Non-infectious Parenchymal Lung Disease
- 1.1k Downloads
Acute dyspnea is a common presenting complaint in the emergency room, emergency medicine and intensive care. It may have a cardiovascular or a non-cardiovascular origin, the latter including pulmonary parenchymal diseases. Depending on the cause, it may be associated with fever, cough, hemoptysis, and/or chest pain, with a duration of symptoms that can range from hours to days.
Prompt identification of the underlying cause of acute dyspnea is essential in guiding appropriate therapy and management, as patients may rapidly progress to acute respiratory failure. Evaluation with chest radiography is vital for initial assessment and may reveal diffuse parenchymal abnormalities, which may require further assessment with computed tomography (HRCT).
Acute non-infectious parenchymal lung diseases are often overlooked and may be under-diagnosed. Their diagnosis requires the evaluation, along with the HRCT pattern, of the clinical and laboratory features and of the bronchoalveolar lavage. Biopsy may be necessary in more complex cases.
Although the most frequent cause of diffuse non-infectious parenchymal lung involvement is acute hydrostatic pulmonary edema, there is a wide variety of diseases that may be encountered, including acute drug toxicity, hypersensitivity pneumonitis (HP), acute respiratory distress syndrome (ARDS) and diffuse alveolar hemorrhage (DAH). In trauma patients, fat embolism syndrome (FES) must be taken into account. Acute respiratory failure is an eventuality that can occur during the course of chronic lung diseases (UIP for example), which may have been unknown until then.
KeywordsAcute Respiratory Distress Syndrome Pulmonary Capillary Wedge Pressure Hypersensitivity Pneumonitis Diffuse Alveolar Damage Diffuse Alveolar Hemorrhage
1 Acute Drug Toxicity
Drug toxicity is a common condition, often underdiagnosed. As a result, the incidence and the prevalence are underestimated. There are numerous agents with potential toxic effects on the lungs including cytotoxic and noncytotoxic drugs. Common causes of drug-induced lung disease include chemotherapeutic agents, amiodarone, antibiotics, and nonsteroidal anti-inflammatory drugs. There are a number of recognized cofactors that may enhance the likelihood of a pulmonary drug reaction, particularly reactions associated with chemotherapeutic agents. These include advanced age, prior radiotherapy, and elevated inspired oxygen levels; the presence of any or all of these factors increases the likelihood of developing a pulmonary drug reaction. Surgery may even be a precipitating event (Camus et al. 2004a).
1.2 Mechanisms of Injury
Generally, pulmonary drug reactions are the result of either direct or indirect effects of the drug. Reactions due to direct effects can be broadly divided into those that are toxic reactions (which to some extent are dose-related, such as reactions to chemotherapeutic agents) and those that are idiosyncratic reactions (which tend not to show a consistent dose-response relationship). This division is artificial and the distinction between toxic reactions and idiosyncratic reactions is not always clear cut. Several risk and exacerbating factors for diffuse lung disease have been identified. Some of them include advanced age (60 years or older) and existing pulmonary lesions (Kubo et al. 2013).
1.3 Terminology and Clinical Issues
The symptoms may be acute/subacute/chronic and are nonspecific and therefore the diagnosis requires a high index of suspicion by clinician and the radiologist. Acute respiratory failure due to drug-associated ILD generally has an unpredictable onset and rapid time course (onset of clinical manifestations within minutes to hours of taking the drug). Patients with acute drug toxicity present with the progressive or rapid onset of dry cough, high fever, and dyspnea. These patients often require admission to the intensive care unit and mechanical ventilation (Prasad et al. 2014; Camus et al. 2004b).
The identification of drug-induced lung disease requires an active consideration of any change in the patient’s clinical course as a possible response to medications. There are no pathognomonic signs, symptoms, laboratory tests, or pathologic features that identify a drug as the cause of the illness. Further, drug-induced lung disease must be distinguished from more common illnesses or causes of acute exacerbation of an ongoing illness such as asthma, infection, congestive heart failure, and pulmonary thromboembolism. A history of drug exposure and a consistent radiological pattern may be diagnostic tools.
Bronchoalveolar lavage (BAL) is particularly helpful in ruling out infectious mostly before corticosteroid therapy. Biopsy can generally be avoided, as it does not always provide a specific diagnosis. Open lung biopsy is rarely performed (Müller et al. 2004).
Acute drug toxicity: main clinical-histopathologic patterns
Acute clinical-histopathologic patterns
Diffuse alveolar damage (DAD/ARDS)
Bleomycin, busulfan, cyclophosphamide, mitomycin, amiodarone
Diffuse alveolar hemorrhage (DAH)
Anticoagulants, amphotericin B, cytarabine (ara-C), penicillamine, cyclophosphamide
Pulmonary edema (PE)
Blood transfusions, tricyclic antidepressants, illicit drugs
Hypersensitivity pneumonia (HP)
Methotrexate, cyclophosphamide, nitrofurantoin
1.5 Management and Treatment
Disease types such as pulmonary edema and hypersensitivity pneumonia generally have a favorable clinical course and most patients resolve following drug discontinuation or treatment with corticosteroids. In contrast, DAD rarely responds to treatment and has a poor prognosis, and even if it resolves, fibrosis may remain as a sequela.
2 Hypersensitivity Pneumonitis (HP)
Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a syndrome that results from repeated inhalation and subsequent sensitization to a wide variety of airborne organic particles. The presentation and clinical course are highly variable and depend from intensity and duration of exposure to the antigen and the nature of the antigen and specific factors of the host, such as an individual predisposition probably genetically determined (Spagnolo et al. 2015). According to data from registries of interstitial lung diseases (ILDs) in three European countries, HP accounts for 4–15 % of all ILD cases (Thomeer et al. 2001). However, the incidence and prevalence of HP are difficult to estimate with precision, mainly because of the number of cases that are misdiagnosed or not recognized and a lack of uniform diagnostic criteria.
The disease is diagnosed on the basis of a history of exposure to an offending antigen with onset of compatible clinical, HRCT, or physiological findings within 4–12 h. Other diagnostic criteria include clinical improvement after removal from exposure and recurrence on reexposure. In cases where the inciting antigen cannot be identified or in the presence of conflicting clinical, radiological, and functional findings, fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy are indicated. Surgical lung biopsy is only required if these prove inconclusive (Elicker et al. 2016).
2.2 Mechanisms of Injury and Causes
HP comes from an immune-mediated inflammatory process involving the lung parenchyma (terminal bronchioles, alveoli, and interstitium), based on mechanisms likely independent from single causative agent, mediated by immune complexes in the acute phases of the disease and an altered response of T lymphocytes in the early stages subacute and chronic (Vogelmeier et al. 1993; Barrera et al. 2008). HP seems that cigarette smoking can play a protective effect by reducing the intensity of hyperimmune response. The immune pathogenesis, not yet fully clarified, is linked to hyperactivity of T cells and the action of immune complexes.
Major classes of antigens and corresponding types of hypersensitivity pneumonitis
Class of antigens
Mushrooms worker’s lung
Hot tub lung
Swimming pool lung
Bird fancier’s lung
Silk production HP
Diisocyanates, trimellitic anhydride
Chemical worker’s lung
2.3 Terminology and Clinical Issues
HP has been conventionally classified as acute, subacute, and chronic (Richerson et al. 1989), although a significant overlap exists and there are no widely accepted criteria to distinguish the various forms. In this regard, (Selman et al. 2012) proposed an alternative classification scheme based primarily on disease behavior, distinguishing between acute nonprogressive and intermittent disease, acute progressive/subacute disease, chronic nonprogressive disease, and chronic progressive disease. Which pattern of illness occurs presumably depends upon the intensity and duration of contact, the nature of the antigen, and host factors.
Acute HP is characterized by an influenza-like syndrome occurring a few hours after a substantial exposure. Symptoms gradually decrease over hours/days but often recur with reexposure. Acute episodes can be indistinguishable from an acute respiratory infection caused by viral or mycoplasmal agents. Attacks often follow exposure to the allergen within enclosed spaces with poor ventilation. Patients typically have a restrictive ventilatory defect with reduced DLCO or, in rare cases, an obstructive pattern. Mild hypoxemia at rest is common. In general, the acute form is nonprogressive and intermittent, with spontaneous improvement after antigen avoidance (Selman et al. 2012).
2.4.1 Radiological Signs
Chest radiograph may be normal. Abnormal radiographic findings observed in some patients include a variable combination of fine nodular opacities and widespread ground-glass opacity or, more rarely, as consolidation. The zonal distribution varies from patient to patient and may vary over time in the same patient (Unger et al. 1973; Mönkäre et al. 1985).
2.4.2 CT Signs
High-resolution CT has greatly improved the radiological diagnosis of hypersensitivity pneumonitis because it is more sensitive and specific than chest X-ray. HRCT may either show typical findings, which may be virtually diagnostic of HP in the appropriate clinical setting, or provide important clues that may suggest a correct diagnosis.
The variable combination of areas of decreased attenuation, ground-glass opacities, and normal lung may produce the so-called head-cheese pattern, which is highly suggestive of HP (Chong et al. 2014). Coexisting thin-walled lung cysts have been reported in 13 % of patients with subacute HP (Franquet et al. 2003) and are believed to be caused by partial bronchiolar obstruction by peribronchiolar lymphocytic infiltration. These cysts are usually few in number and range in size from 3 to 25 mm. Occasionally in patients with an insidious onset of disease, focal consolidation is present, presumably representing organizing pneumonia. Mediastinal lymph node enlargement has been described in approximately 30 % of patients.
2.5 Differential Diagnosis
The differential diagnosis with other disorders manifesting with acute/subacute diffuse GGO e.g., opportunistic infections, pulmonary edema, and cellular nonspecific interstitial pneumonia (NSIP) may be difficult. However in HP the frequent association of lobular air trapping and centrilobular snowflake nodules is crucial for the diagnosis.
The so-called head-cheese pattern may also be observed in respiratory bronchiolitis-associated ILD (RB-ILD). Integrating nicotine poisoning and laboratory findings may indicate the most likely diagnosis (Chong et al. 2014).
GGO combined with cysts resemble those seen in lymphocytic interstitial pneumonia (LIP). However, LIP is often associated with other conditions, such as connective tissue diseases or lymphatic disorders (e.g., human immunodeficiency virus infection, lymphoma) (Ichikawa et al. 1994).
2.6 Management and Treatment
Patients with acute/subacute HP, if correctly and timely diagnosed and treated, generally have an excellent prognosis. The most important recommended therapy is inhibiting exposure to the causal agent by eliminating it from the environment, avoiding settings where it is present, or using a respirator in those settings. Systemic corticosteroids for a few days to weeks may improve symptoms. Indications for the use of such drugs include acute, severe, or progressive disease (Kokkarinen et al. 1992).
Acute respiratory distress syndrome (ARDS) is a condition characterized by sudden onset of severe hypoxemia and diffuse pulmonary infiltrates.
The syndrome was firstly introduced by Ashbaugh and colleagues in 1967 (Ashbaugh et al. 1967), while the criteria for the diagnosis of ARDS were first established in 1994 by the American-European Consensus Conference (AECC) (Bernard et al. 1994).
In 2012 the “Berlin definition,” the new updated consensus definition of ARDS, has been published in a high-impact journal. ARDS is defined as: “[…] type of acute diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue. The clinical hallmarks are hypoxemia and bilateral radiographic opacities […]” (ARDS Definition Task Force 2012).
3.2 Mechanisms of Injury
ARDS may follow several different types of lung injury that ultimately determine the same monomorphic pulmonary response, characterized histopathologically by the presence of diffuse alveolar damage (DAD).
There are many triggering events that have been classically classified as pulmonary or extrapulmonary. Pulmonary or direct injuries are processes determining direct injury to lungs, like infection, gastric aspiration, or toxic inhalation. Extrapulmonary or indirect injuries may be systemic processes like polytrauma, drug toxicity, sepsis, transfusions, or extra-thoracic diseases like acute pancreatitis.
From a histopathologic point of view, “diffuse” refers to the involvement of the whole alveolar structure: endothelium, basal membrane, and epithelium. The process is widespread throughout the lungs, but not always in a homogeneous manner: frequently there is presence of spared areas (Kligerman et al. 2013).
The process is characterized by a sequence of phases. Not necessarily the process develops through all the phases: it can stop and reverse anytime (Castro 2006).
The early or exudative phase lasts up to 7 days and is characterized by the presence of hyaline membranes. The alveolar epithelium is damaged and the basal membrane is exposed.
The next stage is the organizing, or proliferative, phase, characterized by the presence of organizing tissue and fibrosis. If this phase does not resolve favorably, there is progression to the last phase, the fibrotic phase.
The pattern of fibrosis is atypical and usually with predilection of the anterior segments (anti-gravitational distribution). Some patients may show areas of “honeycombing,” more frequently encountered following acute interstitial pneumonia (AIP), which is the “idiopathic” form ARDS (Tomiyama et al. 2001).
3.3 Terminology and Clinical Issues
The term ARDS should not be confused with the term permeability edema and it is not interchangeable with the term noncardiogenic edema. ARDS is the most severe form of permeability edema, but there are other forms of permeability edema without DAD (Ketai and Godwin 1998). Classification of pulmonary edema is discussed in the “Acute pulmonary edema” section.
ARDS, which is a life-threatening condition, is associated histopathologically to DAD.
In the AECC definition, ARDS was defined as an acute onset of hypoxemia, without specifying a timeframe to define acute; the PaO2/FiO2 (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen) must be under <200 mmHg, with presence of bilateral infiltrates on frontal chest X-ray. Presence of left atrial hypertension must be ruled out. PaO2/FiO2 between 200 and 300 is termed acute lung injury (ALI).
When idiopathic, the process is termed acute interstitial pneumonia (AIP), also known as Hamman-Rich syndrome (Kliegerman et al. 2013). AIP may sometimes present with a more subacute course, and as a result, it does not always fulfill the criteria of ARDS (Janz et al. 2000).
The new definition of Berlin introduces several important changes to the old criteria (ARDS Definition Task Force 2012). The timeframe for define acute onset is specified within a week from a determinate event. A minimum level of positive end-expiratory pressure (PEEP) is established to evaluate the severity of the respiratory failure. The need to measure pulmonary wedge pressure is removed and the term ALI is suppressed. ARDS is now classified in three grades: mild (200< PaO2/FiO2 <300 with PEEP or C-PAP >5 cm H2O), moderate (100< PaO2/FiO2 <200 with PEEP >5 cm H2O), and severe (PaO2/FiO2 <100 with PEEP >5 cmH2O). Finally, it is stated that the pathologic correlate of ARDS is DAD.
“Acute” (no specific timeframe)
Acute “within 7 days of a known clinical insult”
Bilateral infiltrates on frontal CXR
“Bilateral infiltrates on frontal CXR not fully explained by effusions, lobar/lung collapse, or nodules /masses” (chest X-ray interpretation set available online)
Bilateral opacities on CT
Pulmonary artery wedge pressure (PAWP)
PAWP <18 mmHg
Acute lung injury (ALI) if PaO2/FiO2 <300 (regardless of PEEP level)
ARDS PaO2/FiO2 < 200 (regardless of PEEP level)
Minimum C-PAP/PEEP level 5 cmH2O
Injury to both the epithelium and the endothelium
DAD (diffuse alveolar damage)
3.4.1 Radiological Signs
The chest X-ray picture of ARDS varies depending on the phase of the process (Sheard et al. 2012).
Subsequently the appearance of radiographic changes is rapid. The opacification is diffuse and symmetric, peripheral, and with presence of air-bronchograms. The heart and the vascular pedicle are not enlarged; pleural effusion is absent or limited (Fig. 5b). Septal thickening and peribronchial cuffing are less common than in HPE.
The picture remains stable for some days, or longer, during the proliferative phase. In more severe cases, the opacification is complete and the picture is that of the so-called “white lungs” (Fig. 5d, e).
In the late phase the alterations begin to reverse. In patients who heal, the lungs return normal (Fig. 5f), while in patients who develop fibrosis, there is evidence of coarse reticular opacities.
3.4.2 HRCT Signs
The HRCT pattern of ARDS depends on the phase of the process, even if we cannot clearly distinguish the phases. In particular, the exudative phase and the early organizing phase of ARDS overlap, as well as the late proliferative phase overlap with the fibrotic phase (Ichikado 2014).
Afterward, the process quickly progress to a more homogeneous opacification of the lungs, which persists for the exudative phase and the organizing phase. At this stage ARDS may show two patterns, named typical and atypical. Originally the typical pattern has been associated with extrapulmonary ARDS, while the atypical was associated with pulmonary ARDS (Goodman et al. 1999). This has not been confirmed by a following study (Desai et al. 2001), and in any case, it is not always possible to attribute a single cause to the insurgence of this syndrome (Desai 2002).
The HRCT pattern of typical ARDS is characterized by the presence of a bilateral symmetric anterior-posterior density gradient (Fig. 6c). The density is lower anteriorly (or may be normal or hyperventilated), while posteriorly the density increases progressively, from a ground-glass opacification to a frank consolidation, in the more dependent regions.
In atypical ARDS there are patchy GGO or consolidations, randomly distributed in dependent and nondependent regions of the lungs, without the symmetric density gradient (Fig. 5c).
CT predictors of mortality in ARDS are signs of right heart failure, involvement of more than 80 % of the lung parenchyma, and presence of varicoid traction bronchiectasis (Chung et al. 2011).
3.5 Differential Diagnosis
Criteria for the radiographic differentiation of permeability edema from hydrostatic pulmonary edema (HPE) have been discussed in the acute pulmonary edema paragraph. Although there are several signs that can help the diagnosis, the distinction is frequently impossible. Moreover, chest radiograph interpretation shows poor interobserver reliability (Rubenfeld et al. 1999; Meade et al. 2000).
Likely HRCT may improve the diagnostic accuracy, but at present there is a scarcity of literature in regard. HRCT findings that suggest presence of HPE are perihilar and upper lobar distribution of GGOs, central predominant distribution of consolidations, dilatation of the pulmonary veins and of the superior cava vein, thickening of the bronchial walls (peribronchovascular thickening), and right pleural effusion. Even distribution of the GGOs and of the consolidations is found more often in ARDS. Gravity-dependent opacities, septal pattern, air bronchograms, and traction bronchiectasis did not show significant difference in prevalence between HPE and ARDS (Komiya et al. 2013).
This difficulty in the differential diagnosis of the nature of the edema is implicitly recognized by the definition of Berlin. In the Berlin definition, a differential diagnosis between cardiogenic and noncardiogenic edema on chest radiograph is not required, nor it is considered relevant: it is now recognized that hydrostatic edema and ARDS may coexist. The diagnosis of ARDS requires that the respiratory failure is not fully explained by cardiac failure, or fluid overload, using all available data (Ferguson et al. 2012). Therefore, radiologically, the focus is on the generic diagnosis of bilateral edema that must not be confused with pleural effusions, lobar/lung collapse, or nodules/masses. In fact, HPE is not the only condition with which the ARDS goes in differential diagnosis: bioptic and autoptic studies have demonstrated only moderate agreement between the clinical diagnosis of ARDS and presence of DAD. Specificity of the various criteria for presence of DAD is variable in literature, but always quite poor (Lorente et al. 2015).
There is no pathognomonic laboratory test or radiological sign to establish the diagnosis of ARDS, which is generally clinical. Apart from HPE, the most common conditions that share a similar clinical presentation are atelectasis, pneumonia, and pulmonary embolism (Murray 1975). In reality there are many more and encountered less frequently: miliary tuberculosis, CMV pneumonia, invasive aspergillosis, hantavirus pneumonia, herpes simplex pneumonia, bronchoalveolar cell carcinoma, drug toxicity, lymphangitis, acute leukemia, lymphoma, veno-occlusive disease, sickle lung, acute eosinophilic pneumonia, acute cryptogenic organizing pneumonia (COP), acute fibrinous organizing pneumonia (AFOP), diffuse alveolar hemorrhage, and acute hypersensitivity pneumonia (Dakin and Griffiths 2002; Schwarz and Albert 2004).
Some of the abovementioned conditions may show peculiar HRCT findings (many are discussed elsewhere in this book). For example, presence of subpleural peripheral distribution of the consolidations is suggestive of acute eosinophilic pneumonia, while peribronchial distribution is suggestive of COP or AFOP (Obadina et al. 2013).
Most of those mimickers (or imitators) of ARDS require a different and specific therapy. Therefore, when performing a HRCT examination in patients with clinical diagnosis of ARDS, maximum attention is required to highlight any sign, or pattern, that may suggest an alternative diagnosis to the complex ARDS/DAD.
3.6 Management and Treatment
No pharmacologic therapy has proved effective in the prevention or management of ARDS.
The only specific therapy for ARDS is ventilation (noninvasive or mechanical) using low tidal volumes (lung-protective strategy), to improve blood oxygen levels, and providing supportive care.
Great deal of attention must be placed to not miss a treatable cause of ARDS and to early diagnose the complications (barotrauma, ventilator-associated pneumonia, and fluid overload, among others).
4 Diffuse Alveolar Hemorrhage (DAH)
Diffuse alveolar hemorrhage (DAH) is not a specific disorder, but a syndrome that suggests a differential diagnosis and a specific sequence of testing. DAH may be a life-threatening condition characterized clinically by the presence of hemoptysis, falling hematocrit, diffuse pulmonary infiltrates, and hypoxemic respiratory failure, which can be severe. However, chest radiographic and CT findings may be nonspecific (the alveolar infiltrates can even sometimes be unilateral), and hemoptysis may be lacking. DAH should be considered a medical emergency due to the morbidity and mortality associated with failure to treat the disorder promptly (Collard and Schwarz 2004; Lara and Schwarz 2010).
The diagnosis of diffuse alveolar hemorrhage is made on the basis of the clinical and radiological pattern and may be confirmed by bronchoalveolar lavage (BAL). In acute and severe forms, the BAL findings include bright red blood from multiple sites in different bronchi and, microscopically, hemosiderin-laden macrophages. BAL is also useful for excluding other differential diagnoses, such as infections or other endobronchial sources of bleeding (Park 2013). Once the diagnosis is established, the underlying cause must be established in order to initiate treatment.
4.2 Mechanisms of Injury and Causes
Causes of diffuse alveolar hemorrhage (DAH)
Main causes of diffuse alveolar hemorrhage
Pulmonary small vessel vasculitides:
ANCA-associated pulmonary vasculitides:
Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis)
Microscopic polyangiitis (MPA)
Non-ANCA-associated pulmonary vasculitides:
Connective tissue disorders (SLE, mixed connective tissue disease, RA)
Other causes of diffuse alveolar hemorrhage
Mitral valve disease
Pulmonary veno-occlusive disease (PVOD)
Diffuse alveolar damage
Autologous bone marrow transplantation
Acute lung transplant rejection
DAH includes diseases associated with pulmonary capillaritis (cellular infiltrate of neutrophils in the capillaries and venules) and those associated with normal vessels (Colby et al. 2001). A pulmonary capillaritis is considered the most common underlying lesion associated with diffuse alveolar hemorrhage.
4.3 Terminology and Clinical Issues
The cardinal sign of DAH, hemoptysis, may be a dramatic event or evolve over days to weeks; however, it may be initially absent in up to 33 % of DAH cases. The other symptoms of DAH are nonspecific and include fever, cough, and dyspnea. Nonpulmonary signs and symptoms are those that accompany the underlying systemic disease. A possible association of hematuria and renal failure due to concomitant glomerulonephritis may be present (Dalpiaz et al. 2003).
Causes of combination of DAH and glomerulonephritis (primary pulmonary-renal syndrome)
Granulomatosis with polyangiitis (Wegener granulomatosis)
Upper airway disease (nasal, oral, or sinus inflammation)
Microscopic polyangiitis (MPA)
Systemic lupus erythematosus (SLE)
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
4.4.1 Radiological Signs
4.4.2 CT Signs
High-resolution CT often yields no additional diagnostic information, merely confirming the presence of infiltrates. The HRCT pattern can vary with time of onset of the hemorrhage and the clinical context is crucial in image interpretation.
Within days of an acute episode of hemorrhage, interlobular septal thickening may be seen in association with ground-glass opacity (crazy-paving pattern) as hemosiderin-laden macrophages accumulate in the interstitium (Fig. 10c) (Rossi et al. 2003; De Wever et al. 2011).
CT may be useful in the follow-up period, given its ability to demonstrate even the mildest relapse arising after reduction or discontinuation of cortisone and immunosuppressant therapy. Some faint scattered nodules or small areas of ground glass and some low-density nodules (snowflake-like nodules) may be seen, sometimes around the smaller vessels, which are not detected by chest radiography (Fig. 10d) (Maffessanti et al. 2005).
After repeated episodes of pulmonary hemorrhage, a persistent reticular pattern may be seen, with areas of peripheral traction bronchiectasis and distortion of the lung architecture; this pattern reflects interstitial hemosiderin deposition and mild lung fibrosis and has been termed pulmonary hemosiderosis.
4.5 Differential Diagnosis
Radiological pattern of DHA is not pathognomonic, but diffuse alveolar hemorrhage is the second cause of acute perihilar alveolar lung disease after pulmonary edema (Ribeiro et al. 2006; Dalpiaz and Maffessanti 2013). Differentiation is usually straightforward based on the clinical data and the frequent co-existence, in hydrostatic edema, of pleural effusion, enlarged vessels, and sometimes cardiomegaly. In all these cases, the differential diagnosis with other acute forms of diffuse lung disease—particularly inhalation and infectious pneumonia—based on radiological data alone becomes impossible. Hemorrhagic alveolar infiltration resolves rapidly (especially after corticosteroid therapy) but slower than pulmonary edema.
4.6 Management and Treatment
The treatment of DAH depends on the underlying cause of hemorrhage and ranges from supportive care and withdrawal of offending drugs to high-dose steroids, immunosuppressants, and plasmapheresis. Massive pulmonary hemorrhage is a life-threatening manifestation and requires aggressive immunosuppressive therapy as soon as possible.
5 Fat Embolism Syndrome (FES)
Fat embolism syndrome (FES) is a rare complication of the fractures, mainly of the long bones. Its importance lies in the fact that it is in the differential diagnosis with other more frequent respiratory complications of trauma and polytrauma, which require a different therapy (such as pulmonary edema or bilateral bronchopneumonia). Also, more rarely, FES can occur in more severe forms such as the acute respiratory distress syndrome (ARDS) or in a fulminant form. While the radiographic findings may be mistaken for other conditions, the CT pattern may be more specific and suggest the diagnosis.
5.2 Mechanisms of Injury
The exact injury mechanism in FES has not been completely explained, nor has the histopathologic picture been completely clarified. The symptomatology has been put in relation to the release of fat particles in the venous blood flow, followed by pulmonary and systemic embolization. At present, it is thought that there are two pathogenic stages that follow one another: the mechanical phase and the biochemical phase (Akhtar 2009). The mechanical phase occurs after release of fat droplets into the venous blood, which determine mechanical obstruction of the pulmonary and systemic capillary bed. The following biochemical phase is due to the toxic effects of free fat acids (FFA) on the endothelia. It is unclear how fat droplets reach systemic circulation: likely they pass through a patent foramen oval or through the pulmonary capillary bed.
Only few studies describe the histopathologic alteration in human FES: in the majority of cases, a toxic vasculitis with alveolar hemorrhage and edema is reported, but also presence of hyaline membranes, the hallmark of diffuse alveolar damage (DAD) and ARDS, has been demonstrated (Berrigan et al. 1966; Dines et al. 1975; Curtis et al. 1979).
Usually fat embolism (FE) is caused by bone fractures, typically by long bone fractures in young patients. Rarely, FE may be due to traumatic subcutaneous fat crushing without fractures (Bolliger et al. 2011) or to nontraumatic causes (Mellor and Soni 2001).
5.3 Terminology and Clinical Issues
Fat embolism (FE) refers to the emergence of fat particles within the venous circulation with the consequent pulmonary embolization. This occurrence is practically constant after fracture, but only a small minority of patients develop clinical symptoms. In those, the resulting syndrome is called fat embolism syndrome (FES) and is characterized by the combination of acute respiratory failure, nervous system impairment, and cutaneous manifestations. The typical petechial rash, that affects the neck, trunk and armpits, characterizes cutaneous manifestations. Petechiae may be evident also in the conjunctiva, retina, or mucosae.
The incidence of posttraumatic FES varies considerably in literature (range from 0.25 % up to 35 %) (Akhtar 2009).
Diagnostic criteria from Gurd and Wilson
High erythrocyte sedimentation rate
There are three possible clinical presentation of the fat embolism syndrome. The first is classical response, characterized by transient respiratory failure. It can occur after the trauma or after fixation of the fracture.
The second presentation is with the adult respiratory distress syndrome (ARDS). The third is the so-called hyperacute syndrome: it is extremely rare, is characterized by cardiovascular collapse, and quickly leads to death.
5.4.1 Radiological Signs
The radiological picture at conventional chest X-ray is considered nonspecific and of little help in the differential from other forms of diffuse airspace disease, like ARDS.
Clearing of the radiographic alterations requires a time varying from few days to more than a week (Feldman et al. 1975).
5.4.2 CT Signs
CT findings in pulmonary FES include multifocal ground-glass opacities (GGO) and consolidations, frequently in association with nodules and micronodules. The alterations tend to be bilateral and widespread, with gravitational distribution: consolidations usually have posterior-basal predominance.
5.5 Differential Diagnosis
Although full-blown or severe FES is not a frequent eventuality, and its frequency is decreasing since early stabilization of the fractures was introduced, it is an important condition to be kept in mind. Its importance lies in the fact that it must be differentiated from other more common and dangerous complications of fractures and polytrauma, such as pulmonary embolism and pneumonia, requiring a specific therapy.
In fact, in the posttraumatic setting, FES has a wide range of conditions from which it must be differentiated: hydrostatic pulmonary edema, fluid overload, neurogenic pulmonary edema, pulmonary contusions, aspiration, viral pneumonia, bilateral bronchopneumonia, ventilator-associated pneumonia, sepsis, ARDS, atelectasis, pulmonary hemorrhage, pulmonary embolism, and drug reactions (Feldman et al. 1975).
Normal heart size, normal vascular distribution, and absence of signs of pulmonary hypertension (Kerley lines, peribronchial cuffing, and widening of the vascular pedicle) are considered findings helpful in differential diagnosis from HPE at chest X-ray (Han et al. 2003). In reality, septal thickening, the equivalent of the Kerley lines at HRCT, is a frequent finding in FES (Malagari et al. 2003).
Lung contusions generally appear at chest X-ray as patchy airspace opacities, unilateral and asymmetric. At HRCT they appear as GGO or consolidations, with ill-defined borders and non-segmental distribution. They may show subpleural sparing. After the trauma they may extend and reach the maximum extension in 24–48 h (Kaewlai et al. 2008; Mirka et al. 2012). This is very helpful in the differential with FES that shows up after a latent period, and its pulmonary alterations are usually bilateral and diffuse.
Viral and bacterial pneumonias may present with several different patterns at CT, with considerable overlap in the imaging appearance (Miller et al. 2011). The presence at HRCT of an “airway- centric” disease, which is characterized by bronchial wall thickening, bronco-centric nodules, lobular opacities, and tree in bud opacities, is highly suggestive of bronchopneumonia (Ketai et al. 2008). Absence of tree in bud opacities and the random distribution of the nodules in FES results to be a useful sign for the differentiation from bronchopneumonia.
Aspiration may show different HRCT patterns: obstruction of the airways by foreign body, tree in bud opacities, or segmental or lobar opacities. Aspiration tends to interest posterior segments of the upper lobes and superior segments of the lower lobes. A massive intake of gastric content causes a severe chemical pneumonia, leading to ARDS (Medelson’s syndrome) (Kim et al. 2008).
5.6 Management and Treatment
The treatment of FES is essentially supportive.
However, it is still unclear what is the best surgical strategy in patients who already show signs of FES. Furthermore, effective pharmacologic therapies have not been found yet, except for steroids. However, their effectiveness has not been proven in prospective studies on a large scale (Akhtar 2009).
6 Acute Pulmonary Edema
Pulmonary edema is defined as presence of excess extravascular fluid in the lungs. The more common type of acute pulmonary edema is hydrostatic pulmonary edema (HPE) due to acute cardiac failure or to fluid overload (overhydration or renal failure).
From a radiological point of view, HPE is the most frequent cause of acute diffuse pulmonary disease (Ketai and Washington 2002).
Chest X-ray is the classical radiological examination for the diagnosis of HPE, while lung sonography is an emerging technique (Cardinale et al. 2014).
CT is not performed for suspected HPE, but HPE is a frequent finding in CT examinations performed for different purposes (e.g., to rule out suspected pulmonary embolism).
6.2 Mechanisms of Injury
The Starling equation describes the factors determining the flow of the fluids between the pulmonary capillary circulation and the lung interstitium (Ware and Matthay 2005). Edema occurs when accumulation of extravascular fluid (transudative or exudative) exceeds the resorption mechanisms (lymphatic absorption). Factors determining the amount of capillary filtration are the transmural hydrostatic pressure, the transmural oncotic pressure, and the permeability of the capillary membrane.
Generally speaking, HPE appears when transmural hydrostatic pressure increases or intravascular oncotic pressure decreases. The fluid is a transudate with low-protein content. The excess of fluid accumulates first in the interstitium and then moves to the pleural and alveolar spaces.
Noncardiogenic edema is due to an increase in permeability of the pulmonary capillaries that allows the outflow of plasma proteins, without increase in transmural hydrostatic pressure. This protein outflow attracts fluids into the interstitial compartment generating an exudative edema, called “permeability edema.” In diffuse alveolar damage (DAD), the injury to the endothelial barrier originates the increase in permeability. This is not the sole mechanism of increased capillary permeability that may also occur without DAD, like in cases of reaction to drugs (illicit drugs, interleukin-2 edema), transfusion reaction (classically defined by Milne “allergic lung”), or infection (e.g., hantavirus pulmonary syndrome) (Ketai and Godwin 1998).
6.3 Terminology and Clinical Issues
Acute pulmonary edema is classically classified into cardiogenic and noncardiogenic pulmonary edema.
Cardiogenic pulmonary edema is also referred to as hemodynamic edema or hydrostatic pulmonary edema (HPE). Elevated hydrostatic pressure follows pulmonary venous hypertension, which can be caused by left heart failure or by volume overload (Ware and Matthay 2005).
Noncardiogenic pulmonary edema is also referred to as permeability or injury edema and it is classified into two types: permeability edema with diffuse alveolar damage (DAD) and permeability edema without DAD (Ketai and Godwin 1998).
Finally, edema may be mixed hydrostatic and permeability. A cardiogenic edema may not be purely hydrostatic, since marked elevation of transmural pressure may generate some degree of epithelial damage, or a volume overload may complicate a permeability edema, generating a mixed edema.
High-altitude, re-expansion, and neurogenic pulmonary edemas are included into the mixed edema group: although their pathogenesis is still incompletely explained, in all cases a hydrostatic component is supposed to combine with some degree of increases in permeability (Ketai and Godwin 1998; Gluecker et al. 1999).
6.4.1 Radiological Signs
Chest radiograph is routinely performed in patients with suspected HPE to confirm the diagnosis or rule out other possible causes. Radiographic findings associated with HPE are increased heart size, increased width of the vascular pedicle, balanced or inverted vascular distribution (redistribution or “cephalization” of the lung vessels), vascular haziness, central or even distribution of the opacities and presence of peribronchial cuffing, septal lines, thickening of the fissures, and pleural effusion.
Measurements of the vascular pedicle width can provide an estimate of the intravascular volume status, both in the upright and in the supine position. A vascular pedicle larger than 53 mm in the upright position and more than 70 mm in the supine is expression of HPE and of fluid overload (Milne and Pistolesi 1994; Ely and Haponik 2002). This measurement may provide evidence of HPE before evidence of clinical signs and help distinguish HPE from permeability edema (Milne 2010).
The radiographic picture is considered to depend from the pulmonary capillary wedge pressure (PCWP), which is an indirect measure of the left atrial pressure: however, in literature, there are great discrepancies and controversies on this topic. With PCWP under 19–25 mmHg, there is equalization or cephalization of the vasculature. Between 20 and 30 mmHg, there is a radiographic picture of interstitial edema. Alveolar flooding appears with over 25–30 mmHg, resulting in the radiological appearance of confluent acinar opacity (Morgan et al. 1991; Ketai and Godwin 1998). It is important to remember how the radiographic picture depends also from the acuteness or chronicity of heart failure: edema in acute heart failure is determined by lower pressure gradients, but may not show at chest X-ray dilatation of the heart and of the vessels. On the contrary, chronic heart failure determines an increase in the compliance of the heart and of the pulmonary vessels, and higher pressures are required to determine vascular dilatation (Ketai and Godwin 1998).
Chest X-ray has some intrinsic and technical issues that limit its diagnostic accuracy (Ware and Matthay 2005; Ketai and Godwin 1998). Before radiographic changes start to appear, the water content of the lungs may have to increase up to 30 %; alterations may persist up to 24 h after regression of the edema; bedside radiograms obtained with portable X-ray equipment have intrinsically poor technical quality, and they are affected by factors related to the difficulty to optimize the technique of execution, such as positioning of the patient, patients’ body weight, degree of inspiration, type of ventilation applied, and focal film distance and exposure; consolidation at chest X-ray is a nonspecific finding, reflecting loss of the air content of the alveoli, and may be subtended by processes other than HPE, such as hemorrhage, pneumonia, inflammation, or tumor.
6.4.2 Lung Sonography
The interstitial syndrome is a nonspecific finding, which reflects any condition of the lung where alveolar air is partially replaced with increase in interstitial fluids or cellularity. The detection of an interstitial syndrome is not an exclusive feature of HPE and does not allow differentiation of the underlying interstitial disease. Combining the distribution and the number of the B-lines, with other sonographic signs (peripheral consolidations and aspect of the pleural line) and with the physical examination, may allow to differentiate cardiogenic and noncardiogenic causes of the interstitial syndrome (Copetti et al. 2008; Gargani and Volpicelli 2014).
The advantages of ultrasound are the low cost, noninvasiveness, repeatability, the possibility to perform bedside (point-of-care sonography), and the lack of use of ionizing radiation.
This technique is meeting a great enthusiasm on the part of clinicians and researchers. Certainly, in the next few years, researchers and scientific societies will clarify the potentialities, and the role, of this innovative approach.
6.4.3 CT Signs
Lung HRCT is more sensitive in detecting edema findings compared to chest X-ray (Rubinowitz et al. 2007).
Unfortunately, it is too irradiating, and expensive, to be used routinely for the detection of HPE. For this reason, there are no studies that correlate the CT findings with the degree of HPE.
In the clinical practice, HPE is some kind of “incidentaloma,” found at a CT examination performed to rule out other diseases (acute pulmonary embolism above all). It is therefore important to readily recognize HPE at CT to address properly the diagnostic and therapeutic procedures.
Other findings are bronchial wall thickening (or smooth peribronchovascular interstitial thickening), enlarged vessels, thickening of the fissures, and ill-defined perivascular and centrilobular opacities and consolidations (Storto et al. 1995; Ribeiro et al. 2006).
GGO are typically patchy, may be lobular, or may present as crazy paving.
At CT the distribution of the alterations tends to show parahilar and posterior distribution. HPE may also show up with a gravity-dependent density gradient (Komiya et al. 2013).
6.5 Differential Diagnosis
Typically, cardiogenic pulmonary edema shows cardiomegaly with vascular redistribution and pleural effusions. The distribution of the opacities is typically even and perihilar (central), prevalent in the middle and lower lung fields, and the vascular pedicle may be enlarged.
Noncardiogenic edema typically shows patchy peripheral or diffuse opacification of the lung fields, with air bronchograms and without cardiomegaly and pleural effusion; vascular pedicle is not enlarged. Septal lines, or Kerley lines, are more frequent in HPE, but may be present in noncardiogenic edema as well.
Unfortunately, these two types of edema frequently do not show up with the typical picture and may share many radiological features: in reality, the distinction becomes frequently impossible, besides the fact that they may coexist in the same patient (Desai 2002).
Furthermore, HPE has to be differentiated from several other conditions sharing a similar clinical and radiographic presentation, the so-called diffuse airspace disease. Those conditions, among others, are infective pneumonias, interstitial pneumonias, massive embolism, pulmonary hemorrhage, and aspiration (Ketai and Washington 2002).
Radiographic differentiation may be challenging and it is not always possible. HRCT may sometimes be very helpful and suggest the correct diagnosis, although in many cases it does not yield additional elements compared to chest X-ray (Ketai and Washington 2002; Rubinowitz et al. 2007).
The main HRCT finding in HPE is the septal pattern, with variable degrees of GGO. This HRCT pattern goes into differential diagnosis with several conditions, much rarer, such as pulmonary veno-occlusive disease (PVOD), lymphangitis carcinomatosis (although in this condition the septal thickening is usually nodular), sarcoidosis (which usually exhibit perilymphatic micronodules), Niemann-Pick disease, Erdheim Chester disease, cystic lymphangiectasia, lymphangiomyomatosis, and North American hantavirus infections (Oikonomou and Prassopoulos 2013).
6.6 Management and Treatment
Acute pulmonary edema is a life-threatening emergency. If necessary immediate intervention is required addressing the ABCs of resuscitation (airway, breathing, and circulation).
Subsequently, the therapy depends on the patient’s condition and the cause of the pulmonary edema: measures may be aimed to preload reduction, afterload reduction, or inotropic support.
- ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS (2012) Acute respiratory distress syndrome: the Berlin Definition. JAMA 307(23):2526–2533Google Scholar
- Dalpiaz G, Maffessanti M (2013) Diffuse lung diseases. In: Geriatric imaging. Springer, Berlin/New YorkGoogle Scholar
- Ferguson ND, Fan E, Camporota L, Antonelli M, Anzueto A, Beale R, Brochard L, Brower R, Esteban A, Gattinoni L, Rhodes A, Slutsky AS, Vincent JL, Rubenfeld GD, Thompson BT, Ranieri VM (2012) The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med 38(10):1573–1582PubMedCrossRefGoogle Scholar
- Kliegerman SJ, Franks TJ, Galvin JR (2013) From the radiologic pathology archives: organization and fibrosis as a response to lung injury in diffuse alveolar damage, organizing pneumonia, and acute fibrinous and organizing pneumonia. Radiographics 33(7):1951–1975Google Scholar
- Kubo K, Azuma A, Kanazawa M, Kameda H, Kusumoto M, Genma A, Saijo Y, Sakai F, Sugiyama Y, Tatsumi K, Dohi M, Tokuda H, Hashimoto S, Hattori N, Hanaoka M, Fukuda Y, Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries (2013) Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig 51(4):260–277PubMedCrossRefGoogle Scholar
- Maffessanti M, Dalpiaz G (2005) Diffuse lung diseases: clinical features, pathology HRCT. Springer, Milan/New YorkGoogle Scholar
- Maffessanti M, Dalpiaz G (2011) Practical pulmonary pathology: a diagnostic approach. Elsevier, PhiladelphiaGoogle Scholar
- Milne EC, Pistolesi M (1994) Reading the chest radiograph: a physiologic approach. Mosby-Year Book, St LouisGoogle Scholar
- Piolanti M, Dalpiaz G, Scaglione M, Coniglio C, Miceli M, Violini S, Trisolini R, Barozzi L. Fat Embolism Syndrome: Lung Computed Tomography Findings in 18 Patients. J Comput Assist Tomogr. 2016 [Epub ahead of print] PubMed PMID: 26938691Google Scholar
- Richerson HB, Bernstein IL, Fink JN, Hunninghake GW, Novey HS, Reed CE, Salvaggio JE, Schuyler MR, Schwartz HJ, Stechschulte DJ (1989) Report of the Subcommittee on Hypersensitivity Pneumonitis. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. J Allergy Clin Immunol 84:839–844PubMedCrossRefGoogle Scholar
- Selman M (2011) Hypersensitivity pneumonitis. In: Schwarz M, King TE Jr (eds) Interstitial lung disease, 5th edn. People’s Medical Publishing House-USA, Shelton, pp 597–625Google Scholar
- Tomiyama N, Müller NL, Johkoh T, Cleverley JR, Ellis SJ, Akira M, Ichikado K, Honda O, Mihara N, Kozuka T, Hamada S, Nakamura H (2001) Acute respiratory distress syndrome and acute interstitial pneumonia: comparison of thin-section CT findings. J Comput Assist Tomogr 25(1):28–33PubMedCrossRefGoogle Scholar