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ECR 2019 / C-2055
Magna Cum Laude
Differential Diagnosis of Diffuse Ground Glass Opacifications Made Easy
Congress: ECR 2019
Poster No.: C-2055
Type: Educational Exhibit
Keywords: Lung, Thorax, CT, Education, Structured reporting, Education and training
Authors: S. Röhrich, F. Prayer, H. Prosch; Vienna/AT
DOI:10.26044/ecr2019/C-2055

Findings and procedure details

 

Pathophysiology of GGO on CT scans

Ground glass opacifications are one of the most commonly encountered pulmonary patterns in chest CTs. The underlying mechanism is an increase in density caused by a partial filling or collapse of the alveoli or the thickening of the interstitial tissue (Fig. 1).

 

Alveoli may fill with:

  • Transudate (pulmonary edema, inflammatory reaction)

  • Aspirated material

  • Hyaline (ARDS)

  • Mucins (mucinous adenocarcinoma of the lung, pulmonary alveolar proteinosis)

  • Pus

  • Blood

  • Cells (adenocarcinoma, lymphoma) 

A collapse of alveoli may be triggered by:

  • Longstanding obstruction of bronchi with consecutive absorption of remaining air

An increase of surrounding interstitial structure occurs in:

  • Sarcoidosis
  • Organizing pneumonia
  • Fibrotic lung disease

 

 

Three questions that guide the differential diagnosis:

 

1.) Is it a pathology? (mind the inspiration depth and the overall quality of the scan)

 

One of the most common findings simulating GGO is insufficient inspiration depth and dependent atelectasis (Fig. 2 & 3). A look at the posterior membranous tracheal wall can help to make sure that the patient has inhaled sufficiently (Fig. 2). The typical distribution of dependent atelectasis in the posterior parts and adjacent to vertebral bodies further helps to distinguish them from GGO.


A second scan in deep inspiration or in a prone position can help to ventilate previously less aerated lung regions (Fig. 3).

 

Another pitfall is the misclassification of normal lung tissue as GGO in mosaic perfusion or next to air trapping. In this situation, scans both during inspiration and expiration are mandatory:

 

Pathology: air trapping and mosaic perfusion (= reduced blood flow, Fig. 4)

  • Hypodense = pathological
  • Hyperdense = normal lung
  • The difference will increase in expiration (i.e., normal lung becomes denser).

Pathology: GGO

  • Hypodense = normal lung
  • Hyperdense = pathological
  • The difference will decrease in expiration (i.e., normal lung becomes denser and harder to differentiate from GGO)

If all three patterns (normal, GGO, air trapping) are present, the distinction between the respective patterns becomes difficult. However, this combination by itself is specific for hypersensitivity pneumonitis and is called head-cheese-sign (Fig. 5).

 

2.) Is the GGO acute or chronic? (Fig. 5)

 

Acute: less than a few weeks

  • Most imaging findings are of little help because they are unspecific in the acute stage. Clinical symptoms and the patient’s history are more important.

Chronic: more than 6 weeks

  • In the chronic stage, there are important imaging findings that may guide the diagnosis (see down below).

Pitfalls:

  • Recurring acute GGO might be misinterpreted as chronic (e.g. pulmonary hemorrhages in pulmonary-renal syndromes)
  • Bronchoalveolar lavage can lead to sudden changes in the image in both directions: either decreased attenuation (e.g., improvement in pulmonary alveolar proteinosis) or increased attenuation (residuary fluid).

 

3.) What is the patient’s medical history?

Table 1 lists clinical features that are associated with pathologies that commonly produce GGO.

 

Review of imaging findings:

 

1.) Spatial distribution of GGO

All causes of acute GGO may lead to similar patterns, rendering the distribution less important in acute situations.
Generally, the following distributions can be distinguished: Mid to lower vs. upper lung zones (Fig. 7 & 8), and peripheral vs. central lung zones (Fig. 9 & 10).

 

2.) Ancillary imaging findings

See table 2 for abbreviations

 

Fibrotic changes (NSIP, late stages of other diseases such as HP, DIP, LIP, Sarcoidosis):
A first look should assess if there are fibrotic changes, including irregular reticulation, traction bronchiectasis, honeycombing and decreased lung volume (Fig. 11).

Whereas there is more GGO and less honeycombing in non-specific interstitial pneumonia, GGO is less common in usual interstitial pneumonia.

 

Airway wall thickening, inflammatory bronchiectasis, air trapping, and tree-in-bud:

These findings are all common in large and small airways disease. If there is a region of distinct tree-in-bud, infection is very likely (Fig. 12).

Bronchiectasis is often irreversible (particularly if there is cystic bronchiectasis as this resembles long-standing pathology). However, cylindrical bronchiectasis in regions of GGO may resolve during convalescence (Fig. 13).

 

Distinct mosaic perfusion and air trapping (HP):
In combination with GGO, this pattern is typical for hypersensitivity pneumonitis (Fig. 4).

 

Cysts (DIP and LIP): (Fig. 14)
GGO is less common in other cystic diseases, therefore the differential diagnosis of acute GGO with cysts should include Pneumocystis jirovecii infection (cysts occur in 30% of cases (2)), and in a chronic setting desquamative and lymphocytic interstitial pneumonia.

 

Emphysema (DIP & RB): (Fig. 15)
Emphysema, GGO, a history of smoking, and cysts are enough for the diagnosis of DIP without a biopsy. However, due to the high prevalence of emphysema, this finding should not be over-interpreted as it may merely coexist with a different disease.

 

Crazy Paving (PAP):
In chronic GGO additional interlobular septal thickening should lead to an inclusion of pulmonary alveolar proteinosis as a differential diagnosis (Fig. 16).
Interlobular septal thickening does not change the differentials of acute GGO. The ancillary finding of pronounced smooth interlobular septal thickening together with an effusion, however, is suspicious for hydrostatic edema.

 

Nodules (infection, aspiration, HP, RB, FB, invasive mucinous adenocarcinoma of the lung, sarcoidosis):
Centrilobular nodules: this pattern shows a sparing of the immediate subpleural space, an even distance between the nodules and resembles peribronchiolar inflammation, fibrosis or lymphatic infiltration. Together with GGO, it is commonly encountered in hypersensitivity pneumonitis, atypical infections, respiratory bronchiolitis and follicular bronchiolitis (when the nodules are of GGO density - Fig. 17) or endobronchial spread of infections, tumor and aspiration (when the nodules are solid - Fig. 18).
 

Consolidations (aspiration, OP, EP, invasive mucinous adenocarcinoma of the lung):
Whereas the spectrum from GGO to consolidations is continuous, some pathologies commonly occur with consolidations next to GGO (Fig. 19).

 

Lymphadenopathy (sarcoidosis, hydrostatic edema, infection):
Bihilar and mediastinal lymphadenopathy is common in sarcoidosis. Additionally, lymph nodes are often enlarged in hydrostatic edema and infection.

 

 

Pathologies with GGO as one of the predominant patterns:

 

1.) Acute:

 

Atypical infections:

The most common atypical pathogens causing infections include viruses, Pneumocystis jirovecii (Fig. 20), and bacteria such as Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae. Compared to common pulmonary infections, atypical infections may cause more subtle respiratory symptoms, present without marked leukocytosis, and frequently do not respond to empirically administered antibiotics.

 

Distribution:

  • Patchy, diffuse, or centrilobular GGO (often found in viral and Pneumocystis jirovecii infections)

Ancillary imaging findings:

  • Cysts (Pneumocystis jirovecii)
  • Airway wall thickening
  • Centrilobular nodules
  • Mosaic perfusion and air trapping

 

Pulmonary edema:

Pulmonary edema is caused by hydrostatic or oncotic pressure changes, and/or increased capillary permeability. In cases of increased pulmonary hypertension, pulmonary edema progresses from vascular congestion to interstitial edema and finally, alveolar edema.

Increased capillary permeability is commonly observed in cases of diffuse alveolar damage (DAD, see further down for details).

 

Distribution:

  • Depending on patient position, lung architecture, cardiac disease, and neurogenic effects (Fig. 21)

 

Ancillary imaging findings:

  • Pulmonary edema is the most common cause for GGO combined with pronounced smooth interlobular thickening, however, this is still a very unspecific finding on its own.

 

Pulmonary hemorrhage: (Fig. 22)

Pulmonary hemorrhage may be focal or diffuse.

Causes of focal pulmonary hemorrhage may be identified on HRCT and include bronchiectasis, malignancy, trauma, mycetoma, and thromboembolic disease.

Diffuse pulmonary hemorrhage is a manifestation of a systemic disorder such as vasculitis, pulmonary-renal syndromes or decreased coagulation.

 

Distribution:

  • Unspecific - focal or diffuse, symmetric or asymmetric GGO

 

Ancillary imaging findings:

  • Consolidations
  • Centrilobular GGO nodules
  • Interlobular septal thickening in the subacute stage when the hemorrhage is removed over the interstitially located lymphatic vessels.

 

Diffuse alveolar damage (DAD):

DAD is the pathological correlate of the adult respiratory distress syndrome (ARDS) which may occur secondarily to a multitude of causes (e.g., trauma, inhalation injury, infection, multi-organ dysfunction, …) or idiopathically (= acute interstitial pneumonia).

 

Distribution:

  • Starts in the periphery followed by a diffuse distribution.

 

Ancillary imaging findings:

  • Patchy consolidations = hyaline organization in the alveoli (Fig. 23).
  • Fibrotic features can be seen in anterior lung parts in patients who survive - this represents ventilator-associated lung damage.

 

Aspiration:

Aspiration shows an acute onset and occurs in a variety of disorders, such as gastroesophageal reflux disease or dysphagia (neurogenic disorders).

 

Distribution:

  • Depending on patient position. In the recumbent patient, GGO or consolidation is frequently seen in the posterior segments of the upper lobes or apical segments of the lower lobes. In the standing patient, GGO or consolidation is usually localized in the basal lower lobes, predominantly on the right side.

 

Ancillary imaging findings:

  • Tree in bud
  • Consolidations

 

Acute hypersensitivity pneumonitis (HP):

An acute presentation of HP is rare and is similar in appearance to the subacute stage of HP (see further down).

 

 

Acute eosinophilic pneumonia (AEP): (Fig. 24)

AEP is characterized by an acute onset of respiratory symptoms and commonly occurs in smokers. While bronchoalveolar lavage and pathology show eosinophilic infiltration, peripheral eosinophilia is often missing in AEP. While Corticosteroids may achieve rapid amelioration within days, AEP may also progress towards fatal ARDS.

 

Distribution:

  • Diffuse or extensive GGO

 

Ancillary imaging findings:

  • Consolidations
  • Unspecific smooth interlobular septal thickening
  • Nodules

 

2.) Chronic:

 

Non-specific interstitial pneumonia (NSIP): (Fig. 25)

NSIP may be cellular (with more inflammation and possibly reversible) or fibrotic (irreversible). Its commonest association is connective tissue disease and when there is an NSIP-pattern in such a patient this is enough for diagnosis even without a biopsy.

 

Distribution:

  • Lower and subpleural with a sparing of the immediate subpleural parts of the lung (in 50% of NSIP-cases)
  • Involves the costophrenic angle

 

Ancillary imaging findings:

  • Cellular: Fine reticulation and traction bronchiectasis are possible (these can be quite extensive but are still reversible)
  • Fibrotic: Irregular reticulation and traction bronchiectasis; honeycombing is rare and only minor compared to usual interstitial pneumonia (UIP) pattern

 

 

Desquamative interstitial pneumonia (DIP) and Respiratory bronchiolitis (RB): (Fig. 26)

An inflammatory reaction in smokers from alveolar macrophages surrounding the bronchioles; there is a strong overlap of RB and DIP. They often coexist as they resemble different manifestations of the same pathological spectrum.
A history of smoking, GGO, emphysema, and cysts are enough for the diagnosis of DIP without a biopsy.

 

Distribution:

  • Centrilobular GGO (RB)
  • Lower and peripheral GGO (DIP)

 

Ancillary imaging findings:

  • Cysts (not as many as in other cystic lung diseases)
  • Emphysema
  • Mosaic perfusion and air trapping (not as much as in hypersensitivity pneumonitis)

 

Lymphocytic interstitial pneumonia (LIP) and follicular bronchiolitis (FB): (Fig. 27)

An infiltration with lymphoid follicles in the interstitium (LIP) and around bronchioles (FB); there is a strong overlap of LIP and FB. They often coexist as they resemble different manifestations of the same pathological spectrum.
The diagnosis of LIP or FB is more likely in patients with a history of immunosuppression or connective tissue disease (especially Sjögren’s disease).

 

Distribution:

  • Centrilobular GGO (FB) 
  • Patchy GGO (LIP) 

 

Ancillary imaging findings:

  • Cysts make LIP more likely and may be the only finding in LIP, especially in association with Sjögren’s disease.
  • Sometimes perilymphatic nodules and consolidations (LIP)
  • Rarely slight mosaic perfusion and air trapping

 

Organizing pneumonia (OP): (Fig. 28)

50% of OPs are idiopathic (= cryptogenic OP; COP) and 50% are in association with other diseases (especially infections and hypersensitivity pneumonitis). OP responds to steroids but can recur after the treatment has finished.

 

Distribution:

  • Lower lobes
  • Curvilinear bands in a subpleural or peribronchovascular location

 

Ancillary imaging findings:

  • Mass-like or focal consolidations
  • Reversed-halo or atoll sign = surrounding consolidations with central GGO

 

Subacute/chronic hypersensitivity pneumonitis (HP): (Fig. 5)

Overshooting immune reaction to organic antigen exposure (e.g., bird droppings, hay, …) leads to symptoms over the course of weeks to months. An acute progression after exposure to large amounts of antigen is rare.

 

Distribution:

  • Patchy and bilateral
  • Upper lung, but may involve mid to lower lung as well
  • Spares the costophrenic angle

 

Ancillary imaging findings:

  • Distinct mosaic perfusion and air trapping
  • Centrilobular GGO-nodules representing peribronchiolar inflammation (HP is the commonest cause of GGO-nodules and these are diagnostic together with an antigen-exposure) 
  • Headcheese-sign 
  • Additional fibrotic alterations in chronic HP

 

Eosinophilic pneumonia (EP): (Fig. 24)

EP shows a peripheral eosinophilic infiltration of the lung and an increase in blood eosinophiles. Chronic EP is the most common idiopathic eosinophilic disease.
There are several clinical associations depending on the subtype of EP, especially  asthma (chronic EP, and others), cardiac and nervous system (hypereosinophilic syndrome), central nervous system and skin (eosinophilic vasculitis = Churg-Strauss-Syndrome).

 

Distribution:

  • Upper and peripheral
  • Sometimes peribronchovascular (chronic eosinophilic pneumonia)
  • Diffuse GGO (hypereosinophilic syndrome)

 

Ancillary imaging findings:

  • Consolidation and reversed-halo-sign (chronic eosinophilic pneumonia)
  • Centrilobular GGO-nodules (Churg-Strauss)

 

Sarcoidosis: (Fig. 29)

Normally, a perilymphatic distribution is the typical finding in pulmonary sarcoidosis. However, in rare cases, GGO can be the predominant pattern.

 

Distribution:

  • Peripheral patchy GGO (representing alveolar collapse due to multiple micro-granulomas)

 

Ancillary imaging findings:

  • Mediastinal and bihilar lymphadenopathy
  • Other, more typical findings of sarcoidosis such as consolidations surrounded by nodules (= galaxy-sign) and perilymphatic nodules. 

 

Mucinous adenocarcinoma of the lung: (Fig. 30)

Whereas the non-mucinous type of adenocarcinoma is more likely to result in a single GGO-nodule, the mucinous type grows alongside the inner walls of the bronchioles (= lepidic growth), secretes fluids and leads to a bronchopneumonia-like image.
Patients may produce large amounts of watery sputum (= bronchorrhea)

 

Distribution:

  • Asymmetric, focal or diffuse, uni- or bilateral

 

Ancillary imaging findings:

  • Centrilobular nodules are common
  • Consolidations
  • Crazy paving

 

Pulmonary alveolar proteinosis (PAP): (Fig. 16)

An autoimmune reaction leads to a decreased removal of lipoproteins in the alveoli. Nearly 90% are idiopathic and symptoms are nonspecific.
CT can guide the bronchoalveolar lavage and monitor the treatment effect.

 

Distribution:

  • Diffuse and geographical distribution

 

Ancillary imaging findings:

  • Crazy paving is typical but nonspecific. After bronchoalveolar lavage, the GGO decreases, whereas the septal thickening may remain.
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