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Review |
1 Both authors: Department of Radiology, University of Pennsylvania School of Medicine, 3400 Spruce St., Silverstein 1, Philadelphia, PA 19104.
Received April 19, 2004;
accepted after revision July 1, 2004.
Address correspondence to W. T. Miller
(wallacejr.miller{at}uphs.upenn.edu).
Introduction
 Top Introduction ObjectiveImmunocompromised PatientsPatients Who Have Received...Outpatients with Slowly...Patients with Acute Development...Acutely Ill Hospitalized...ConclusionReferences |
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TopIntroductionObjectiveImmunocompromised PatientsPatients Who Have Received...Outpatients with Slowly...Patients with Acute Development...Acutely Ill Hospitalized...ConclusionReferences |
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Four large categories of diseases may produce ID-GGO: diffuse pneumonias, primarily opportunistic infections; some chronic interstitial diseases; acute alveolar diseases; and a group of unusual miscellaneous disorders [9]. Table 1 lists the most common causes of ID-GGO.
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There are five clinical scenarios in which ID-GGO is most often encountered: patients who are immunocompromised, patients who are receiving bone marrow–suppressing medications, outpatients who have slowly progressive dyspnea, inpatients and outpatients who have acutely developing dyspnea, and inpatients who are acutely ill. We will review these clinical scenarios and the etiologies most commonly encountered with each scenario.
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TopIntroductionObjectiveImmunocompromised PatientsPatients Who Have Received...Outpatients with Slowly...Patients with Acute Development...Acutely Ill Hospitalized...ConclusionReferences |
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Infections Appearing as ID-GGO
Diffuse infections, particularly Pneumocystis carinii pneumonia
(PCP), are among the most common causes of ID-GGOs. In a series of
pathologically proven causes of ID-GGO, the most common causes were a variety
of diffuse pneumonias, which accounted for 38% (12 of 32) of cases
[9]. Most of these infections
are opportunistic and should be among the first entities to consider when
ID-GGO is the dominant finding on a CT scan of an immunocompromised host.
Pneumocystis carinii pneumonia.—PCP is a globally distributed saprophytic fungus [10]. Patients with AIDS and other causes of immunosuppression, such as organ transplant recipients, patients with lymphoproliferative disorders, and patients on high-dose corticosteroids are predisposed to this opportunistic infection [11, 12]. Despite dramatic declines in the incidence of PCP in HIV-infected patients as a result of highly active antiretroviral therapy (HAART) and PCP prophylaxis, PCP remains the most common opportunistic infection in this population [11, 13, 14]. PCP most commonly occurs in the 4th to 6th month following transplantation and may have up to a 47% mortality rate [15, 16]. A history of high-dose corticosteroid administration, cancer chemotherapy, or a hematologic malignancy also may predispose a patient to PCP infection [11, 14].
Patients characteristically will present with fever, nonproductive cough, and dyspnea [17]. Marked hypoxemia also is characteristic of PCP. In those patients who have received corticosteroids, a characteristic presentation of PCP is the occurrence of fever, dyspnea, and ID-GGO toward the end of the steroid taper. Survival with modern therapy has improved dramatically in patients with HIV and now approaches 90%. However, PCP continues to have an ominous prognosis in other patients, with a 30–60% mortality rate [11].
ID-GGOs, either uniformly distributed or in a mosaic pattern, are the most common manifestations of PCP on CT scans [18] (Fig. 1). In HIV-positive patients, this appearance is so characteristic of PCP that some physicians argue that it is pathognomonic of PCP and no further testing is necessary. With more severe disease, GGO may progress to consolidation. The CT appearance of PCP rarely may take a variety of more unusual patterns including upper-lobe-predominant disease, focal areas of consolidation, nodules, and thin-walled cavities [18–22].
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Cytomegalovirus pneumonia.—Cytomegalovirus (CMV) is a DNA virus of the herpes group and like other herpes viruses, it can remain dormant within a host cell for years and be reactivated when host immune defenses are depressed. CMV may be an important pathogen in immunocompromised patients such as HIV-positive patients and in patients who have undergone organ transplantation [12]. The majority of adults have been exposed to CMV and, as a result, CMV infection usually is a reactivation of dormant foci. In patients receiving organ transplants, the timing of immunosuppression is well defined, corresponding to the date of transplantation. Thus, the timing of CMV reactivation also is well defined and most often occurs 1 to 6 months following transplantation [23]. CMV infection in HIV-positive individuals has declined dramatically with the institution of HAART [24]. However, the occurrence of CMV disease in patients with AIDS is associated with greater levels of immunosuppression and greater mortality rates than in the general HIV-positive population [25].
Many patients in whom CMV can be detected in blood, urine, and respiratory secretions clinically will be asymptomatic. In patients with clinical symptoms, fever, cough, dyspnea, tachypnea, and an increased alveolar-arterial gradient (Aa gradient) most often will be the presenting symptoms [26].
Many patients with CMV viremia will have normal imaging studies. However, in those with imaging findings, CMV pneumonia usually will appear as ID-GGO on CT scans [23, 26, 27] (Fig. 2). In some cases, small (< 5 mm) nodules may be detected and in more severe cases, diffuse consolidation may be present.
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P. carinii and CMV pneumonias affect similar populations, often have similar imaging characteristics, and often cannot be distinguished on the basis of imaging. In general, PCP is more common; however, in certain select settings or situations, such as during the first months after organ transplantation, CMV is a frequent cause of ID-GGO [23, 26, 27].
Herpes simplex virus.—Herpes viruses are a type of DNA virus, which may remain dormant within host cells and reactivate at times of reduced host immunity. A large percentage of the adult population is infected with herpes simplex virus (HSV), which in most cases produces no clinical symptoms [28]. HSV pneumonia is a rare event and most commonly is seen in immunocompromised patients such as organ transplant recipients, patients with AIDS, patients with severe burns, and patients with malignancies [29–32].
Because it represents a reactivation infection, herpes simplex pneumonia characteristically will occur in the first few months following organ transplantation [33, 34]. Patients usually will have oral or genital ulcers before the onset of pulmonary symptoms. Dyspnea, cough, and fever herald the onset of pneumonia.
Herpes pneumonias may appear as ID-GGO, widespread consolidation, or a combination of both on chest radiographs and CT scans [35, 36]. Rarely, only GGO will be present [35]. Associated small pleural effusions commonly are found both by CT and chest radiographs [35].
Respiratory syncytial virus.—Respiratory syncytial virus (RSV) is a common cause of bronchiolitis and pneumonia in children and adults. Infection is most likely to occur in the late winter and early spring and commonly causes fever, cough, dyspnea, and otalgia with clinical signs of rales, rhonchi, or wheezes. In immunocompetent adults, the course usually is self-limited and is treated on an outpatient basis. However, in immunocompromised adults, RSV infection may result in a clinically significant pneumonia [37, 38].
The majority of patients with RSV pulmonary infection will have normal radiographic findings [39]. CT scans in 10 patients with RSV infection following lung transplantation revealed diffuse GGOs in seven patients, pulmonary consolidation in five patients, and tree-in-bud opacities in four patients [40] (Fig. 3).
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Other viruses.—Many other viruses commonly produce upper–respiratory tract illnesses and occasionally may produce a limited pneumonia. It is likely that many of these will appear as widespread or small focal regions of GGO, which are self-limited and radiographically resolve spontaneously. Because few of these patients are definitively diagnosed, it is unknown how often ID-GGO is a manifestation of community-acquired viral pneumonias.
Patients Who Have Received Bone Marrow–Suppressing Chemotherapy
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TopIntroductionObjectiveImmunocompromised PatientsPatients Who Have Received...Outpatients with Slowly...Patients with Acute Development...Acutely Ill Hospitalized...ConclusionReferences |
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In our study of the causes of ID-GGO, drug toxicity accounted for 4% of all pathology-proven cases and therefore represents an important cause of ID-GGO [9]. Because of the wide variety of pharmacologic agents that can result in ID-GGO, there are several histopathologic patterns of drug-related damage to the pulmonary parenchyma. These include noncardiogenic pulmonary edema, diffuse alveolar damage (DAD), nonspecific interstitial pneumonia (NSIP), DAH, bronchiolitis obliterans with organizing pneumonia (BOOP), hyper-sensitivity pneumonitis (HP), eosinophilic pneumonia, bronchiolitis obliterans, and venoocclusive disease [41]. Note that the first six patterns of damage listed here often will appear as ID-GGO on CT scans. Drugs, which can cause permeability edema, include cytosine arabinoside (ara-C), gemcitabine, interleukin-2, tumor necrosis factor, and all-transretinoic acid (ATRA). Other chemotherapy medications that have been shown to cause ID-GGO include daunorubicin, bleomycin, vincristine, carmustine, methotrexate, topotecan, carboplatin, and vinorelbine [41] (Figs. 4 and 5). There likely are many more. In a study of drug toxicity in patients with autologous bone marrow transplantation, 65% of cases of drug toxicity manifested as GGO [42].
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Outpatients with Slowly Progressive Dyspnea
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TopIntroductionObjectiveImmunocompromised PatientsPatients Who Have Received...Outpatients with Slowly...Patients with Acute Development...Acutely Ill Hospitalized...ConclusionReferences |
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Chronic Interstitial Diseases Appearing as ID-GGO
An outpatient with chronic respiratory symptoms but without other
clinically relevant medical conditions who presents with ID-GGO often will
have a chronic interstitial lung disease. In our study of causes of ID-GGO,
chronic diffuse interstitial lung diseases accounted for 31% (10/32) of
pathology-proven cases [9].
Those interstitial diseases that most likely will present as ID-GGO include
HP, DIP, RBILD, and NSIP. Other interstitial diseases that rarely may present
as ID-GGO include sarcoidosis and BOOP.
Hypersensitivity pneumonitis.—Inhalation of organic or inorganic particles by sensitized individuals may result in the allergic phenomenon known as HP. In most cases, the allergens are a variety of microorganisms that may reside in decaying vegetable matter such as thermophilic actinomycetes, the Penicillium species, the Aspergillus species, and the Mycobacterium avium-intracellulare complex [43]. A notable exception to this general rule is bird fancier's disease in which the allergens are proteins contained in bird feathers, serum, or guano. Acute HP causes a capillary leak pulmonary edema secondary to an overwhelming allergic response. With lower-dose, chronic exposures, a granulomatous fibrosis develops in the interstitial spaces of the lungs [44].
There are many of causes of HP, including farmer's lung, cotton worker's lung (byssinosis), sugar cane worker's lung (bagassosis), and mushroom worker's diseases [43]. Urban populations can be exposed via contaminated ventilation systems, especially humidifiers and air conditioners. Hobbies such as raising pigeons or parakeets can result in a form of HP called bird fancier's disease.
CT examinations of HP result in a wide spectrum of findings including diffuse alveolar consolidation in acute HP, diffuse nodular interstitial lung disease in subacute and chronic HP, and irregular bands of fibrosis with distortion of the hila in chronic HP [45–49]. However, ID-GGO is among the more common manifestations of subacute HP and, other than pulmonary edema, HP is probably the most common cause of ID-GGOs in normal hosts [45, 47, 49] (Fig. 6). These ID-GGOs often will appear as a mosaic pattern.
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Desquamative interstitial pneumonia.— DIP is characterized pathologically by infiltration of alveoli by macrophages associated with mild interstitial fibrosis. In the past, many individuals believed that DIP was an early phase of usual interstitial pneumonia (UIP). Currently, DIP is believed to be a direct result of smoking-related lung toxicity. Patients with DIP typically are between ages of 30 to 50 years and present with chronic progressive dyspnea, with or without fevers [50]. Most patients will improve clinically and radiographically with corticosteroid therapy or smoking cessation [6, 51].
CT scans show ID-GGO in many patients with DIP. Some studies have found that the GGOs predominantly are distributed in the periphery of the lung [52–54]. However, in many other cases, GGOs also may show a diffuse or random distribution (Fig. 7). A pattern of subpleural reticulation may be seen in a minority of patients.
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Respiratory bronchiolitis interstitial lung disease.—The histology of RBILD reveals extensive infiltration of alveoli by macrophages associated with mild interstitial fibrosis in a peribronchiolar distribution [55]. Thus, it is histologically identical to DIP with the additional criterion that it be most severe in the centrilobular regions of the secondary pulmonary lobule. This similarity has led some authors to suggest that DIP and RBILD are two manifestations of the same disease [55, 56]. On CT, RBILD often will appear as ID-GGO. Very fine, often centrilobular, nodules also may be apparent on chest CT [56].
Nonspecific interstitial pneumonia.—NSIP represents an interstitial pneumonia that does not meet criteria for UIP, DIP, AIP, or BOOP and thus has a variable histologic and radiologic appearance [57, 58]. It has been associated with collagen vascular disorders, chronic passive congestion, and drug toxicity but is most often an idiopathic disorder. When idiopathic, NSIP most often affects patients in their 40s, 50s, and 60s and presents with an insidious onset of cough and dyspnea [55].
ID-GGOs are the most common radiographic findings in NSIP and are found in nearly 100% of cases. GGO often is found in a subpleural distribution but may also show a random or diffuse distribution [56, 57, 59, 60] (Fig. 8). Reticulation, either randomly or in a subpleural distribution, also is a common finding in one half to four fifths of cases [56, 57, 60, 61]. Irregular linear opacities and traction bronchiectasis also may be seen [56, 59, 60].
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Acute interstitial pneumonia.—AIP is a rapidly progressive interstitial fibrosis that resembles the organizing stage of DAD. It usually will present with progressive dyspnea leading to respiratory failure over several weeks or months, and occasionally with an antecedent viral-like prodrome [55]. Chest CT may show alveolar consolidation, GGOs, or both, often with associated traction bronchiectasis [55, 62].
Lymphocytic interstitial pneumonia.— Lymphocytic interstitial pneumonia (LIP) is an idiopathic interstitial abnormality characterized by diffuse lymphocytic infiltration of the interstitium of the lung [63]. It usually is associated with Sjögren's syndrome in adults and HIV infection in children. Some reports have suggested that LIP may represent a precursor to lymphoma or a low-grade lymphoma; however, others suggest that LIP represents a variant of lymphoid hyperplasia and is not a premalignant condition [64–66]. Diffuse GGO appears to be the most common CT finding in LIP and is present in nearly all patients [66–71]. Bronchovascular and septal thickening also have been reported [70, 71]. Thin-walled cysts also may be present in some cases. Serial CT examinations show reversibility of all findings except cysts [70].
Cryptogenic organizing pneumonia and bronchiolitis obliterans with organizing pneumonia.—BOOP is a histologic pattern of lung injury. This often is due to a variety of pulmonary insults such as infectious pneumonia, connective tissue disorders, and bone marrow transplantation. However, in some cases it may have no recognizable cause. The American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification Conference has identified cryptogenic organizing pneumonia (COP) as the preferred term for idiopathic BOOP [66]. COP is a rare inflammatory condition presenting with progressive dyspnea and often with fever and constitutional symptoms that are unresponsive to standard pneumonia therapies. It is persistent and can lead to serious illness if not treated with corticosteroids, a therapy that in most cases will result in a complete cure of the disease. BOOP, regardless of cause, most often will appear as multifocal alveolar opacities scattered throughout the lungs [72]. Rarely, BOOP may appear as ID-GGO.
Sarcoidosis.—Sarcoidosis is an idiopathic granulomatous disorder with multisystemic ramifications including changes in the meninges, bone, eyes, heart, and skin. Racial predilections include African American and Puerto Rican residents of the United States and West Indians in the United Kingdom. It characteristically presents in patients between the ages of 20 and 40 years but may be encountered at nearly any age.
There are a wide variety of CT manifestations of sarcoidosis. Hilar and mediastinal adenopathy is present in the early and middle stages of the disease. The interstitial lung disease most commonly appears as many small nodules, usually along the bronchovascular bundles but occasionally as randomly distributed interstitial nodules [73–75]. Irregular linear bands of fibrosis, traction bronchiectasis, and coarse cystic spaces may develop in stage IV sarcoidosis. GGOs are among the least common presentations of sarcoidosis (Fig. 9). When GGOs do occur in patients with sarcoidosis, careful inspection of the CT image often will reveal a fine stippled appearance to the GGO, as if it were composed of innumerable, tiny, 1- to 2-mm, ill-defined nodules. Sarcoidosis, HP, and RBILD are the causes of GGO most likely to give this fine stippled appearance. Rarely, sarcoidosis may appear as multiple large ground-glass masses. This pattern is known as alveolar sarcoid. This appearance is virtually pathognomonic of sarcoidosis.
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Other Diseases Appearing as ID-GGO
PAP.—Other disorders that present as ID-GGO include PAP and
BAC. PAP is a rare, idiopathic disorder of middle-aged adults. Accumulation of
protein and lipid-rich material within the lung alveoli results in the
subacute onset of slowly progressive and often incapacitating dyspnea
[76–78].
This accumulation appears to be a result of an abnormality of surfactant
production, metabolism, or clearance. Occasionally PAP may be associated with
exposure to a variety of inorganic dusts, most commonly silica, such as is
seen in sandblasters [79].
When found in association with silica or other exposures, PAP typically will
present with an acute onset of symptoms. Leukemia and lymphoma also may
predispose patients to PAP
[80,
81]. PAP was fatal in
approximately one third of patients before the availability of therapy
involving high-volume bronchoalveolar lavage; since the introduction of this
therapy, many patients can be cured of the disorder and others may be treated
successfully with repeated episodes of bronchoalveolar lavage
[82].
Thin-section CT characteristically will show GGOs in association with thickening of the interlobular septa of the secondary pulmonary lobules [83–85] (Fig. 10). This combination of findings has been termed the "crazy paving appearance" and, when present, is quite suggestive of PAP. However, occasionally PAP will present as ID-GGO.
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Bronchoalveolar carcinoma.—A form of well-differentiated pulmonary adenocarcinoma, BAC, has a wide variety of radiographic appearances including solitary pulmonary nodules, focal alveolar opacities resembling pneumonia, ground-glass nodules, diffuse alveolar consolidation, and ID-GGOs. Most diffuse BACs will have a dominant mass, nodule, or area of consolidation with associated ID-GGO. Rarely, there will be no such sentinel patch and only ID-GGOs will be present [86].
Patients with Acute Development of Dyspnea
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TopIntroductionObjectiveImmunocompromised PatientsPatients Who Have Received...Outpatients with Slowly...Patients with Acute Development...Acutely Ill Hospitalized...ConclusionReferences |
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Acute Alveolar Diseases Appearing as ID-GGO
In our study of the causes of ID-GGO, acute alveolar diseases such as DAH,
cardiogenic edema, and noncardiogenic pulmonary edema accounted for 19% (6/32)
of pathology-proven causes of ID-GGO
[9]. Because of the need for
pathologic proof, pulmonary edema as a cause of ID-GGO is probably
underrepresented in this series and pulmonary edema likely represents the
single most common cause of ID-GGO. Thus, an acute clinical presentation of
respiratory symptoms in a patient with ID-GGO should raise the possibility of
hydrostatic and capillary leak pulmonary edema and DAH.
Pulmonary Edema
Pulmonary edema is a result of imbalances in the Starling forces, which
govern the transport of fluids between the vascular and interstitial spaces of
the lung. During homeostasis, there is a near balance between these forces,
and the small net transfer of fluid into the interstitium is removed via the
pulmonary lymphatics. However, a disturbance of this equilibrium will lead to
excessive transport of water and solutes into the interstitial space. If the
process continues, the interstitial lymphatics become overwhelmed and fluid
overflows into the alveoli, leading to alveolar edema
[87].
Typically, pulmonary edema is subdivided into two major etiologic subcategories: hydrostatic pulmonary edema and increased permeability pulmonary edema. In hydrostatic edema, there is increased intravascular hydrostatic pressure, which results in a net force driving water and solutes into the interstitial and, subsequently, alveolar spaces of the lung. Hydrostatic edema most often is a manifestation of left-sided heart failure. Increased permeability edema usually is a result of disruption of the capillary epithelial membrane, which allows plasma proteins to pass into the interstitial space. These proteins exert an osmotic force drawing water into the interstitial space, and if of sufficient volume, they spill into the alveolar spaces [87]. Permeability edema most often is a result of ARDS but has a number of other causes.
Cardiogenic pulmonary edema.—Left-sided heart failure is by far the most common cause of hydrostatic edema and thus commonly is known as cardiogenic pulmonary edema. On thin-section CT, the most common manifestation of cardiogenic pulmonary edema is ID-GGO (Fig. 11). CT also may show thickening of the interlobular septa. The GGOs associated with hydrostatic edema often will have a central, perihilar distribution and be associated with enlarged pulmonary vessels and an enlarged heart.
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Adult respiratory distress syndrome.— ARDS is the most common cause of noncardiogenic pulmonary edema and is a common physiologic response to a wide variety of insults including sepsis, aspiration of gastric contents, overwhelming pneumonia, severe trauma, multiple fractures, major burns, pancreatitis, prolonged hypotension, disseminated intravascular coagulation, drug overdose, and thoracic surgery [88, 89].
CT scans of ARDS most often will show bilateral GGO, pulmonary consolidation, or a combination of both [90, 91]. ID-GGO is most often a manifestation of the earlier exudative phase of disease [90, 91]. Pulmonary opacities often will be most severe in the more gravity-dependent regions of the lung. Unlike chest radiographs, which characteristically show uniform consolidation across the lung parenchyma, 75% of the time CT scan opacification will appear inhomogeneous or patchy.
Other noncardiogenic pulmonary edema.— It is likely that all causes of pulmonary edema can occasionally result in ID-GGO (Fig. 4). ID-GGO has been reported in cases of near drowning [92] and fat emboli syndrome [93].
Diffuse Alveolar Hemorrhage
Alveolar hemorrhage may result from a large number of disorders; however,
when the process is diffuse, the differential diagnosis is moderately limited.
The most common causes of DAH in outpatients are the group of entities often
referred to as the pulmonary–renal syndromes
[19]. Goodpasture's syndrome,
Wegener's granulomatosis, and systemic lupus erythematosus are prime examples.
Although these disorders may have other pulmonary manifestations, DAH is among
the most common radiographically identifiable abnormality. Vasculitises other
than Wegener's granulomatosis, such as Churg-Strauss vasculitis and
microscopic polyangiitis, also are less common causes of DAH. Patients with
lymphoma and leukemia also are inclined to DAH as a result of platelet
deficiency or platelet malfunction. DAH is a feared complication of bone
marrow transplantation because of its high mortality in this population
[94]. Bleeding disorders such
as antiphospholipid-antibody syndrome and use of anticoagulatory drugs also
may predispose patients to DAH.
CT scans of DAHs may reveal frank consolidation with obliteration of the pulmonary vascular markings, but often they will appear as ID-GGOs (Fig. 12). On thin-section CT images, ID-GGO may be spread uniformly throughout the lung, be randomly distributed, appear as centrilobular opacities, or have a mosaic pattern.
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Acutely Ill Hospitalized Patients
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TopIntroductionObjectiveImmunocompromised PatientsPatients Who Have Received...Outpatients with Slowly...Patients with Acute Development...Acutely Ill Hospitalized...ConclusionReferences |
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TopIntroductionObjectiveImmunocompromised PatientsPatients Who Have Received...Outpatients with Slowly...Patients with Acute Development...Acutely Ill Hospitalized...ConclusionReferences |
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TopIntroductionObjectiveImmunocompromised PatientsPatients Who Have Received...Outpatients with Slowly...Patients with Acute Development...Acutely Ill Hospitalized...ConclusionReferences |
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