Etiology

The causes of persistent pulmonary infiltrate may be infectious or noninfectious.[1][2][3]​ Patients with persistent pulmonary infiltrate may present with or without clinical symptoms (e.g., cough, hemoptysis). Comprehensive investigation of the nature of persistent pulmonary infiltrate may be warranted when clinical improvement has not occurred with treatment, if chest radiographic findings remain unchanged or worsen, or if the rate of radiographic resolution is delayed.[2]

Infectious

About 10% to 25% of patients with community-acquired pneumonia and 30% to 60% of those with nosocomial pneumonia do not improve despite therapy.[13][16]

Community-acquired pneumonia may be secondary to atypical organisms (e.g., Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, or respiratory viruses) and is often seen in young adults living in close proximity to those infected by these microorganisms.

Older and immunosuppressed patients are more susceptible to viral pneumonia, and secondary or superinfection with other organisms (e.g., Staphylococcus aureus, Haemophilus influenzae) is common.

Tuberculosis, in endemic areas, should be considered whenever pulmonary infiltrate persists after conventional antibiotic therapy. Fungal pneumonia (e.g., Pneumocystis jiroveci) may be accompanied by fungal granulomas. Viral pneumonia is often associated with organizing pneumonia leading to persistent pulmonary infiltrate. It may present clinically in a manner similar to community-acquired pneumonia (i.e., flu-like illness with fever, malaise, fatigue, cough), with a persisting recurrent or migratory bilateral diffuse alveolar infiltrate.[17][18][19]

Resistant or unusual pathogens (fungi, Mycoplasma tuberculosis, Nocardia, or Actinomyces), and allergic bronchopulmonary Aspergillus may also cause persistent pulmonary infiltrate.[20][21]

Complications of pneumonia, like empyema and abscess, can result in nonresolving pneumonia especially in patients with comorbid conditions. Computed tomography (CT) scan is generally used as a diagnostic modality, with or without an air bronchogram in the presence of an alveolar infiltrate. Thoracentesis is a definitive procedure in case of empyema and no other tests are required. Obstruction caused by lung cancer (e.g., bronchogenic carcinoma, bronchial carcinoid tumors, papillomas, or metastatic lesions such as breast, kidneys, or gastrointestinal tract) can lead to recurrent postobstructive nonresolving pneumonia or abscess.

[Figure caption and citation for the preceding image starts]: Causes of nonresolving pneumoniaCreated by the BMJ Knowledge Centre based on tables from Athanasia Pataka [Citation ends].com.bmj.content.model.assessment.Caption@60941bd6

Immunosuppressed

Patients with AIDS and non-HIV-immunocompromised hosts may present several possibilities for persistent pulmonary infiltrate (e.g., P jiroveci pneumonia, tuberculosis).[22][23][24][25][26][27]​ Kaposi sarcoma may cause persistent pulmonary infiltrate.[Figure caption and citation for the preceding image starts]: Posterior-anterior chest x-ray in Pneumocystis jiroveci pneumonia showing severe, bilateral pulmonary interstitial infiltrates with pneumatocelesFrom the collection of Matthew Gingo, UPMC [Citation ends].com.bmj.content.model.assessment.Caption@5303fe3a

[Figure caption and citation for the preceding image starts]: Causes of persistent pulmonary infiltrate in immunocompromised patientsCreated by the BMJ Knowledge Centre based on tables from Athanasia Pataka [Citation ends].com.bmj.content.model.assessment.Caption@36aedc98

Malignant

Smokers ages >45 years with recurrent pneumonia, hemoptysis, and weight loss should be evaluated for a possible malignancy.[2] Bronchoalveolar cell carcinoma may present as an alveolar infiltrate with an air bronchogram, resembling nonresolving pneumonia. Lymphoma may also present as an alveolar infiltrate, often with an air bronchogram. Kaposi sarcoma may cause persistent pulmonary infiltrate, particularly in patients with AIDS.

Pulmonary parenchymal

A foreign body in the airways may cause recurrent postobstructive nonresolving pneumonia distal to the obstructing object.[2][28]

Aspiration pneumonia is characterized by a history of recumbency, halitosis, and dysphagia in a debilitated or paralyzed patient. The classic radiologic finding is an infiltrate in dependent lung fields with a sputum culture of oral or mixed flora.

Lipoid pneumonia develops when lipids enter the bronchial tree.[29] Lipids may be inhaled (e.g., nose drops with an oil base, accidental inhalation of cosmetic oil) or may fill the lumen of bronchi and microairways distal to the obstruction. Typical biopsy findings include lipid-laden foamy macrophages and giant cells. Infiltrating amyloidosis is an uncommon cause of persistent pulmonary infiltrate.[30]

Cardiovascular

Cardiogenic pulmonary edema can manifest as asymmetric infiltrative patterns in patients with COPD.[31][32][33] It persists if treated only with antibiotics. Migrating, transient infiltration is typically found on serial chest x-ray. Comparison of supine and prone views may be helpful, as the basilar infiltrate of pulmonary edema generally improves with the prone position. These patients typically have clinical signs (e.g., heart murmurs, S3, peripheral edema, elevated jugular venous pressure) that facilitate correct diagnosis.

Pulmonary embolism with infarction can mimic pneumonia that resolves slowly. The classic triad of acute dyspnea, chest pain, and hemoptysis is only rarely seen clinically. The chest x-ray findings of thromboembolic disease may be nonspecific, with cavitated consolidation and right heart enlargement. Serial studies of the chest using conventional radiography or CT demonstrate gradual clearing from the periphery of the infiltrate toward its center (melting ice sign). CT angiogram or spiral (helical) CT scanning with intravenous contrast permits visualization of the embolus, which may be accompanied by wedge-shaped consolidation.[34][35]

Inflammatory/immunologic

Patients with connective tissue disorders also may present with pulmonary infiltrate. Systemic lupus erythematosus may affect the lung, its vasculature, the pleura, and even the diaphragm. The most common manifestation of pulmonary disease in patients with rheumatoid arthritis is interstitial lung disease. Pulmonary disease in patients with dermatomyositis or polymyositis may reflect either a complication of the underlying inflammatory myopathy or an adverse effect of medications used for treatment. Scleroderma may cause recurrent aspiration pneumonitis due to esophageal disorders.

Interstitial lung diseases can cause different types of radiologic abnormalities, including persistent pulmonary infiltrate. These diseases may be idiopathic or associated with occupational or environmental exposures, drugs, and collagen-related or vascular diseases.[36]

[Figure caption and citation for the preceding image starts]: Etiologies and possible differential diagnosis of interstitial lung diseaseCreated by the BMJ Knowledge Centre based on tables from Athanasia Pataka [Citation ends].com.bmj.content.model.assessment.Caption@31d4e2b2

Organizing pneumonia can also be associated with connective tissue disorders, other interstitial pneumonias, infection, drugs, or malignancies. It may have clinical presentation similar with that of community-acquired pneumonia (i.e., flu-like illness with fever, malaise, fatigue, cough) and chest imaging findings similar to those of persisting recurrent or migratory bilateral diffuse alveolar infiltrates.

Diffuse alveolar hemorrhage can be caused by a variety of diseases (e.g., connective tissue vascular disorders, drugs, mitral valve disease, infection) and may mimic pneumonia that persists with diffuse opacities on chest imaging.[5][17][18][37][38][39]

Systemic vasculitis may affect the lower respiratory tract and present as cough, dyspnea, hemoptysis, persistent alveolar opacities, diffuse hazy opacities (which may reflect alveolar hemorrhage), cavitary nodules, and pleural effusion.[17]

Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) is a systemic vasculitis that primarily involves the upper and lower respiratory tracts and kidneys. Pulmonary granulomatosis with polyangiitis can present as multifocal lung involvement or solitary lung lesions with no evidence of extrapulmonary disease.

Sarcoidosis can involve any organ, but respiratory symptoms combined with chest radiographs with pulmonary infiltration alone, without the characteristic bilateral hilar lymphadenopathy, can mimic pneumonia that persists despite antibiotic treatment.[40]

Occupational and environmental exposures are important.[41][42][43][44]

  • Inhaled aerosols from electronic cigarettes (e-cigarettes) can contain harmful or potentially harmful substances (e.g., heavy metals, ultrafine particles, volatile organic compounds and other chemicals. Radiologic findings in people with severe pulmonary disease associated with e-cigarette use include pulmonary infiltrates on chest x-ray and bilateral ground glass infiltrates on chest CT.[45]

  • Silicosis may account for diffuse persistent opacities on chest x-ray.[44]​ Progressive massive fibrosis is usually associated with coal workers' pneumoconiosis and silicosis.

  • Asbestosis may be responsible for persistent interstitial and pleural infiltrates or rounded atelectasis (pleural adhesions and fibrosis causing deformation of the lung and bending of some small bronchi).[42][43]

[Figure caption and citation for the preceding image starts]: Posterior-anterior chest x-ray with bibasilar linear interstitial changes consistent with asbestosisFrom the personal collection of Kenneth D. Rosenman, MD [Citation ends].com.bmj.content.model.assessment.Caption@5b7c8b84

Eosinophilic pneumonias are a heterogeneous group of disorders characterized by abnormally increased numbers of eosinophils within the pulmonary parenchyma (with or without serum eosinophilia). They may cause persistent pulmonary infiltrate, but most patients improve with glucocorticoids.[46][47][48][49][50]

  • Acute idiopathic eosinophilic pneumonia may manifest as acute fever, cough, dyspnea, and pulmonary opacities that can lead to respiratory failure. Peripheral eosinophilia is rare at the time of presentation of idiopathic acute eosinophilic pneumonia (cause of acute infiltrates).

  • Idiopathic chronic eosinophilic pneumonia is characterized by subacute or chronic respiratory symptoms, alveolar and blood eosinophilia, and peripheral pulmonary infiltrates on chest imaging.

  • Loeffler syndrome was first described in 1932 in the context of parasitic infection, systemic eosinophilia, and chest infiltrates. Generally, these patients clinically present with a mild respiratory illness, with nonproductive cough, pleuritic chest pain, fever, and (rarely) hemoptysis.

  • Allergic bronchopneumonic aspergillosis is a hypersensitivity reaction to A fumigatus mold that has colonized the bronchi.[50] The disease typically affects patients with asthma or cystic fibrosis, but it is also associated with diminished immunity. Serology for Aspergillus may help to support the diagnosis. Skin-prick sensitivity for the organism is also a useful diagnostic adjunct.[Figure caption and citation for the preceding image starts]: Chest x-ray of a patient with eosinophilic pneumoniaFrom the collection of Athanasia Pataka, MD [Citation ends].com.bmj.content.model.assessment.Caption@3132fda7

Hypersensitivity pneumonia (extrinsic allergic alveolitis) can lead to persistent pulmonary infiltrate with mid- to upper-zone predominance if exposure to the offending antigen continues.[51][52][53]

Pulmonary alveolar proteinosis is a rare lung disease resulting from decreased surfactant clearance, and it presents as persistent pulmonary infiltrate and shortness of breath.[17][54][55]

Infiltrating amyloidosis is an uncommon cause of persistent pulmonary infiltrate.

Pharmacologic/iatrogenic

Some medications (e.g., amiodarone, bleomycin, cyclophosphamide, vincristine, taxanes), cocaine, or other illicit drug use may cause persistent pulmonary abnormalities.[18][56][57][58]​ Patients with malignancies undergoing chemotherapy or radiotherapy may present with persistent pulmonary infiltrate due to not only their malignancy but also complications of treatment.[26][59][Figure caption and citation for the preceding image starts]: Chest CT scan of a patient with amiodarone pulmonary toxicity showing asymmetric opacities with a peripheral distributionFrom the collection of Athanasia Pataka, MD [Citation ends].com.bmj.content.model.assessment.Caption@2e9e09d1[Figure caption and citation for the preceding image starts]: Chest x-ray of a patient with amiodarone pulmonary toxicityFrom the collection of Athanasia Pataka, MD [Citation ends].com.bmj.content.model.assessment.Caption@370d866b

[Figure caption and citation for the preceding image starts]: Possible causal agents of drug-induced pulmonary parenchymal diseaseCreated by the BMJ Knowledge Centre based on tables from Athanasia Pataka [Citation ends].com.bmj.content.model.assessment.Caption@20b84b48

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