Chronic Pneumonia (not TB)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has chronic pneumonia? What should you expect to find?

Chronic pneumonia is a pulmonary parenchymal process that can be infectious or non-infectious and that has been present for weeks to months rather than days. Chronic pneumonia is manifested by abnormal chest radiographic findings and by chronic or progressive pulmonary symptoms. As is true with many causes of pneumonia, no single symptom is common to all etiologies. Nonspecific and constitutional symptoms, such as fever, chills, and malaise, may be present early and are followed by progressive anorexia and weight loss indicative of chronic illness. Pulmonary symptoms may be present early, but frequently appear later in the course of the illness. In any patient with chronic illness and nonspecific constitutional complaints who develops pulmonary symptoms, including any new or persistent cough, sputum production, hemoptysis, chest pain (particularly pleuritic pain), or dyspnea, chronic pneumonia should be considered as a possibility.

Because respiratory symptoms of chronic pneumonia are non-specific, an important clue to the etiologic diagnosis of chronic pneumonia is the presence of extrapulmonary findings. For instance, characteristic skin lesions are common among patients with coccidioidomycosis, blastomycosis, or paracoccidioidomycosis. A history of chronic pneumonia with persistent headache and focal cranial nerve findings should raise suspicion for tuberculosis, cryptococcosis, or coccidioidomycosis. Similarly, a search for other findings including monoarticular or polyarticular arthritis, polyarthralgia, or localized bone tenderness may indicate systemic vasculitis or sarcoidosis. The presence of focal neurologic signs and symptoms suggesting space-occupying lesion should lead one to consider chronic suppurative lung disease due to Nocardia species or a mixed aerobic and anaerobic bacterial pneumonia.

Physical findings are not usually helpful in differentiating specific causes of chronic pneumonia. Findings on chest exam may be normal or indicate signs of local consolidation. Wheezing may be seen among patients with etiologies causing both pneumonia and asthma, such as extrinsic allergic alveolitis, allergic bronchopulmonary aspergillosis, or allergic angiitis and granulomatosis (Churg-Strauss syndrome). The presence of skin lesions may suggest disseminated fungal disease and can be particularly helpful when taken together with an accurate clinical and epidemiologic history. Clubbing and/or cyanosis may be present among patients with chronic symptoms who have significant underlying pulmonary disease. Adenopathy, with or without hepatosplenomegaly, can be indicative of a disseminated infectious or inflammatory process, such as histoplasmosis, tuberculosis, or sarcoidosis.

How did the patient develop chronic pneumonia? What was the primary source from which the infection spread?

Most cases of chronic pneumonia due to an infectious etiology result from inhalation of aerosolized organisms or aspiration of oral contents. As it relates to noninfectious causes of the chronic pneumonia syndrome, the lungs may be the primary target of disease (e.g., sarcoidosis, hypersensitivity pneumonitis), or the lungs may simply be “innocent bystanders” of a systemic disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease).

Knowledge of the demographics and relevant epidemiology is key in trying to narrow one’s focus to the potential etiologic agents in determining the specific cause of chronic pneumonia. Age, gender, and race may play important roles in the development of chronic pneumonias.

• Age is important in that it may predispose to aspiration associated with chronic underlying conditions, such as stroke, malnutrition, and chronic immobility.

• Gender plays an important role in some chronic pneumonias. For example, pulmonary lymphangioleiomyomatosis is a rare neoplastic disorder that occurs almost exclusively in adolescent and young adult women. In contrast, pulmonary paracoccidioidomycosis is seen overwhelmingly in adult men.

• Racial and genetic factors are increasingly recognized as important predisposing factors associated with severe disease manifestations from a variety of pathogens. For example, chronic cavitary pulmonary tuberculosis is more common among African Americans; disseminated coccidioidomycosis is much more likely to occur in African Americans and other dark-skinned races. Conversely, chronic cavitary histoplasmosis is much more likely in older Caucasian men with a history of chronic lung disease.

Occupation and hobbies are also important in the evaluation of these patients. For instance, tuberculosis is an important consideration among healthcare workers, incarcerated individuals, and recent immigrants from high incidence regions. Coccidioidomycosis is an important consideration among rock collectors, laboratory technicians, archeologists conducting excavations, and construction workers exposed to desert dust in endemic areas; histoplasmosis is an important consideration in persons exposed to pigeon, starling, or bat roosts, or among those who clean old chicken houses with dirt floors; and blastomycosis is an important consideration in forestry workers, heavy equipment operators, and campers and hunters from endemic areas.

Travel is also an important consideration, and a detailed travel history can shed important light on the potential etiology of chronic pneumonia. Exposure to areas endemic for certain fungal pathogens, such as Coccidioides spp, Histoplasma capsulatum, Blastomyces dermatitidis, and Cryptococcus gattii is obvious. Paracoccidioidomycosis (due to Paracoccidioides brasiliensis) should be considered only in persons who have lived in Mexico and Central and South America. For patients who have lived in or visited rural southeast Asia, especially those with exposure to rice-growing areas, chronic pneumonia due to Penicillium marneffei or Burkholderia pseudomallei should be a consideration. Among those visiting southeastern Asia or the Philippines with a history of consumption of raw or partially cooked shellfish and chronic pulmonary symptoms, paragonimiasis due to Paragonimus westermani should be a consideration.

Increasingly, pulmonary tuberculosis is associated with homelessness, alcoholism, HIV infection, and immigrant population groups. Alcoholism can be associated with aspiration pneumonia and chronic gram-negative bacillary pneumonia or mixed aerobic/anaerobic chronic necrotizing pneumonia. Intravenous (IV) drug use can be associated with tricuspid valve endocarditis and associated septic pulmonary emboli that can be the initial manifestation of chronic pneumonia syndrome. Moreover, the use of crack cocaine has been associated with bronchiolitis obliterans and organizing pneumonia, eosinophilic lung disease, and interstitial pneumonitis.

Chronic pneumonia can also be associated with exposure to prescribed pharmaceutical agents. There are more than 100 pharmaceutical agents associated with acute and chronic pulmonary symptoms. Those most likely to cause chronic pulmonary disease include cytotoxic agents, such as bleomycin, busulfan, cyclophosphamide, and methotrexate. Detailed history of recent drug exposure is essential in defining the likely causative agent in drug-associated chronic pneumonia syndrome.

Which individuals are of greater risk of developing chronic pneumonia?

Chronic and/or refractory pneumonia are especially common among patients with advanced HIV and other conditions associated with impaired host immunity, such as those receiving high dose glucocorticoid therapy, cytotoxic therapy, hematopoietic stem cell and organ transplantation, chronic granulomatous disease, and other inherited disorders of immune function.

Patients with chronic obstructive pulmonary disease and diabetes are at higher risk for development of complications of chronic pneumonia, including persistent pneumonia and chronic cavitary disease.

Patients with chronic obstructive pulmonary disease (COPD) are predisposed to chronic fibrocavitary histoplasmosis and Mycobacterium avium complex lung disease. Structural lung disease, such as bronchiectasis, endobronchial lesions, and endobronchial lesions may predispose to chronic pneumonia.

Other considerations include a recent history of dental problems, oral manipulation, disorders of swallowing associated with neurological and esophageal disorders, seizure disorders, recent anesthesia, excessive alcohol consumption, and any disorder leading to an unconscious state.

When these conditions and circumstances are taken into consideration to determine predisposing factors among patients with chronic pneumonia syndrome, a thoughtful approach to the evaluation of these patients is possible. However, by far the most important predisposing conditions are underlying lung disease (including, especially, chronic obstructive pulmonary disease and chronic interstitial lung disease, with or without fibrosis) and iatrogenic immunosuppression.

Beware: there are other diseases that can mimic chronic pneumonia:

Strictly speaking, many cases of chronic pneumonia are not due to an infectious agent. Accordingly, when one encounters a patient in whom chronic pneumonia seems likely, the differential diagnosis is necessarily broad and should include both infectious and noninfectious etiologies. Diseases that can mimic infectious causes of chronic pneumonia are diverse. Among the most common conditions are primary or metastatic carcinoma, lymphoma, sarcoidosis, amyloidosis, systemic vasculitis syndromes, chemicals, pharmaceutical agents, radiation, recurrent pulmonary emboli, bronchial obstruction with atelectasis, and hypersensitivity pneumonitis. Other causes include idiopathic chronic organizing pneumonia/bronchiolitis obliterans with organizing pneumonia (COP/BOOP), chronic interstitial pneumonia, including fibrosing alveolitis and various forms of diffuse interstitial pneumonia, alveolar proteinosis, Goodpasture’s syndrome, and lymphangioleiomyomatosis.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Routine laboratory studies provide important clues to the diagnosis of chronic pneumonia. Pancytopenia may suggest disseminated histoplasmosis, metastatic tumor, or miliary tuberculosis. Isolated anemia is commonly associated with chronic pneumonia and not particularly helpful in discerning a cause. A normal leukocyte count does not exclude infection, and, in particular, chronic fungal pneumonia may be associated with a normal or minimally elevated leukocyte count. Leukopenia or lymphopenia should raise suspicion of co-existing HIV infection and is also consistent with diagnosis of sarcoidosis, systemic lupus erythematosus, and histoplasmosis. Leukocytosis with polymorphonuclear cell predominance is suggestive of, but not diagnostic of, a bacterial infection.

Routine laboratory tests that measure organ function may provide more helpful information. Liver tests, including bilirubin, alkaline phosphatase, and hepatocellular enzyme assays, should be performed and can provide evidence of granulomatous hepatitis (particularly seen in mycobacterial and fungal infections). Elevation of these enzymes can suggest a systemic disorder involving multiple organs. Non-infectious conditions that lead to findings consistent with granulomatous hepatitis include sarcoidosis, the vasculitides, neoplastic, and certain lymphoproliferative diseases. Elevated renal function tests can be helpful in discerning conditions associated with multiple organ dysfunction. Urinalysis with particular attention to urinary sediment should be performed as this can provide information suggesting renal damage and a glomerular or tubular injury. Other routine studies that can be helpful in supporting a diagnosis of chronic pneumonia include total serum protein and quantitative serum immunoglobulin levels. These are particularly helpful in discerning diagnosis of a common variable immunodeficiency disorder associated with hypogammaglobulinemia.

C-reactive protein and an erythrocyte sedimentation rate (ESR) can also be helpful studies. Both of these assays are typically elevated among patients with chronic pneumonia, but they are nonspecific abnormalities. Serologic tests for connective tissue disorders, including anti-nuclear antibodies (ANA), rheumatoid factor, and anti-neutrophil cytoplasmic autoantibodies (C-ANCA and P-ANCA) can also be useful in this setting. Finally, angiotensin-converting enzyme (ACE) is a useful, but nonspecific, assay with levels elevated in several granulomatous disorders, including sarcoidosis.

Results that confirm the diagnosis

Isolation by culture of a characteristic organism in the appropriate clinical setting is generally diagnostic of the etiology of chronic pneumonia. Cultures of sputum, bronchoscopically obtained specimens (BAL and/or transbronchial biopsy), and open-lung biopsy specimens for routine, fungal, mycobacterial, and atypical pathogens (Legionella, etc.) are typically most useful. Anaerobic cultures from expectorated sputum and bronchoscopically obtained specimens are less reliable and frequently misleading. Other cultures that may provide useful information include routine, anaerobic, fungal, and acid fast cultures from pleural fluid, when present. Blood cultures are usually negative among patients with chronic pneumonia syndrome, except for patients with right-sided endocarditis and septic pulmonary emboli. Occasionally, cultures of bone marrow, liver, or lymph node tissue can lead to or confirm a diagnosis of chronic pneumonia among patients with histoplasmosis, cryptococcosis, and other fungal infections, such as blastomycosis and coccidioidomycosis.

Gram stains, special preparations for fungi and mycobacteria, and special histologic stains are important in establishing a presumptive diagnosis before culture data are available. For instance, adequately obtained expectorated sputum revealing abundant neutrophils and pleomorphic, gram-positive, gram-negative, and/or gram-variable bacterial organisms consistent with a mixed aerobic-anaerobic lung infection coupled with a cavitary lesion on plain chest x-ray or chest CT scan are strongly suggestive of a mixed aerobic-anaerobic lung abscess. Similarly, gram-variable filamentous rods on a respiratory specimen are suggestive of an infection due to Nocardia species. The finding of broad-based budding yeasts on a potassium hydroxide preparation from an expectorated sputum sample is strong evidence for blastomycosis in the appropriate clinical setting.

Non-culture-based diagnostics can be very useful in this setting. In particular, the galactomannan (GM) assay for Aspergillus can be performed with serum or bronchoalveolar lavage (BAL), and a positive test strongly suggests a diagnosis of invasive aspergillosis in the appropriate host, especially patients with hematologic malignancies and/or stem cell transplant recipients, other immunocompromised patients, including lung transplant recipients, and other patients receiving iatrogenic immunosuppression.

Among patients, such as those with chronic obstructive pulmonary disease, lung neoplasia, bronchiectasis, and interstitial lung disorders, the sensitivity of the test is relatively poor. Nonetheless, a positive Aspergillusgalactomannan (GM)-positive assay is generally regarded as evidence for presumptive invasive pulmonary aspergillosis when coupled with a consistent radiographic finding obtained on a chest x-ray or CT of the chest. Other serologic tests of value among these patients include the Histoplasma antigen in urine and serum, the Blastomyces antigen in urine and serum, and Coccidioides serology (multiple assays). For each of the conditions, a positive assay is strongly indicative of invasive fungal disease, although there is significant cross reactivity between the Histoplasma and Blastomyces antigen assays, and these tests must be interpreted in light of existing clinical, epidemiology, and radiographic findings.

What imaging studies will be helpful in making or excluding the diagnosis of chronic pneumonia?

Routine chest radiographs are almost always abnormal among patients with chronic pneumonia. In the absence of typical radiographic findings on chest x-ray, CT, or chest MRI, it is difficult to make a diagnosis of this disorder. The radiographic abnormalities found among patients with chronic pneumonia are highly varied. As noted, an infiltrate of some sort is virtually always present, but may vary from patchy infiltrates with bronchopneumonia, lobar consolidation, infiltrates with pulmonary cavitation, those that are associated with one or more dense, well-circumscribed pulmonary nodules, and infiltrates associated with chronic diffuse pulmonary infiltration with or without fibrosis.

Patients with chronic pneumonia and patchy infiltrates or lobar consolidation can be a manifestation of mixed aerobic and anaerobic infection. Necrotizing pneumonia due to Pseudomonas aeruginosa, Staphylococcus aureus, Nocardia spp, Actinomyces spp, blastomycosis, cryptococcosis, and paracoccidioidomycosis are common examples. Necrotizing pneumonia associated with pulmonary cavitation is often a manifestation of lung abscess, complicating aspiration pneumonia due to mixed aerobic and anaerobic bacteria, tuberculosis, other non-tuberculous mycobacterial infections, chronic cavitary histoplasmosis, blastomycosis, nocardiosis, coccidioidomycosis, and several noninfectious conditions, such as ANCA-positive microvascular angiitis, bronchogenic carcinoma, and lymphoma.

Nodular lung disease is often a manifestation of either fungal or mycobacterial infection, and is a typical manifestation of cryptococcosis, histoplasmosis, coccidioidomycosis, tuberculosis, and selected non-tuberculous mycobacteria.

Diffuse pulmonary infiltrates, with or without fibrosis, are frequently associated with the following noninfectious conditions: sarcoidosis, hypersensitivity pneumonitis, allergic angiitis and granulomatosis, alveolar proteinosis, idiopathic pulmonary fibrosis, and radiation pneumonitis

Among infectious disorders causing chronic interstitial disease, most are associated with granulomatous infection due to disseminated histoplasmosis, blastomycosis, coccidioidomycosis, and disseminated mycobacterial infection.

The cost of imaging studies varies significantly, but, in general, the cost of a routine PA and lateral chest x-ray is least expensive, about $370. The average cost of a routine CT chest with/without contrast is between $1500 and $2500. A high resolution CT scan, which is typically not necessary in the work-up of a patient with chronic pneumonia, is more expensive. An MRI, which generally adds little to the work-up of a patient with chronic pneumonia, has an average cost between $2700 and $3000 for studies limited to the chest.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has chronic pneumonia, what therapies should you initiate immediately?

If the patient with chronic pneumonia is unable to produce adequate sputum samples, then a pulmonologist is most helpful in obtaining a deep (bronchoscopic) specimen. Less commonly, a thoracic surgeon is needed to obtain tissue from an open lung biopsy, often using the video-assisted thorascopic surgery (VATS) procedure. An infectious disease specialist can be very helpful with respect to considering less common diagnoses, especially those not evident following routine diagnostic studies.

For most patients presenting with chronic pneumonia, the condition does not constitute a medical emergency. Accordingly, there is usually time to establish a presumptive diagnosis before initiating antimicrobial therapy. As such, the patient with a clinical diagnosis of chronic pneumonia based on symptoms and abnormal imaging studies should undergo testing of expectorated sputum, if possible, immediately. Routine, acid fast, and fungal smears should be obtained on available specimens.

If patients are unable to produce a meaningful sputum sample, then bronchoscopy is usually necessary as the most efficient means of establishing a diagnosis. Respiratory isolation is warranted among patients with upper lobe infiltrate and cavitation or among those with an illness compatible with pulmonary tuberculosis. For other conditions, isolation is not necessary. Among patients from endemic areas, testing for urinary Histoplasma antigen, Blastomyces antigen, and serum for Coccidioides antibodies are warranted pending results of expectorated sputum and/or bronchoscopic results.

While pursuing a specific diagnosis, many clinicians choose to initiate empiric therapy for the more common bacterial pathogens. Antibacterial agents with activity against a broad array of common aerobic and anaerobic bacteria associated with chronic pneumonia are reasonable. Thus, the selection of agents, such as ampicillin/sulbactam or piperacillin/tazobactam, co-administered with vancomycin or nafcillin, are common initial approaches. The addition of metronidazole is advocated by some when there is strong suspicion of anaerobic pneumonia, but the use of and expanded spectrum penicillin combined with a beta-lactamase inhibitor provides excellent anaerobic coverage in most circumstances. Ceftriaxone plus metronidazole or clindamycin is an alternative for patients in whom a penicillin is not appropriate. If a fungal pathogen is likely, based on patient epidemiology and risk status, empiric antifungal therapy with voriconazole, itraconazole or posaconazole could be contemplated if aspergillosis, blastomycosis, coccidioidomycosis, or histoplasmosis is suspected.

For suspected non-tuberculous mycobacterial disease, empiric therapy for nontuberculous infection requires considerable knowledge of the patient’s history; for instance, a history of Mycobacterium avium infection in a patient with ongoing immunosuppression might warrant re-initiation of therapy directed at this organism.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection, what anti-infective should I order?

Chronic pneumonia is generally not a medical emergency, and the clinician has adequate time to conduct a reasonable assessment before having to decide on specific therapy. In most circumstances, empirical therapy is initiated once adequate diagnostic studies have been obtained. With the suspicion of aspiration pneumonia due to mixed aerobic and anaerobic bacteria, the combination of pipercillin/tazobactam or ampicillin/sulfabactam plus vancomycin or nafcillin is often utilized. Metronidazole may be added to this regimen if broader anaerobic coverage is desired.

For patients with other suspected bacterial pathogens, therapy should be driven by the results of Gram stain or other data that provide insight into the etiologic agent. For instance, a sputum sample revealing abundant gram-positive cocci in clusters should lead to the initiation of vancomycin. Conversely, if gram-negative bacilli are the dominant organisms, then use of pipercillin/tazobactam, cefepime, or ceftazodine would be reasonable. If infection due to higher order bacteria, such as Nocardia, is suspected based on clinical circumstances or the results of respiratory sample reviewing gram-variable branching filamentous rods, then initial therapy with sulfamethoxazole plus another agent, such as linezolid, moxifloxacin, or ceftriaxone, is reasonable. If respiratory samples reveal yeast forms compatible with Cryptococcus, Histoplasma, Blastomyces, or Coccidioides, then an azole, such as fluconazole or itraconazole, is probably the best empiric choice.

For patients with respiratory samples revealing acid fast organisms, the patient should be placed in respiratory isolation and four-drug therapy with rifampin, isoniazid, pyarzinamide, and ethambutol should be initiated until confirmation of the organism as M. tuberculosis or a nontuberculous mycobacteria. Table I lists agents that typically cause chronic pneumonia.