adults are influenza A and B, respiratory syncytial virus, parainfluenza virus, and adenoviruses. Viral cultures are not obtained routinely. To prove that the cultured virus is responsible for disease, it may be necessary to show histologic evidence of virus activity in affected tissue (i.e., characteristic intranuclear or intracytoplasmic inclusions). Retrospectively, indirect evidence of viral infection is shown by a fourfold or greater rise in serum antibodies to a specific virus strain. Viral pneumonias typically have radiographic findings of a reticular or reticulonodular interstitial pattern that pathologically represents hemorrhagic pulmonary edema, involving the bronchioles and interlobular ~ e p t a e . Significant 2 ~ ~ ~ ~ focal or diffuse air-space disease may be found frequently, alone or in combination with the interstitial pattern. Pleural effusions occasionally may be present. Influenza is the most serious viral airway infection in adults, causing significant morbidity and mortality. Influenza pneumonia can be localized or diffuse, unilateral or bilateral. For the ambulatory patient, a nasal wash or combined nasopharyngeal/throat swab is optimal for diagnosis. Samples should be placed into viral transport medium and delivered rapidly to the virology laboratory. Characteristic cytopathic effects or hemadsorption identifies positive cultures. Most positive cultures are identified within 3 days, although 2 weeks may be necessary. Rapid antigen detection systems are less sensitive than viral cultures. Superimposed secondary bacterial infection, usually caused by S. pneumoniae or S. aureus, occurs frequently in patients with viral pneumonia.



Although varicella-zoster virus usually causes cutaneous disease, pneumonia is a life-threatening complication of primary varicella in healthy adults as well as immunocompromised hosts. About 90% of cases of varicella pneumonia occur in patients older than 19 years old. Smokers may be at greater risk for development of varicella pneumonia. Pregnant women appear to have greater morbidity and mortality from this infection. Varicella pneumonia may present as patchy, bilateral air-space disease. Clearance is slow, taking several months with occasional residual scattered punctate calcifications seen on follow-up radiographs.*O

Unusual Organisms Actinomycosis and mixed anaerobic pulmonary disease may occur after aspiration in patients with poor dental hygiene, resulting in a necrotizing pneumonia. Clinical presentation is that of fatigue, low-grade fever, weight loss, and cough. With actinomycosis, the pleural space may be crossed, with sinus track formation being common. The presence of sulfur granules is characteristic of actinomycosis. Nocardiosis may have a similar presentation, but tends to disseminate hematogenously. Presentation may be subacute in the immunocompetent patient. Initially the presentation may be a localized bronchial pneumonia, progressing to complete lobar consolidation and eventual cavitation. Nocurdiu can be diagnosed by finding weakly acid-fast organisms on sputum examination. Rhodococcus equi is another rare cause of chronic cavitating pneumonias, particularly in immunosuppressed individuals often with a history of exposure to animals (Fig. 2). Pseudornonas pseudomallei, which is endemic in Southeast Asia, is another cause of indolent cavitary apical infiltrates. Q fever (Coxiella burnetii) may follow exposure to parturient cats, sheep, goats, or cattle. Psittacosis should be suspected when there has been contact with birds. Pneumocystis carinii Pneumonia

Pneurnocystis carinii pneumonia, a more common disease in HIV-infected individuals, is a serious complication in HIV-seronegative immunocompromised hosts. P. carinii pneumonia should be considered as a possible diagnosis in a patient with nonresolving bilateral infiltrates, even in the absence of known immunodeficiency. P. carinii pneumonia can present with fever, cough, dyspnea, chills, chest pain, and occasionally sputum production, but some patients may be asymptomatic. Tachypnea or bibasilar rales may be present, although some may have a normal examination. Clinical features of P. carinii pneumonia in HIVseronegative immunocompromised patients differ significantly from features of HIV-related disease. In contrast to acquired immunodeficiency syndrome (AIDS) patients, non-HIV-infected patients with P. carinii pneumonia experience an abrupt onset of symptoms, a shorter duration of symptoms before seeking medical evaluation, and a more fulminant course of illness. Non-HIV-infected patients may require a shorter duration of specific therapy and have a lower organism burden in the lungs, making the diagnosis by bronchoalveolar lavage more difficult. Diffuse alveolar or interstitial pulmonary infiltrates are the classic radiologic findings of P. carinii pneumonia, but patchy, asymmetric infiltrates have been reported. Other findings include cyst formation, spontaneous pneumothorax, and nodular infiltrates; a normal chest radiograph also has been reported.”


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Figure 2. A, PA chest radiograph of 63-year-old man with diabetes who had a kidney transplant. Patient has a nonresolving pneumonia in the right lower lobe. B, CT scan demonstrates cavitary process and hilar enlargement. Fiberoptic bronchoscopy isolated Rhodococcus equi.

Workup After therapy for CAP, patients should be followed until radiographic baseline is reached. Further evaluation, such as fiberoptic bronchoscopy (FOB) or computed tomography (CT) scanning of the chest may be indicated in patients



who fail to resolve chest radiographic abnormalities in the expected time frame, especially if the patient remains clinically ill. FOB is usually an essential part of the diagnostic workup. Quantitative cultures of bronchial washings are sensitive and specific in diagnosing CAP as well as tuberculosis. FOB may reveal a previously unrecognized endobronchial lesion or a foreign body, which may have prevented timely resolution of an infiltrate. FOB is especially useful in detecting selected pathogens, such as P. carinii, Mycobacterium, cytomegalovirus, and unusual organisms. For detection of acid-fast bacilli, specimens obtained by FOB offer no advantage over sputum samples but are helpful in patients suspected of having mycobacterial infection who are unable to produce adequate sputum samples. High-resolution CT scan is a useful modality when the chest radiograph is nonspecific and may help diagnose or rule out specific diseases. High-resolution CT gives information on the pattern, distribution, and activity of disease, which may help guide areas suitable for biopsy. Transthoracic needle aspiration has been used for cytologic evaluation of suspected neoplasms as well as in the investigation of pulmonary infiltrates in immunocompromised hosts. FOB has been found to be most helpful in making a specific diagnosis in nonsmoking patients younger than age 55, without underlying chronic obstructive pulmonary disease or immunocompromised state, who had multilobar infiltrates of long duration.I9 Patients with negative FOB may be observed further if not clinically ill. If symptoms are persistent, further invasive procedures, including open-lung biopsy, need to be considered. MIMICS OF PNEUMONIA

Several noninfectious disease states may masquerade as pneumonia. Chest radiographs may have features identical to an infectious cause; the term mimics of pneumonia has been used. Some of the mimics of pneumonia are as follows: Bronchiolitis obliterans organizing pneumonia (BOOP) Neoplasms, including bronchogenic carcinoma, lymphoma, bronchioloalveolar carcinoma Acute or chronic eosinophilic pneumonia Pulmonary vasculitis, including Wegener’s granulomatosis, Churg-Strauss syndrome Lupus pneumonitis Acute alveolar hemorrhage Sarcoidosis-alveolar type Pulmonary alveolar proteinosis Drug-induced pulmonary infiltrates (e.g., amiodarone) Aspiration pneumonia-lipoid pneumonia Acute sickle chest syndrome Occupation-related lung infiltrates (e.g., nylon flock) Radiation pneumonitis In mechanically ventilated patients with suspected pneumonia, conditions such as aspiration pneumonitis, pulmonary hemorrhage, adult respiratory distress syndrome, and cardiogenic pulmonary edema should be considered. Bronchiolitis Obliterans Organizing Pneumonia

BOOP is an infiltrative pulmonary disorder that presents with dyspnea and cough. There may be a preceding flulike illness suggestive of a slowly resolving


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viral pneumonia. Physical examination reveals inspiratory crackles. Chest radiography may show patchy bilateral multifocal areas of consolidation, interstitial pneumonia, or a solitary mass. This disease may be associated with rheumatoid arthritis; drugs such as penicillamine, amiodarone, and sulfasalazine; lung transplantation; radiation injury; and inflammatory bowel disease. Most cases are idiopathic, however. High-resolution CT scan frequently reveals characteristic peripheral subpleural nodules and patchy ground-glass air-space consolidation (Fig. 3). Transbronchial or preferably open-lung biopsy often is needed to rule out underlying malignancy and to obtain sufficient tissue for diagnosis. Pathologically, there is granulation tissue in the lumen of bronchioles and alveolar ducts with interstitial and air-space infiltration by mononuclear cells and macrophages. The treatment of BOOP is a course of corticosteroids often for prolonged periods at high doses. Avoidance of any offending drug and treatment of the underlying disorder also are ne~essary.~, l4 Bronchial Neoplasms

Benign and malignant neoplasms may present as a nonresolving pneumonia. Benign tumors such as carcinoid and malignant tumors, including carcinoma, lymphoma, and bronchioloalveolar carcinoma, are known to present as indolent pulmonary infiltrates (Fig. 4). Bronchioloalveolar Carcinoma

Bronchioloalveolar carcinoma is an indolent peripheral, well-differentiated adenocarcinoma that does not distort the pulmonary interstitium. Of patients with bronchioloalveolar carcinoma, 45% to 60% are identified by chest radiographs obtained for other indications. Lobar consolidation with air bronchograms may occur and can mimic an infectious pneumonia. Patients with bronchioloalveolar carcinoma are usually young women with a smoking history. Occupations such as construction workers, paper mill workers, and sugarcane farmers and chronic interstitial disease, especially in patients with scleroderma, are associated with an increased incidence of bronchioloalveolar carcinoma. Cough, chest pain, dyspnea, weight loss, and hemoptysis are usual presenting features. Cachexia, cyanosis, clubbing, inspiratory rales, signs of consolidation, and peripheral lymphadenopathy may be present. Large-volume bronchorrhea is seen in about 6% and can be severe enough to produce fluid and electrolyte abnormalities. Refractory hypoxemia may occur secondary to intrapulmonary shunting. Chest radiography usually reveals a single, peripheral nodule or mass. Bilateral pulmonary nodules, lymphangitic carcinomatosis, and diffuse parenchymal disease also have been reported. Diagnosis of diffuse bronchioloalveolar carcinoma can be made by sputum cytology in about 80% of cases. Transthoracic needle aspiration and biopsy often are needed for peripheral lesions. Surgical resection is the treatment of choice in localized disease. Because bronchioloalveolar carcinoma is chemoresistant and radioresistant, supportive management is recommended for advanced cases.' Pulmonary Lymphoma

Primary lymphoma of the lung most commonly presents as an area of poorly defined consolidation with an air bronchogram. Pleural involvement is



Figure 3. A, PA chest radiograph demonstrates a diffuse, peripheral, interstitial pneumonic process in an 80-year-old woman unresponsive to antibiotics. 6,CT scan demonstrates peripheral, nodular characteristics of bronchiolitis obliterans organizing pneumonia. Confirmed by open lung biopsy.

rare. Hilar or mediastinal lymphadenopathy may be a feature. Patients have nonspecific symptoms or may be asymptomatic, making clinical diagnosis difficult. Pulmonary involvement occurs in 30% to 40% of patients with Hodgkin’s disease. Increasing incidence of B-cell non-Hodgkin’s lymphoma is noted in


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Figure 4. A, PA chest radiograph of an 85-year-old smoker who presented with a febrile illness and multilobar pneumonia. 6, Two months later, clearing of the right lower lobe process but masslike consolidation in the right upper lobe. Biopsy confirmed adenosquamous carcinoma.

posttransplant patients as a result of intense immunosuppressive therapy. Primary lymphoma of the lung may be AIDS related in 8% to 15%. Pseudolymphoma is a benign inflammatory lymphocytic infiltrate that may be related to certain drugs, such as phenytoin. Lymphocytic interstitial pneumonia is another benign process frequently seen in AIDS or autoimmune diseases.8,4o Eosinophilic Pneumonia

Chronic eosinophilic pneumonia is a rare disorder that presents with fever, weight loss, cough, wheeze, and night sweats. It is more common in women. Several drugs are reported to induce pulmonary eosinophilia, including anticonvulsants, antidepressants, P-blockers, captopril, nonsteroidal anti-inflammatory drugs, nitrofurantoin, and cytotoxic agents. Peripheral blood eosinophilia is noted in 95%. Peripherally located fluffy consolidation (photographic negative of pulmona y edema) may be seen in 25% of chest radiographs. Pleural effusions are uncommon. Bilateral migratory infiltrates with ground-glass discrete opacities are seen on chest CT scans. There often is a prompt response to corticosteroid therapy. Close follow-up is advised in view of a relapse rate of 25%. Acute eosinophilic pneumonia is a febrile illness with severe hypoxemia and diffuse ground-glass pulmonary infiltrates. Bronchoalveolar lavage fluid reveals an increased eosinophil count. No infectious cause is found, and there is a dramatic improvement with corticosteroids.43 Pulmonary Vasculitides

Pneumonia is a common finding in various vasculitides of the lung. Wegener 's granulomatosis, allergic granulomatosis and angiitis (Churg-Strauss syn-



drome), bronchocentric granulomatosis, and lymphomatoid granulomatosis often present with features of pneumonia. Wegener’s Granulomatosis

Wegener ’s granulomatosis is a necrotizing granulomatous vasculitis involving the lungs, nasal passages, sinuses, and kidneys. Mononuclear cells, histiocytes, giant cells, plasma cells, eosinophils, and neutrophils infiltrating small arteries, venules, and arterioles are characteristic findings. Fever, night sweats, weight loss, hemoptysis, epistaxis, and arthralgia are presenting features. Chest radiography reveals multiple nodular infiltrates with cavitation in about 50% of cases. Of patients with radiographic abnormalities, 34% are asymptomatic. In most cases, upper airway and pulmonary disease precede renal involvement. There is a poor correlation between the presence of lung infiltrates and symptoms. Infiltrates may wax and wane as well as migrate throughout the lung. Antineutrophil cytoplasmic antibody is 80% to 100% specific for Wegener ’s granulomatosis. Prednisone and cyclophosphamide have induced remission in 75% of cases with a survival rate of 80%?9 Allergic Granulomatous Angiitis (Churg-Strauss Syndrome)

Asthma; peripheral eosinophilia; diffuse, patchy, or nodular pulmonary infiltrates; and systemic vasculitis characterize the Churg-Strauss syndrome. Fever, migratory polyarthralgia, and peripheral neuropathy are seen frequently. Peripheral eosinophil counts often are greater than 1500/mm3. Lung biopsy shows vascular thrombosis with eosinophilic infiltrates. Churg-Strauss syndrome has been reported after introduction of leukotriene antagonists while tapering previous steroid therapy. It is the opinion of most authors that this phenomenon is due to unmasking of previous vasculitis suppressed by steroids. Treatment includes corticosteroids and cytotoxic agents.70,71

Lupus Pneumonitis

Acute lupus pneumonitis is seen in 1%to 4% of patients with systemic lupus erythematosus. Presenting symptoms are cough, dyspnea, pleuritic pain, hypoxemia, and fever identical to an infectious process. Chest radiographs reveal infiltrates that may be unilateral or bilateral. Histologic features are alveolar wall damage, necrosis, inflammatory cell infiltrate, and hemorrhage. Chronic interstitial pneumonitis is seen in 3% to 13% of patients. Corticosteroids are the treatment of choice. Cytotoxic agents are used in steroid-recalcitrant ~ases.4~ Acute Alveolar Hemorrhage

Alveolar hemorrhage in systemic lupus erythematosus is rare and has a mortality rate of 50% to 90%. Clinical features are nonspecific with dyspnea, diffuse alveolar infiltrates, hypoxemia, and anemia. The presence of gross blood in the airways, presence of hemosiderin-laden macrophages, and absence of infection by sputum culture strongly support the diagnosis. Treatment of choice is high-dose steroids with or without cyclophosphamide; plasmapheresis is reserved for severe refractory cases.”


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Rare cases of sarcoidosis presenting as pulmonary consolidation have been reported. The typical radiographic appearance of pulmonary sarcoidosis is bilateral Mar lymph node enlargement and interstitial infiltrates. In 20% of patients, an acinar or alveolar pattern has been described. The differential diagnosis includes BOOP and lymphoma. Sarcoidosis should be considered in cases of a 65 nonresolving alveolar opacity in populations at risk for this disea~e.3~8 Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis is a disease characterized by the filling of alveoli with periodic acid-SchiffTpositive proteinaceous material, rich in lipid. It may mimic a diffuse pneumonia. Most patients are in their teens to 40s, with a male preponderance. Pulmonary alveolar proteinosis has been described in lung infections, hematologic malignancies such as myeloid leukemia, lymphoma, and exposure to inhaled chemicals and minerals. An increased incidence of infections with Nocardia asteroides, M . tuberculosis, Mycobacterium avium-intracellulare, and I? carinii has been reported in patients with pulmonary alveolar proteinosis. Presenting symptoms are exertional dyspnea, nonproductive mild cough, and white sputum that is gummy or chunky in consistency. Fine crackles and clubbing may be noted. There is usually a two to three fold elevation of lactate dehydrogenase. The chest radiograph typically reveals bilateral air-space disease. A perihilar interstitial pattern suggestive of bat's wing pattern without cardiomegaly, Kerley B lines, and pleural effusions are seen in 50% of cases. The differential diagnosis includes infections, noncardiogenic pulmonary edema, bronchioloalveolar carcinoma, sarcoidosis, and other interstitial lung diseases. High-resolution CT scan of the chest shows ground-glass opacification and thickening of septa called crazy paving. Pulmonary function tests show restriction and reduction in diffusing capacity with hypoxemia. Bronchoalveolar lavage typically yields a milky effluent. Whole-lung lavage is treatment of choice in symptomatic patients.57,69 Drug-Induced Pulmonary Infiltrates

Several drugs cause pulmonary infiltrates that may simulate infection. The classic examples are penicillamine, nitrofurantoin, bleomycin, and amiodarone. Penicillamine, a disease-modifying agent used in the treatment of rheumatoid arthritis, has been associated with the development of BOOP. Amiodarone is an antiarrhythmic drug used in the management of supraventricular and ventricular tachycardia. Pulmonary toxicity represents the most serious adverse reaction, which occurs in 5% to 7% of patients. The common presentation is the insidious onset of nonproductive cough, dyspnea, weight loss, fever, and diffuse interstitial infiltrates. Daily doses of more than 400 mg of amiodarone increase the risk of toxicity. In one third of patients, pulmonary toxicity may have an acute onset of fever, dyspnea, nonproductive cough, and pleuritic pain, which may mimic an acute pneumonia. Physical examination may reveal bilateral rales and a pleural rub. Pleural effusions are uncommon. CT scan of the chest showing high Hounsfield numbers and gallium lung scan may be helpful in the diagnosis. CT scan of the liver may show uptake of contrast medium resulting from increased tissue iodide accumulation. Foamy macrophages have been described in specimens obtained by transbronchial lung



biopsy or bronchoalveolar lavage. These macrophages represent a marker of drug exposure and are not specific for toxicity. BOOP occurs in some patients. Treatment is discontinuation of amiodarone and corticosteroid therapy in severe cases.12,33 Aspiration Pneumonia

The inflammatory response that occurs in the lungs after aspiration commonly is referred to as aspiration pneumonia. Major risk factors are altered level of consciousness, neuromuscular diseases, esophageal dysmotility, incompetent lower esophageal sphincter, and mechanical factors, such as an endotracheal tube. Aspiration of a large volume of acidic gastric contents, shock, multilobar infiltrates, adult respiratory distress syndrome, and secondary infection indicate a poor prognosis. Aspiration of gastric acid results in ventilation-perfusion mismatch, intrapulmonary shunt, and profound hypoxemia, with occasional development of adult respiratory distress syndrome. The lower lobes in the erect posture and posterior segments of upper lobes and superior segments of lower lobes in the supine posture are the most frequent sites of aspiration. Radiographic infiltrates usually resolve rapidly. Failure of resolution or worsening infiltrates require further investigation. The pathogens associated with early aspiration pneumonia in hospitalized patients usually are polymicrobial from the oropharynx. Subsequently, gram-negative organisms or methicillin-resistant S. aureus predominates. Choice of antibiotics depends on the duration of hospitalization and local resistance of organisms.50 Lipoid Pneumonia

Nasal oil drops and oral laxatives have been associated with lipoid pneumonia. Saline has replaced oil as a vehicle for nasal drops and sprays, making lipoid pneumonia a rare diagnosis today. Radiographic findings can mimic infectious pneumonia. Aspiration of mineral oils such as liquid paraffin and fats of animal or vegetable origin can result in an exogenous lipoid pneumonia. Risk factors for lipoid pneumonia are extremes of age, impaired swallowing and cough reflexes, mental status change, and recumbent posture. Alveolar macrophages ingest lipid and have a foamy appearance. Oil may elicit a foreign body reaction in the alveoli, with fibrosis and giant cells resulting in a paraffinoma. Most patients are asymptomatic but often have an abnormal chest radiograph. Some patients may present as acute infectious pneumonia with leukocytosis. Pulmonary function tests may show a restrictive pattern with hypoxemia. Air-space consolidation is seen in dependent lung segments. Chest CT scan is useful in detecting fat density within the pulmonary infiltrates (Fig. 5). Demonstration of lipid-laden macrophages stained with Oil Red 0 or Sudan Black in bronchoalveolar lavage confirms lipoid pneumonia in the proper clinical setting. Lung biopsy is unnecessary in most cases. Continued oil use and concurrent debilitating illness can result in progressive disease. Treatment is cessation of the offending agent, supportive care, and antibiotics for secondary Acute Sickle Chest Syndrome

Acute sickle chest syndrome accounts for 3% of deaths in adults with sickle cell disease. Approximately 30% of patients develop acute sickle chest syndrome


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Figure 5. A, PA chest radiograph of an 80-year-old woman who used mineral oil for chronic constipation. Note ill-defined right middle lobe infiltrate (arrow). 6,CT scan (rnediastinal technique) demonstrates fat density within the infiltrate. Bronchoalveolar lavage confirmed presence of copious lipid laden macrophages consistent with the clinical diagnosis of lipoid pneumonia.



during their lifetime. Acute sickle chest syndrome is known to recur in about half of the patients who develop it. Fever, cough, and pleuritic chest pain are typical presenting features. Patients may be hypoxemic with rales on physical examination resembling infectious pneumonia. Fat embolism is thought to play an important role in adults with acute sickle chest syndrome. Patients with acute sickle chest syndrome may develop worsening hypoxemia, progressive infiltrates, and multiorgan failure. Empiric use of antibiotics, adequate oxygen, hydration, and red cell exchange transfusion are the treatments of Occupational Lung Diseases

Several occupational lung diseases may cause pulmonary infiltrates with constitutional symptoms mimicking infectious pneumonia. Nylon flock associated interstitial pneumonitis is a newly described occupational disease. Nylon flock is pulverized nylon fiber that is applied to adhesive-coated fabrics. Presenting complaints are persistent cough without wheezing and exertional dyspnea unresponsive to inhaled bronchodilators and corticosteroids. Many cases have been misdiagnosed as asthma or recurrent pneumonia. Resolution may take weeks to months after leaving the workplace. Interstitial markings on chest radiographs and peripheral ground-glass opacities may be noted on highresolution CT scan. Pulmonary function tests show a restrictive pattern with reduction in the diffusing capacity. Public health measures to reduce worker exposure, respiratory protection devices, control of dust levels, and medical surveillance are p~eventive.'~, 38 Radiation Pneumonitis

Radiation-induced changes in the lung may present as a slowly resolving pneumonia. Predisposing factors are a radiation dose of more than 35 to 40 Gy, single-dose versus twice-daily fractionated treatments, prior radiation, volume of lung irradiated, and concurrent use of various chemotherapeuticagents (radiation recall). There are two types of presentation-early radiation pneumonitis and late fibrosis. Early pneumonitis occurs in the first 3 months after radiation therapy. Symptoms may precede radiographic change. Nonproductive cough, dyspnea, and low-grade fever are presenting symptoms. Chest radiograph shows areas of consolidation usually confined to the radiation port. Treatment with prednisone, 60 to 100 mg daily, after excluding active infection, is recommended for acute early pneumonitis. Late fibrosis, occurring more than 6 months after treatment, is not responsive to steroids, and supportive measures, such as low-flow oxygen, are the recommended appr0aches.4~ References 1. Barkley JE, Green MR Bronchioloalveolar carcinoma. J Clin Oncol 14:2377, 1996 2. Bartlett JG, Mundy L M Community-acquired pneumonia. N Engl J Med 3331618,1995 3. Bartlett JG, Breiman RF, Mandell LA, et a1 Community-acquired pneumonia in adults. Clin Infect Dis 262311, 1998 4. Carratala J, Gudiol F, Parrares R Risk factors for nosocomial Legionella pneumophila pneumonia. Am J Respir Crit Care Med 149:625, 1994


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