2015-04-24 18:08 Source：DingxiangYuan Author：sd3212 Font size-|+
The differential diagnosis of idiopathic pulmonary fibrosis (IPF) remains one of the common diagnostic challenges encountered by respiratory physicians today. To enhance clinicians’ ability to recognize IPF, Dr. Paolo Spagnolo et al. from the Clinical Hospital of the University of Basel Medical School in Liestal, Switzerland, analyzed the difficulties in the diagnosis of IPF through a clinical case and comprehensively introduced the clinical, imaging and pathological features of the related disease, and reviewed the techniques, advances and related knowledge in the differential diagnosis of this disease. The article was published in a recent issue of Eur Respir Rev. Tong Xiaobing, Department of General Thoracic Surgery, Karamay Central Hospital
IPF and UIP
Idiopathic pulmonary fibrosis (IPF) is the most common and fatal form of idiopathic interstitial pneumonia. Radiologically and/or pathologically, it mainly presents as a common type of interstitial pneumonia (UIP).
However, UIP is not the same as IPF, and many conditions or diseases, including chronic allergic pneumonia, collagen vascular disease, drug toxicity, asbestosis, familial idiopathic pulmonary fibrosis, and Hermansky-Pudlak syndrome, can lead to the development of UIP (secondary UIP).
Patients with IPF (idiopathic UIP) are now known to reduce the rate of decline in lung function and slow the progression of their disease with timely and appropriate drug therapy compared to secondary UIP. Therefore, accurate differentiation of IPF from other secondary UIP is of great therapeutic and prognostic importance.
Studies have shown that numerous imaging and histologic clues can help distinguish IPF from other secondary UIP-like fibrosis, which often requires an integrated multidisciplinary approach and the involvement of pulmonologists, radiologists, and pathologists with extensive expertise in interstitial lung disease (ILD), among others.
Interdisciplinary discussions can facilitate the early diagnosis of IPF and lead to more timely treatment. This is a concept that is strongly emphasized in the 2011 edition of the American Thoracic Society / European Respiratory Society / Japanese Respiratory Society / Latin American Thoracic Society (ATS/ERS/JRS/ALAT) related joint guidelines.
Clinical Case Presentation
The patient, a 62-year-old male, presented to his primary care physician in June 2012 with slowly progressive shortness of breath and dry cough for nearly 1 year. The patient also had fatigue, heartburn, and mild weight loss. The patient had been treated with antibiotics, inhaled bronchodilators, and a short course of steroid hormones without significant improvement in symptoms. Chest radiograph showed the presence of predominantly reticular infiltrative changes at the base of both lungs, consistent with interstitial lung disease.
The patient smoked, 60 packs – year. In addition, he was diagnosed with atrial fibrillation in 2004 and was started on amiodarone (200 mg/day). The patient had a history of parrot exposure for nearly 5 years prior to 1995. Significant occupational exposure, allergies, recent foreign travel, or family history of chronic respiratory disease was denied, and the mother had a history of rheumatoid arthritis.
The patient was referred to the authors’ institution for further evaluation. Chest auscultation revealed the presence of a fine end-inspiratory rhotic sound at the base of both lungs, with no other clinical examination being significant. The patient denied any joint pain, stiffness, or swelling, Raynaud’s phenomenon, or other symptoms suggestive of connective tissue disease (CTD).
Pulmonary function tests showed that the patient had restrictive ventilatory impairment. His FVC was 68% of the expected value and was associated with a moderate reduction in pulmonary carbon monoxide diffusion (DLCO) (42% of the expected value). Blood tests showed negative CTD serology (including rheumatoid factor, anti-cyclic citrullinated peptide, antinuclear antibody titers and their patterns), and allergic pneumonia (HP) antibody testing.
High-resolution CT of the chest (HRCT) showed bilateral subpleural reticular abnormalities, but no traction bronchiectasis or honeycomb changes, and no radiological features “inconsistent” with a common interstitial pneumonia (UIP) pattern.
Together, these findings suggest that the patient is consistent with a suspected UIP type (Figure 1). This patient requires further diagnostic evaluation according to the current ATS/ERS/JRS/ALAT guidelines.
Interstitial pneumonia 1.jpg
The CT scan shows reticular abnormalities with a predominantly subpleural and bilateral lung base distribution, but no foveal changes. Although this patient had the possibility of IPF (in the appropriate clinical setting), the diagnosis still needed to be confirmed by surgical lung biopsy.
Further examination showed an increased total cell count (240 cells/μL) in the bronchoalveolar lavage (BAL) fluid and a lymphocyte and neutrophil ratio of 18% and 7%, respectively; transbronchial biopsy was nonspecific. Subsequently, the patient underwent a surgical lung biopsy (SLB), and a lesion consistent with a UIP pattern was suggested (Figure 2).
Interstitial pneumonia 2.jpg
Figure 2. a) Open chest lung biopsy specimen. Shows the presence of fibrotic lung disease with spatial and temporal heterogeneity consistent with the pattern of presentation of common interstitial pneumonia (hematoxylin and eosin staining, 40×); b) shows cellular changes with enlarged subpleural alveoli and their fine bronchial epithelial hyperplasia, mucus plug formation, and mild chronic inflammatory infiltrates (hematoxylin – eosin staining, 40×).
Based on the patient’s clinical, imaging, and pathological data, the patient was diagnosed with idiopathic pulmonary fibrosis (IPF), and evaluation for pirfenidone therapy and lung transplantation was initiated.
Case Discussion
1. IPF diagnostic challenges
This case highlights some of the challenges one faces in clinical practice when encountering a patient with suspected IPF. As a chronic progressive, fibrotic interstitial pneumonia of unknown origin, IPF occurs primarily in the elderly; and its lesions are limited to the patient’s lungs.
Patients with chronic exertional dyspnea of unknown cause who are older than 60 years of age (especially current or former smokers) should be alerted to the possibility of IPF. In contrast, IPF is quite rare in those younger than 50 years of age. Therefore, when dealing with younger patients with pulmonary fibrosis (especially women), it is important to actively look for known causes of pulmonary fibrosis, such as those of a systemic, or environmental nature.
As mentioned above, IPF is primarily defined by the patient’s imaging and/or pathologic pattern of UIP presentation. However, several other causes, including CTD (primarily rheumatoid arthritis), drug toxicity, chronic HP, asbestos, and Hermansky-Pudlak syndrome, can also contribute to its UIP-like presentation pattern. Therefore, the diagnosis of IPF must be preceded by a thorough workup to determine whether the patient has secondary UIP from a currently known cause.
In current clinical practice, it is difficult to make an accurate differential diagnosis of IPF, as the gold standard for diagnosis includes multidisciplinary evaluation criteria and the diagnosis often requires the combined efforts of chest physicians, radiologists, and pathologists with extensive experience in ILD.
In addition, the combined diagnostic approach is of greater value in patients with inconsistent imaging and histopathological abnormalities (e.g., HRCT not consistent with UIP but SLB suggestive of UIP).
2. Reasons for delayed diagnosis of IPF
IPF initially presents with exertional dyspnea and dry cough, which are often overlooked or attributed to smoking and increasing age. Other common reasons for delayed diagnosis include reluctance of patients to undergo invasive tests (thus hindering access to tissue samples) and inexperience of some primary care physicians in the diagnosis of ILD.
Studies have shown that community physicians are more likely to make the final diagnosis of IPF than physicians at university hospitals, but their diagnosis is sometimes incorrect, highlighting the importance of referring patients with suspected IPF to specialized treatment centers. Timely referral to an ILD specialty center not only allows for early admission to the appropriate treatment facility, but also facilitates access to relevant clinical trials or evaluation for lung transplantation.
In addition, studies have found that the longer the time between the onset of dyspnea and a patient’s first visit to an IPF specialty clinic, the higher the risk of death. This correlation is independent of the severity of the patient’s disease.
Exclusion of known causes of pulmonary fibrosis
The most common diagnostic challenge for patients with suspected IPF is to rule out inflammatory diseases (mainly CTD and chronic HP) that can cause the patient’s pulmonary fibrosis. In this case, a family history of rheumatoid arthritis, amiodarone exposure, and parrot exposure are etiologies that need to be carefully ruled out.
In a recent case-cohort study, nearly half of the subjects initially diagnosed with IPF based on 2011 diagnostic criteria were finally diagnosed with chronic HP through detailed history taking and comprehensive diagnosis.
Although it is sometimes difficult to distinguish IPF from chronic HP. However, the distinction between IPF and HP has important therapeutic and prognostic implications. Because immunosuppressive therapy is often appropriate for chronic HP (and requires the removal of its known allergens), this therapy may be associated with an increased risk of death in patients with IPF.
The differential diagnosis in this case can be approached in several ways.
First, HP should be excluded. although the presence of HP should be highly suspected in this patient with a history of avian influenza antigen exposure (cessation of exposure for almost 20 years before the onset of symptoms), there are no clear laboratory indications (positive serum antibodies or lymphocytosis in the BAL fluid), radiological indications (HRCT showing hairy glassy shadows, faint lobular central nodules, mosaic-like hypodensity and air trapping shadows and few pulmonary The diagnosis of chronic HP is supported by radiological indicators (HRCT showing hairy glassy shadows, faint lobular central nodules, mosaic-like hypointense and air trapping images, and few lesions in the lower fields), or pathological indicators (centralized and aggravated inflammation of the fine bronchi, peribronchial fibrosis, bronchial epithelial hyperplasia, granulomas or multinucleated giant cells).
Second, UIP due to CTD needs to be excluded. although ILD can sometimes be the only clinical manifestation of CTD, there are also no clinical, serologic, or pathologic findings that would suggest an underlying systemic disease in this patient. In addition, patients with IPF may also have mild antinuclear antibody, and/or rheumatoid factor-positive serology, which should also be noted.
Finally, drug-induced ILD should be ruled out; although this patient has a history of amiodarone exposure, this possibility can be definitively excluded at this time based on the patient’s unique imaging features and BAL and pathologic presentation.
Timing of validated SLB
In clinical practice, SLB has been performed in only a small number of patients with suspected IPF, either because of concerns about the risks associated with the procedure versus the benefits of confirming the diagnosis, or because most such patients are not willing to undergo the procedure.
In addition, although SLB has become safer due to improvements in surgical techniques, the impaired pulmonary function and poor oxygen metabolism and functional status that are common in these patients increase the risk of postoperative complications, which also hinders the performance of SLB in patients.
It is currently considered that in the appropriate clinical context (male current or former smokers older than 60 years with unexplained exertional dyspnea and unexplained pulmonary fibrosis), if the patient’s HRCT examination gives a clear diagnosis (the presence of UIP manifestations on HRCT has a high positive predictive value), no further histological verification of the patient’s diagnosis is required.
Chest CT in patients with UIP shows mainly honeycomb lesions distributed in the peripheral and basal lung tissues with distended bronchial dilatation, irregular lobular septal thickening and small ground glass shadows. It has been shown that when all of these features are present, the diagnostic accuracy of CT for UIP can approach 90-100%. Foveal changes, on the other hand, are the strongest predictor for the diagnosis of UIP. However, these typical CT findings are usually seen in only about half of patients with IPF.
A number of studies have evaluated the level of concordance between clinical/imaging diagnoses in patients with UIP, including the final diagnosis of pathological data, and have shown that HRCT has a high specificity for the diagnosis of UIP (pathologically confirmed), especially when the CT findings can be accurately interpreted. In contrast, HRCT cannot be used to exclude the diagnosis of UIP, regardless of whether the patient’s HRCT presentation can be accurately interpreted.
Therefore, if the CT findings do not confirm a definite UIP, it is necessary to clarify the diagnosis by SLB. However, if the patient is elderly, the diagnosis of IPF can be almost 100% established (without the need for SLB verification) even if there is only moderate fibrosis on HRCT (only reticular abnormalities and traction bronchiectasis without foveal changes).
More recently, it has also been shown that in the appropriate clinical context, a CT examination showing “suspected UIP” is sufficient to diagnose a patient with IPF without the need for SLB verification. However, this study has excluded patients with radiological indications of “probable UIP and SLB indications of other diagnoses”. These were mainly patients with chronic HP and non-specific interstitial pneumonia (NSIP), two of the most common diseases that are similar to IPF and difficult to differentiate.
A number of clinical, laboratory and imaging findings may also preclude the need for SLB screening in relevant patients. For example, asbestosis can be diagnosed directly without biopsy in patients with a history of significant asbestos exposure, pleural plaques and typical CT findings.
A clear history of environmental, occupational, or drug exposure suggests that one should be alert to the possibility of HP, pneumoconiosis, or drug-related pulmonary toxic reactions. Likewise, the diagnosis is made directly without a lung biopsy in patients who present with pulmonary fibrosis and have clinical and serologic features suggesting some underlying CTD.
In addition, the fact that IPF rarely occurs in people younger than 50 years of age may be a clue to exclude the diagnosis of IPF.
Differential diagnosis of UIP
1. Clinical features of common ILDs
A thorough clinical evaluation is a key factor in the diagnosis of ILD. This includes a careful analysis of the patient’s complaints, a thorough understanding of the medical history and multisystem review, a comprehensive review of the patient’s past medical, medication, social, family, and occupational history, and a focused understanding of his or her history of exposure to relevant potential environmental risk factors. Likewise, a careful physical examination is essential.
(1) Clinical features of IPF
Almost all patients with IPF present with a complaint of slowly progressive exertional dyspnea, often accompanied by chronic cough. The incidence of the disease is significantly higher in the elderly population. The average time from symptom onset to diagnosis is 24 months. On chest auscultation, a fine end-inspiratory rales are present at the base of both lungs in most patients with IPF. Mortar and pestle fingers are more common in patients with IPF compared to other ILDs, with an incidence ranging from approximately 40% to 75%.
(2) Clinical features of rheumatoid arthritis
Rheumatoid arthritis is the most common CTD, with a prevalence of nearly 1% in the population. Although the ratio of male to female prevalence is about 3:1, the incidence of ILD in men with rheumatoid arthritis is twice as high as that in women. The reported prevalence of ILD in patients with rheumatoid arthritis ranges from 5% to 58%, depending on the method of diagnosis and diagnostic criteria. Smoking and high titers of rheumatoid factor are recognized risk factors for the development of ILD in patients with rheumatoid arthritis.
In most cases, joint manifestations precede the development of ILD in these patients, but approximately 10-20% of patients may also have interstitial lung abnormalities as their characteristic presentation. Recent data suggest that the prevalence of ILD in patients with rheumatoid arthritis increases with age. Also, if HRCT in these patients shows a UIP pattern, their prognosis will be comparable to that of patients with IPF.
The most common complaints of patients with rheumatoid arthritis-related ILD are progressive exertional dyspnea (which may be masked early by the patient’s joint involvement and disability) and dry cough. Pestle fingers and velcro-like sounds may also be found on physical examination in patients with advanced disease. From a clinical standpoint, youth, joint or skin involvement, and serologic abnormalities are the main differentiating points between this type of ILD and IPF.
(3) Clinical features of HP
HP, also known as exogenous allergic alveolitis, is a diffuse and substantial lung disease. It is caused by an abnormal immune response to inhaled allergens (mainly organic substances) in sensitive individuals.
The prevalence of HP varies widely across the globe and is mainly related to the definition of the disease, the method of diagnosis, the type and intensity of antigen exposure, local agricultural and industrial practices, and the patient’s own risk factors. In addition, the disease is often underdiagnosed or misdiagnosed, so its exact incidence is difficult to determine.
Several studies have shown a lower prevalence of smoking in HP patients compared to controls at the same risk of exposure. Furthermore, smoking appears to slow the progression of HP patients by inhibiting macrophage activation, lymphocyte proliferation, and suppressing T-cell function, among other mechanisms.
The onset of chronic HP is often insidious and is characterized by slowly progressive shortness of breath with activity, cough, fatigue, malaise, and weight loss. On examination, bursting sounds can be heard at the base of both lungs, but pestle fingers are seen in only 20%-50% of these patients.
A unique feature of chronic HP, compared to other chronic fibrotic interstitial lung diseases, is the presence of inspiratory croup due to coexisting capillary bronchitis. Pulmonary function tests usually show restrictive hypoventilation and impaired gas exchange. Patients with a UIP pattern on lung biopsy or HRCT will have a prognosis comparable to that of patients with IPF.
To diagnose HP, the following conditions are required: (i) a proven or suspected antigen exposure and symptoms associated with that antigen exposure; (ii) evidence of allergy (e.g., serum antibodies or lymphocytosis in BAL fluid); and (iii) abnormalities on chest radiograph and HRCT consistent with the disease (which may or may not be associated with restrictive ventilation and impaired gas exchange).
In contrast, the serum precipitating antibody test has low sensitivity and specificity for detecting many of the common causative antigens of the disease; therefore, while a positive result is helpful in the diagnosis of HP, a negative result is not helpful. The diagnosis of chronic HP can sometimes be quite difficult, especially if detailed clinical history questioning does not show a temporal association between the patient’s antigen exposure and its onset.
(4) Clinical features of amiodarone pulmonary toxicity
Amiodarone is an iodine-containing preparation commonly used in the treatment of supraventricular and ventricular arrhythmias. This drug has a relatively large number of side effects, and pulmonary toxicity, via direct (cytotoxic) or indirect (immune-mediated) mechanisms, is one of the most serious. Amiodarone pulmonary toxicity (APT) refers to a group of pharmacogenic ILD diseases with multiple patterns of clinical, imaging and pathologic lung involvement, and with varying severity and prognosis.
Although APT can occur at any time after a patient starts amiodarone therapy, it is currently believed that individuals at a daily dose of 400 mg for more than 2 months or at a low dose (e.g., 200 mg per day) for more than 2 years are at greatest risk of developing APT.
The incidence of APT is higher in male users and increases with increasing age of the user. Pre-existing pulmonary disease, cardiothoracic surgery, and a history of high oxygen exposure appear to increase the risk of APT in drug users.
The most common clinical presentation of patients with APT is progressive shortness of breath, dry cough, malaise, fever, and occasionally subacute episodes of pleuritic chest pain. In mild cases, there are no obvious abnormal signs; however, in severe cases, diffuse bursting sounds can be heard in the lungs on examination, and there may be signs of hypoxemia and respiratory distress.
Pulmonary function tests in such patients usually show a restrictive pattern of impaired ventilation with a decrease in DLCO. A very small number of patients may also present with significant acute respiratory failure and the typical imaging manifestations of acute respiratory distress syndrome. Interstitial pulmonary fibrosis is seen in approximately 5-10% of patients with this disease and may occur prior to the onset of typical amiodarone pneumonia.
Any patient taking amiodarone with new or worsening respiratory symptoms and/or new infiltrative foci on chest radiographs should be suspected of having APT, but an open lung biopsy is rarely needed to confirm the diagnosis in such patients. Given that patients with APT often have impaired cardiac and pulmonary function and a tendency for APT to worsen after chest surgery, open lung biopsy should be limited to carefully selected cases.
2. Imaging features of common ILD
Due to the improved diagnostic accuracy of CT, a significant proportion of IPF diagnoses can now be made on the basis of the patient’s clinical and imaging data without the need for confirmation by surgical biopsy. Unfortunately, only about half of the patients with IPF have a radiologically certain diagnosis of UIP. This is mainly related to the difficulty in identifying the foveal lesions on imaging, which are the imaging feature of UIP. In fact, imaging abnormalities, including cysts or traction bronchiectasis, can be incorrectly interpreted as foveal lesions.
Given that a variety of diseases may exhibit imaging similar to UIP on HRCT, radiologists should insist on a clear diagnostic imaging level of confidence and use all available methods (e.g., multidimensional reconstruction, comparison with previous exams, etc.) to differentiate between a patient with a foveal lesion, traction bronchiectasis, or bronchiectasis and their subpleural septal parapneumonias.
Although reticular lesions can be seen in the peripheral lung fields of patients with fibrotic NSIP, they are relatively uncommon in the subpleural region of patients with this disease, i.e., they are an important imaging component of the disease. This is an imaging feature that should not be overlooked.
Other additional imaging features commonly seen in patients with HP include hypodensity in the lobar region of the lung (suggestive of air trapping) and central lobar nodules.
Although these abnormalities can also be seen in patients with IPF who smoke (suggesting constrictive fine bronchitis and respiratory fine bronchitis, respectively), a sufficient number of these additional features are also a good basis for diagnosing patients with chronic HP.
Interstitial pneumonia 3.jpg
Figure 3. CT scan image of chronic HP showing extensive reticular and ground glass shadows. Traction bronchiectasis is also present in the apical segment of the left lower lung lobe. The left lung fissure is separated by underlying fibrosis.
SILVA et al. evaluated the accuracy of using HRCT to differentiate HP from patients with IPF and NSIP. It was found that 80% of patients with chronic HP had hypodensity in the lobular region of the lung; this feature was present in only 43% of patients with IPF and 34% of patients with NSIP.
Similarly, lobar central nodules were found in 56% of patients with chronic HP, significantly more than in 15% of patients with IPF and 14% of patients with NSIP. Thin-walled cysts were present in 39%, 0%, and 12% of these three diseases, in that order. This suggests that these features are important for the identification of HP.
Notably, although patients with IPF were more likely to have cellular changes and fibrosis at the base of the lung compared with patients with chronic HP (52% vs. 11%), the frequency of cellular lesions was similar in patients with chronic HP and IPF (64% vs. 67%).
The pattern of UIP on CT may also be seen in patients with CTD, particularly in patients with rheumatoid arthritis, and TOKURA et al. have reported a higher frequency of air retention on breath CT scans in patients with rheumatoid arthritis-related ILD compared to patients with IPF. This may be a reflection of the presence of airway disease in these patients.
However, in patients with rheumatoid arthritis, a pattern of imaging UIP may be observed that is in fact identical to that of patients with IPF, such as vague lobular central nodules, ground glass shadows; or thickened bronchial and fine bronchial walls with varying degrees of pulmonary hypodensity. This is especially true in those patients with rheumatoid arthritis who do not have airway abnormalities.
In contrast, emphysema is also seen in both rheumatoid arthritis-associated ILD and IPF patients. For example, a recent study showed that emphysema was seen in 35% (66/186 cases) and 48% (22/46 cases) of patients with IPF and rheumatoid arthritis-associated ILD who smoked, respectively, suggesting a possible pathologic association between smoking and the two diseases.
The CT abnormalities of drug-related lung diseases are a true reflection of their underlying histopathology, and these CT abnormalities and pathologies can include diffuse alveolar injury, NSIP, mechanized pneumonia, eosinophilic pneumonia, and pulmonary hemorrhage. In contrast, imaging manifestations of UIP are less common in drug-related lung disease.
Pulmonary fibrosis due to amiodarone generally appears on CT as interstitial and perifollicular reticular shadows predominantly at the base of the lung, consistent with fibrotic NSIP, as well as regional ground glass shadows; however, deformation of lung structures and foveal changes are sometimes seen.
It is believed that in the appropriate clinical context, the diagnosis of ILD due to amiodarone can be made largely on the basis of CT findings if the high-density pulmonary infiltrates on CT are thought to be due to the properties of the iodine-containing drug used and its long half-life.
3. Histologic UIP findings
The UIP appearance of biopsied tissue has always been a key factor in the diagnosis of IPF. However, the limitations of histologic diagnosis have been better understood in the last few years. This limitation is more evident when there are errors in the collection of tissue specimens or when pathologists have different diagnoses of the specimens.
For example, the lungs of patients with UIP often contain areas of fibrotic NSIP, and if a physician collects a specimen in this incorrect area, the pathologist is likely to arrive at an incorrect histologic diagnosis of NSIP. However, in fact, the patient’s prognosis will depend on the UIP in his or her non-specimen collection area rather than the histologic NSIP described above.
When a pathologist evaluates a tissue specimen from a patient with fibrotic ILD, the primary task should be to distinguish the UIP pattern of presentation from the multiple similar patterns of pathologic presentation. Once the UIP pattern is identified, a second goal should be to help clinicians distinguish those with idiopathic UIP, or IPF, from those with secondary UIP secondary to possible causes or systemic disease.
Although the histologic pattern of presentation of UIP has some key features, many “secondary” UIPs can also present with the same histologic presentation as “idiopathic” UIP/IPF. Therefore, the differential diagnosis of these patients should be based on relevant clinical and laboratory findings in combination with their histological manifestations.
The role of BAL in the differential diagnosis of IPF
The majority of patients with ILD have no significant specificity of BAL fluid findings. This test alone is not sufficient to establish a reliable diagnosis for the patient. However, when the results of BAL fluid cytology are considered in conjunction with the patient’s clinical and HRCT findings, it can help narrow the differential diagnosis and save the patient from an open lung biopsy. Studies have shown that in up to 8% of patients with a UIP pattern on HRCT, BAL findings may suggest a diagnosis other than IPF.
The BAL fluid of patients with IPF is typically characterized by a moderate increase in eosinophil count (10%-30% of total cells) with or without an increase in eosinophil count. In general, the eosinophil count in the patient’s BAL fluid is about two times higher than the eosinophil count. In all patients with IPF, the percentage of BAL fluid showing increased eosinophil and eosinophil counts was 70%-90% and 40%-60%, respectively.
In addition, about 30% of patients showed a moderate increase in lymphocyte counts. However, the BAL fluid of patients with IPF does not tend to show a significant increase in lymphocytes alone. Therefore, when encountering such patients, care should be taken to rule out other diseases that are associated with increased lymphocytes in the BAL fluid.
BAL fluid findings in patients with rheumatoid arthritis are highly variable and lack specificity. Overall, increased lymphocytes and neutrophils can be seen in these patients. However, the presence of lymphocytosis within the BAL fluid of patients with rheumatoid arthritis appears to be more prominent compared to non-systemic sclerosis.
The total cell count in the BAL fluid of patients with HP is the highest of all interstitial lung diseases. Their total cell count is often very high (>20 million /100 ml BAL), and the percentage of lymphocytes is mostly above 50%.
The increase in lymphocytes in the BAL fluid may be less pronounced in chronic HP with imaging manifestations of fibrotic UIP or NSIP. In contrast, some asymptomatic sensitized individuals may also have increased lymphocytes in their BAL fluid.
HP patients also have increased numbers of activated T cells in their BAL fluid, but their CD4/CD8 ratios can be lower, higher, or normal. This ratio is usually higher in patients with chronic HP compared to patients with acute or subacute HP. In addition, alveolar macrophage-derived foam cells are often seen in the BAL fluid of HP patients. Plasma cells may also be seen in the BAL fluid of those patients who have had recent exposure to relevant antigens.
There may be a transient increase in BAL fluid neutrophil counts during an acute episode of HP. In addition, it is important to note that a patient with a normal BAL fluid cell count or an isolated increase in neutrophils or eosinophils can be largely excluded from HP.
Many drugs can cause interstitial lung reactions in patients who use them, either through their toxic effects or immune-mediated mechanisms. Various types of alveolitis, including lymphocytes, neutrophils, eosinophils, or mixed inflammatory cells, as well as diffuse alveolar hemorrhage, are often seen in the BAL fluid of such patients. Lymphocytic alveolitis, in which CD8+ T cells predominate, is the most common pattern of inflammation.
The presence of alveolar macrophages in the BAL fluid showing tiny vacuolated foam in the cytoplasm is an important feature of patients with APT. The presence of such foamy macrophages is suggestive of amiodarone exposure, but it is not necessarily a toxic reaction to amiodarone. In addition, such cells are also seen in the BAL fluid of patients with HP, mechanized pneumonia, and those without clinical manifestations of ILD. The absence of foamy alveolar macrophages is generally considered to largely exclude the possibility of APT in patients. A normal BAL examination, however, does not exclude the diagnosis of APT.
Conclusion
When dealing with patients with ILD, the most important task for the clinician is to identify those cases of UIP and to distinguish between IPF and secondary UIP.
Although UIP manifestations are, by current definition, the main imaging and pathological features of IPF, similar UIP manifestations are in fact seen in other diseases (mainly CTD and chronic HP). Since IPF differs significantly from these diseases in terms of pathogenesis, treatment, response to therapy and their prognosis, it is crucial to make a correct differential diagnosis of these related diseases.
It is currently believed that expert evaluation can mostly provide important clues for the differential diagnosis of such patients. However, as in the case described earlier in this article, it is still sometimes challenging to accurately identify true IPF in clinical practice because of the possible coexistence of multiple confounding factors in the patients involved. A comprehensive analysis of the patient’s clinical, imaging, and pathological data in conjunction with relevant experts is often the most important and useful way to manage such patients.