Infectious Diseases

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.

Table I.

Agents That Typically Cause Chronic Pneumonia
Organism Primary Therapy Alternative Therapy
Bacterial
Mixed aerobic/anaerobic bacteria Piperacillin/tazobactam 3.375 gms iv q6 hours or ampicillin/sulbactam 1.5-3 gms iv q 6 hours. May add vancomycin or nafcillin if S aureus suspected Ceftriaxone 1-2 gms/d plus metronidazole 500 mg tid. May add vancomycin or nafcillin if S aureus suspected
Actinomyces spp Ampicillin 4-8 gms daily or pencillin G 10-20 million units/d iv for 4 weeks, then po Pen VK 2-4 gms/d 3-6 weeks Ceftriaxone, doxycycline, clindamycin or erythromycin
Nocardia spp Trimethoprim/sulfamethoxazole plus imipenem Imipenem plus amikacin; linezolid plus a fluoroquinolone
Rhodococcus equi Azithromycin, levofloxacin or rifampin (use 2 drugs) Vancomycin or imipenem, plus levofloxacin, azithromycin or rifampin
Burkholderia pseudomallei Ceftazidime or imipenem for 10-14 days, then po TMP/SMX 5 mg/kg bid plus doxycycline 100 mg bid for 3 months
Mycobacteria
Mycobacteria tuberculosis Isoniazid 300 mg/d, rifampin 600 mg/d, ethambutol 15 mg/kg/d and pyrazinamide 2 gms/d for 8 weeks, then isoniazid and rifampin for 18 weeks (Isoniazid resistant M tb): Rifampin, ethambutol, pyrazinamide, and a fluoroquinolone for 6 months
M kansasii Isoniazid 300 mg/day, rifampin 600 mg/day, and ethambutol 15 mg/kg/d for 18 months Clarithromycin 500 mg bid plus rifampin plus ethambutol for 18 months
M avium complex Clarithromycin 500 mg bid or azithromycin 250 mg/day plus ethambutol 15 mg/kg/day plus rifampin 600 mg/day. May add daily streptomycin or amikacin to combination regimen Moxifloxacin 400 mg/day may be given in place of azithromycin or clarithromycin if poorly tolerated
Fungi
Aspergillus spp Voriconazole 6 mg/kg q12 hours X 2 doses loading, then 4mg/kg q12 hours, or voriconazole 200 mg po bid. An echinocandin may be added as adjunctive therapy for more severe cases Posaconazole 400 mg po bid, lipid AmB 3-5 mg/kg/d, or an echinocandin (caspofungin 70 mg/d, micafungin 150 mg/d or anidulafungin 200mg/d)
Blastomyces dermatitdis Itraconazole 200 mg po bid; lipid AmB 3-5 mg/kg d for more severe cases Fluconazole 800 mg/d, voriconazole 200 mg po bid, ketoconazole 400 mg po bid, or posaconazole 400 mg po bid
Coccidioides spp Fluconazole 400 mg/d, or itraconazole 200 mg bid, or lipid based AmB 3-5 mg/kg daily Posaconazole 400 mg po bid
Cryptococcus spp Fluconazole 400mg/day or lipid-based AmB 3-5 mg/kg/day x 2 weeks for severe cases, then step down to fluconazole Voriconazole 200 mg po bid or posaconazole 400 mg po bid
Histoplasmosis capsulatum Itraconazole 200 mg po bid or lipid based AmB, 3-5 mg/kg/day x 2 weeks for severe cases, then transition to itraconazole Posaconazole 400 mg po bid, or fluconazole 800 mg/day
Paracoccidioides brasiliensis TMP/SMX 800mg/160mg 2-3 x daily x 30 day, for 18-24 months OR itraconazole 200 bid po for 6-18 months OR AmB 1.5-2 gms total dose, then po itraconazole Ketoconazole 200-400 mg daily OR voriconazole 200 mg po bid OR posaconazole 400 mg po bid for 6-18 months
Sporothrix complex Lipid based AmB 3-5 mg/kg/day or conventional AmB 0.6-1.0 mg/kg daily (up to 6 weeks), then itraconazole 200 mg bid for 12 months Itraconazole 200 mg po bid for 12 months for less severe cases
Scedosporium spp Voriconazole 4mg/kg q12 hours iv or 200mg po bid Posaconazole 400 mg po bid or itraconazole 200 mg po bid
Dematiaceous molds Voriconazole 4mg/kg q12 hours IV or 200mg po bid Posaconazole 400 mg po bid or itraconazole 200 mg po bid
Parasites
Dirofilaria immitis Surgical excision, no effective drugs
Echinococcus granulosus Albendazole 400 mg po bid for 28 days
M bancrofti, B malayi Diethylcarbamazine (DEC) 6 mg/kg d X 14d plus doxycycline 100-200 mg/day x 6-8 weeks Albendazole plus DEC plus doxycycline for 6 weeks
Paragonimus westermani Praziquantel 25 mg/kg pot id x 2 days Triclabendazole 10 mg/kg po 2 doses over 24 hours
Protozoa
Entameoba histolytica Metronidazole 750 mg IV tid or tinidazole 2 gm/day x 5 days, then po paramomycin 25-35 mg/kg/day po for 7 days or po iodoquinol 650 mg tid for 20 days

2. Next list other key therapeutic modalities.

In addition to antimicrobial therapy, there are several other potential interventions that may be beneficial to patients with chronic pneumonia. Chief among these options is use of therapeutic bronchoscopy and surgery. Therapeutic bronchoscopy may play a role among patients with exuberant secretions and in whom pulmonary toilet can be facilitated by bronchoscopy coupled with chest physiotherapy. Surgery plays a limited role in the treatment of chronic pneumonia. Lobectomy or pneumonectomy can be considered among patients with chronic obstructive pneumonia, multiple abscesses or extensive abscess involving an entire lobe or lung, and among patients with nonfunction of a lobe or lung due to extensive infection. Surgery can also play a role among patients with reactive pleura or large pleural effusions leading to restrictive lung disease. In these situations, removal of the pleural effusion and/or decortication of the pleural reactive tissue can lead to significant improvement in pulmonary function.

The use of corticosteroids in the treatment of chronic pneumonia is controversial. If the cause of the illness is an infectious agent, particularly a bacterium or fungus, glucocorticoids are usually not indicated. However, some experts advocate a short course of glucocorticoids for patients with advanced pulmonary histoplasmosis, tuberculosis, and cryptococcosis with severe respiratory compromise. Steroids are generally part of routine management for selected patients with non-infectious causes of chronic pneumonia, such as sarcoidosis, chronic interstitial lung disease, ANCA-positive microvascular angiitis, and chronic organizing pneumonia. Other non-steroidal immunosuppressive agents, such as azathioprine and cyclophosphamide, can play a role in treating patients with pulmonary vasculitis and parenchymal disease involving the lung.

What complications could arise as a consequence of chronic pneumonia?

What should you tell the family about the patient's prognosis?

Death resulting from untreated chronic pneumonia is seen among patients with limited access to care and advanced disease and among those who develop massive hemoptysis. More commonly, inanition with wasting, worsening chronic pulmonary disease, pneumothorax, empyema necessitans, and mild to moderate hemoptysis may occur.

Delay in diagnosis and extensive multilobar disease are important factors linked to poor outcome, including death. Patients with multilobar disease at presentation are at risk for clinical deterioration and respiratory failure even after appropriate therapy is initiated. Patients with significant underlying lung disease, such as COPD or restrictive lung disease, are at greatest risk of complications, including worsening lung function, pneumothorax, massive hemoptysis, and death. Pre-existing malnutrition is an important predisposition for a poor outcome as well, and many patients have advanced malnutrition at presentation because of prolonged illness. Organ failure syndromes, such as chronic liver and kidney disease, congestive heart failure, and diabetes mellitus, are important co-morbid conditions that adversely affect outcome.

Add what-if scenarios here:

  • Be aware that the specific etiology of suspected mixed aerobic/anaerobic pneumonia can be very elusive (e.g., “heavy normal flora” may be the only culture data to support a diagnosis). A good sputum specimen and appropriately interpreted Gram stain can be essential.

  • Fungal pneumonia (i.e., blastomycosis, histoplasmosis, coccidioidomycosis) is often overlooked as a possibility, because the Gram stain is negative for fungal elements. A good history, including relevant epidemiology, and a compatible clinical and radiographic scenario should prompt specific testing for fungal agents (i.e., KOH sputum preparation, special stains for fungi, appropriate serum and urine non-culture based assays).

  • Non-infectious etiologies are a common cause of chronic pneumonia syndrome. A careful search for neoplasia, non-infectious inflammatory conditions (e.g., sarcoidosis, rheumatoid arthritis), and environmental/drug exposure should be undertaken when no infectious etiology can be demonstrated.

  • Look for more than one cause of chronic pneumonia, particularly among patients with pre-existing cavitary lung disease. In these patients, two infections may co-exist. For example, patients with chronic cavitary tuberculosis may develop chronic pulmonary aspergillosis (aspergilloma or chronic necrotizing aspergillosis).

How do you contract chronic pneumonia and how frequent is this disease?

With the exception of pulmonary tuberculosis, chronic pneumonia is an uncommon condition seen mainly in adolescents and adults. Men are generally affected more commonly than women, and the disease is seen more commonly among patients with limited access to health care. In evaluating a patient with chronic pneumonia, a history of travel and residing in certain geographic areas is important in considering certain diagnoses. Exposure to parts of the eastern, midwestern, and southcentral United States; most of the Amazon region of South America; and throughout much of the tropics should lead to a consideration of histoplasmosis. Similarly, patients with exposure to the upper midwestern and southcentral United States and central Canada should consider blastomycosis. Paracoccidioidomycosis should be considered among patients with exposure to the Amazon region and parts of Central America, particularly those who have resided there for long periods. Cryptococcus gattii infection should be suspected among patients who have lived in or visited the Pacific Northwest.

Among the other more common mold pathogens, such as Aspergillus, Fusarium, and black molds, of more value is the underlying condition, such as COPD, chronic immunosuppression, and chronic renal and/or hepatic disease. A history of alcoholism, swallowing disorders, seizure disorder, and illicit drug use is an important predisposition to chronic pneumonia due to aerobic and anaerobic bacteria. Infections due to Burkholderiapseudomallei are seen almost exclusively among residents of Southeast Asia, Indonesia, the Philippines, India, and northern Australia. A history of ingestion of raw or undercooked shellfish should lead to suspicion of infection due Paragonimus westermani.

With few exceptions, there is little known seasonal variation with chronic pneumonia as it relates to its specific etiology. One exception is disease due to Coccidioides species. There is seasonal variability associated with newly acquired coccidioidomycosis that relates to a change in weather patterns, including warm, windy conditions following heavy rains, typically a phenomenon of spring and fall in endemic areas of California and Arizona. Infection due to B pseudomallei is strongly linked to heavy rainfall in southeast Asia.

The means of acquisition for agents causing chronic pneumonia varies considerably. For most fungal organisms, the mode of spread is inhalation, with the lungs serving as the primary site of infection. For patients with chronic pneumonia due to aerobic and anaerobic bacteria, the presumed pathogenesis is aspiration of oral contents. For other bacterial agents, such as Nocardia species, Actinomyces, Rhodococcus, and the nontuberculous mycobacteria, acquisition is assumed either through inhalation of aerosolized organisms or ingestion followed by aspiration, but studies exploring in detail the mode of transmission have not been performed. The two chief parasitic causes of pneumonia, filariasis and dirofilariasis, are mosquito-borne diseases.

Epidemiologic studies focusing on the incidence of chronic pneumonia overall or as it relates to a specific etiology are generally unavailable and/or poorly performed. Collectively, these studies shed little useful light on the understanding and pathogenesis of chronic pneumonia. The overall incidence of chronic pneumonia is difficult to ascertain. There are limited data pertaining to specific pathogens, but these data are sparse. A reasonable estimate for some of the more common disorders associated with chronic pneumonia in the general population specifically is likely no more than 1/100,000. It is much less common for some conditions, such as pulmonary sporotrichosis, which occurs in fewer than 1/1,000,000 people.

There is little evidence of zoonotic transmission as an important means of acquiring the agents of chronic pneumonia. Among the most common agents, most are related to exposure to soil, water or ingested material, and arthropod exposure.

What pathogens are responsible for this disease?

  • Mixed aerobic and anaerobic bacteria, including routine aerobic gram-negative bacilli, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and other Enterobacteriaceae; occasionally Staphylococcus aureus; “higher order bacteria,” such as Actinomyces spp, Nocardia complex, and Rhodococcus equi; selected “endemic bacteria,” such as Burkholderia pseudomallei.

  • M tuberculosis, M kansasii, M avium complex, M abscessus, M fortuitum, M malmoense, M szulgae, M xenopi, M smegmatis, M simiae, and rarely M scrofulaceum.

  • Aspergillus spp, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Blastomyces dermatitidis. Coccidioides immitis/posadosii, Paracoccidioides brasiliensis, Scedosporium apiospermum/prolificans, Sporothrix complex, Fusarium spp, zygomycetes, and dematiaceous fungi (darkly pigmented fungi, black molds).

  • Paragonimus westermani, Echinococcus granulosus, agents of filariasis (esp W bancrofti and B malayi), and Dirofilaria immitis.

  • Entameoba histolytica.

How do these pathogens cause chronic pneumonia?

Fungi

The endemic fungal pathogens, including B. dermatitidis, H. capsulatum, P. brasiliensis, C. immitis/posadasii, and S. schenckii, typically cause vigorous granulomatous inflammation. For B. dermatitidis, a mixture of granulomatous and neutrophilic inflammation (“pyogranulomatous” inflammation) is often seen with infection. For patients with severely impaired T-cell function, granulomatous inflammation may be absent. Following inhalation of these organisms into the alveoli, they are phagocytized by tissue microphages. The organisms divide intracellularly and spread to regional lymph nodes via the macrophages. Subsequently, containment of the organisms can occur at this point or further dissemination to extra-regional lymph nodes and/or other components of the reticuloendothelium occurs.

The specific virulence factors for the endemic fungi are poorly understood. For Cryptococcus species, granulomatous inflammation is also a primary host response, but the organism is less adenopathic than the endemic fungal pathogens. Following primary pulmonary infection, dissemination to distant organs via the bloodstream, including the central nervous system (CNS), prostate, skin, and subcutaneous tissues, may be seen. The polysaccharide capsule of Cryptococcus is one of its more important virulence factors.

For mold infections, exemplified by Aspergillus species, direct invasion of blood vessels leads to invasive disease characteristically causing necrosis as infection progresses. Following inhalation of aerosolized spores, these structures can transform into hyphal forms with invasive potential. Extrapulmonary dissemination occurs through the bloodstream with most mold infections, including Aspergillus, Fusarium, the pigmented fungi, and Scedosporium species.

Bacteria

Mycobacteria gain access to the lungs via inhalation (especially M tuberculosis) and possibly through ingestion or drinking contaminated material. The primary host response is to mycobacteria is granulomatous in the normal host. In patients with significant T-cell dysfunction, granulomatous inflammation may be attenuated or entirely lacking. Following initial infection with non-tuberculous mycobacteria, through ingestion or inhalation, organisms are phagocytized by alveolar macrophages where the infection is either contained or a chronic inflammatory response with tissue destruction ensues. Reactivation of infection following a long period of latency has not been reported. Most bacteria, including mouth anaerobes and common aerobic bacteria, cause pneumonia following aspiration of oral contents. This is followed by local inflammation with or without tissue necrosis.

Virulence factors for bacteria vary broadly, but most of anaerobic bacteria produce proteases, lipopolysaccharides (LPS), hemolysin, and leukotoxin. For aerobic bacteria, including Staphyloccocus aureus, a variety of virulence factors, including biofilm production, capsule, hemolysins, and other toxins, may play a role. For gram-negative bacteria LPS is a very potent virulence factor. In addition, many gram-negative rods possess a polysaccharide capsule as well as fimbria that allow for attachment to mucosal surfaces. Taken together, bacterial virulence factors associated with anaerobic and aerobic bacterial pneumonia are large and varied in both form and function. The role and importance of different virulence factors are affected by the host in significant ways: acquired immune function, comorbid conditions, medications, and other factors play a major role in determining host response, and whether a given bacterial virulence factor plays a major or minor role in the development of pneumonia.

What other clinical manifestations may help me to diagnose and manage chronic pneumonia?

It is difficult to over-emphasize the importance of a detailed history as a key in making a specific diagnosis of chronic pneumonia. A complete history of recent travel, vocation, hobbies, other relevant activities, and potential drug exposures is essential in arriving at a limited list of possibilities until a specific diagnosis can be established.

For patients with chronic pneumonia, the physical examination is first helpful in establishing the diagnosis of pulmonary disease. However, it is the extrapulmonary findings that are essential in helping to shed light on a specific etiology; for instance, a plaque-like, papulosquamous lesion on the foot, suggesting blastomycosis; the verrucous nasal lesion in a black individual, suggesting coccidioidomycosis; diffuse umbilicated papular skin lesions, suggesting cryptococcosis; right upper quadrant pain and hepatomegaly, suggesting amebiasis; focal neurologic findings, suggesting CNS nocardiosis.

What other additional laboratory findings may be ordered?

Newer assays for cryptococcal antigen and Histoplasma antigen are being developed and have potential use for early rapid diagnosis for pneumonia due to these agents. The technology is based on a lateral flow assay (LFA), much like a urine dipstick test. The tests are rapid, sensitive, inexpensive, and ideally suited for point of care diagnostics.

How can chronic pneumonia be prevented?

Avoidance of exposure is the only sure way to prevent disease. For much of the world's population, this is impractical because of the ubiquitous nature of many of these pathogens, especially the non-tuberculous mycobacteria, the endemic pathogens, such as B. pseudomallei and the endemic fungi, Cryptococcus spp, and other fungi, both higher order and typical bacteria, and exposure to arthopod vectors. Thus, prevention per se entails careful attention to avoidance of endemic areas for specific pathogens and reducing exposure to certain vectors (e.g., mosquitoes). Currently, there are no vaccines to prevent the causes of chronic pneumonia.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Bradsher, RW, Chapman, SW, Pappas, PG. "Blastomycosis". Infect Dis Clin North Am. vol. 17. 2003. pp. 21-40.

(This review is co-written by 3 experts and provides the most recent detailed review of blastomycosis.)

Brizendine, KD, Baddley, JW, Pappas, PG. "Pulmonary cryptococcosis". Semin Respir Crit Care Med. vol. 32. 2011. pp. 727-34.

(This recent review of pulmonary cryptococcosis provides important insights into the underlying diseases, diagnosis, clinical and radiographic appearance, and therapy of pulmonary cryptococcosis.)

Chiller, TM, Galgiani, JN, Stevens, DA. "Coccidioidomycosis". Infect Dis Clin North Am. vol. 17. 2003. pp. 41-57.

(This is a very well written review of coccidioidomycosis and includes a broad description of pulmonary and extrapulmonary disease. The therapeutic section is up to date, with the exception that there is no mention of posaconazole as a therapeutic possibility.)

Cortez, KJ, Roilides, E, Quiroz-Telles, F. "Infections caused by Scedosporium spp". Clin Microbiol Rev. vol. 21. 2008. pp. 157-97.

(This is an exhaustive review of scedosporiosis, including extrapulmonary manifestations, and a recently updated antifungal susceptibility and therapeutic data. It is a very good reference for virtually any complication of scedosporiosis.)

Goodwin, RA, Owens, FT, Snell, JD. "Chronic cavitary histoplasmosis". Medicine. vol. 55. 1976. pp. 413-52.

(Written in the pre-azole era, this is an excellent and often quoted review that provides important perspective on the radiographic, clinical, and diagnostic features of cavitary histoplasmosis.)

Jarzembowski, JA, Young, MB. "Nontuberculous mycobacterial infections". Arch Pathol Lab Med. vol. 132. 2008. pp. 1333-41.

(Excellent overview of laboratory aspects of atypical mycobacteria)

Kirtland, SH, Winterbauer, RH, Dreis, DF. "A clinical profile of chronic bacterial pneumonia: Report of 115 cases". Chest. vol. 106. 1994. pp. 15-22.

(Older, but still valuable overview of chronic bacterial pneumonias)

Maertens, J, Verhaegen, J, Lagrou, K. "Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: A prospective validation". Blood. vol. 97. 2001. pp. 1604-10.

(These authors provide a strong foundation for routine screening with Aspergillus galactomannan in high risk stem patients with hematologic malignancies and stem cell transplant recipients.)

Martinez, R, Reyes, M, Menedez, R. "Pulmonary nocardiosis: risk factors, clinical features, diagnosis and prognosis". Current Opin Pulm Med. vol. 14. 2008 May. pp. 219-27.

(This is a very nice review of pulmonary nocardiosis from a Spanish group with much clinical experience with this disorder. There is an increasing emphasis on the recognition of non-asteroides isolates and highly variable susceptibility data.)

Maschmeyer, G, Haas, A, Cornely, OA. "Invasive aspergillosis: Epidemiology, diagnosis and management in immunocompromised patients". Drugs. vol. 67. 2007. pp. 1567-601.

(Drawing on their extensive personal experience in Germany, these 3 investigators provide important insights into the diagnosis and management of invasive aspergillosis from a European perspective.)

Peacock, SJ. "Melioidosis". Curr Opin Infect Dis. vol. 19. 2006. pp. 421-8.

(Helpful review of infection due to this organism rarely seen in the U.S.)

Plus, JL, Opal, SM. "Pulmonary sporotrichosis: Review of treatment and outcome". Medicine. vol. 65. 1986. pp. 143-53.

(This is the “classic” paper on pulmonary sporotrichosis, emphasizing its clinical and radiographic presentation.)

Queiroz-Telles, F, Escuissato, DL. "Pulmonary paracoccidioidomycosis". Semin Respir Crit Care Med. vol. 32. 2011. pp. 764-74.

(In this review of paracoccidioidomycosis, two Brazilian investigators provide the most recent update on the current approaches to diagnosis, imaging, clinical features and treatment of paracoccidioidomycosis.)

Schluger, NW. "Tuberculosis and nontuberculous mycobacterial infections in older adults". Clin Chest Med. vol. 28. 2007. pp. 773-81.

(Nice review of mycobacterial infections in older adults)

Shorr, AF, Susla, GM, O’Grady, NP. "Pulmonary infiltrates in the non-HIV-infected immunocompromised patient: Etiologies, diagnostic strategies, and outcomes". Chest. vol. 125. 2004. pp. 261-71.

(Authors give an approach to diagnosis of infiltrates in immunocompromised patients)

Yildiz, O, Doganay, M. "Actinomycoses and Nocardia pulmonary infections". Curr Opin Pulm Med. vol. 12. 2006. pp. 228-34.

(Recent commentary on pulmonary infections by the Actinomycetes

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