Aetiology

The causes of persistent pulmonary infiltrate may be infectious or non-infectious.[1][2][3]​ Patients with persistent pulmonary infiltrate may present with or without clinical symptoms (e.g., cough, haemoptysis). 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

Between 10% and 25% of patients with non-resolving 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 micro-organisms.

Older and immunosuppressed patients are more susceptible to viral pneumonia, and 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 organising 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) may also cause persistent pulmonary infiltrate.[20][21]

Complications of pneumonia, such as empyema and abscess, can result in non-resolving 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 tumours, papillomas, or metastatic lesions such as those in the breast, kidneys, or gastrointestinal tract) can lead to recurrent post-obstructive non-resolving pneumonia or abscess.

[Figure caption and citation for the preceding image starts]: Causes of non-resolving pneumoniaCreated by the BMJ Knowledge Centre based on tables from Athanasia Pataka [Citation ends].com.bmj.content.model.assessment.Caption@3ee716e2

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's 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 pneumatocoelesFrom the collection of Matthew Gingo, UPMC [Citation ends].com.bmj.content.model.assessment.Caption@66c37445

[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@519c8f6c

Malignant

Smokers aged >45 years with recurrent pneumonia, haemoptysis, 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 non-resolving pneumonia. Lymphoma may also present as an alveolar infiltrate, often with an air bronchogram. Kaposi's sarcoma may cause persistent pulmonary infiltrate, particularly in patients with AIDS.

Pulmonary parenchymal

A foreign body in the airways may cause recurrent post-obstructive non-resolving pneumonia distal to the obstructing object.[2][28] Aspiration pneumonia is characterised by a history of recumbency, halitosis, and dysphagia in a debilitated or paralysed patient. The classic radiological 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 micro-airways 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 oedema 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 oedema generally improves with the prone position. These patients typically have clinical signs (e.g., heart murmurs, S3, peripheral oedema, elevated jugular venous pressure) that facilitate correct diagnosis.

Pulmonary embolism with infarction can mimic pneumonia that resolves slowly. The classic triad of acute dyspnoea, chest pain, and haemoptysis is only rarely seen clinically. The chest x-ray findings of thromboembolic disease may be non-specific, 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 towards its centre (melting ice sign). CT angiogram or spiral (helical) CT scanning with intravenous contrast permits visualisation of the embolus, which may be accompanied by wedge-shaped consolidation.[34][35]

Inflammatory/immunological

Patients with connective tissue disorders 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 medicines used for treatment. Scleroderma may cause recurrent aspiration pneumonitis due to oesophageal disorders.

Interstitial lung diseases can cause different types of radiological 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]: Aetiologies 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@172cbf2

Organising pneumonia can also be associated with connective tissue disorders, other interstitial pneumonias, infection, drugs, or malignancies. It may have a clinical presentation similar to 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 haemorrhage 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, dyspnoea, haemoptysis, persistent alveolar opacities, diffuse hazy opacities (which may reflect alveolar haemorrhage), cavitary nodules, and pleural effusion.[17]

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

Sarcoidosis can involve any organ, but respiratory symptoms combined with chest radiographs showing 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, ultra-fine particles, volatile organic compounds and other chemicals. Radiological 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@223cee76

Eosinophilic pneumonias are a heterogeneous group of disorders characterised 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, dyspnoea, and pulmonary opacities that can lead to respiratory failure. Peripheral eosinophilia is rare at the time of presentation of idiopathic acute eosinophilic pneumonia.

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

  • Loeffler's 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 non-productive cough, pleuritic chest pain, fever, and (rarely) haemoptysis.

  • Allergic bronchopneumonic aspergillosis is a hypersensitivity reaction to Aspergillus fumigatus mould that has colonised 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@72c1ce9f

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.

Pharmacological/iatrogenic

Some medications (e.g., amiodarone, bleomycin, cyclophosphamide, vincristine, taxanes), and cocaine or other illicit drugs, 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@cb1b754[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@25f3c176

[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@990e4e7

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