Invasive diagnostic techniques in idiopathic interstitial pneumonias

BAL

Recognition of an inflammatory cellular pattern (increased lymphocytes, eosinophils or neutrophils) in the BAL frequently helps clinicians to narrow the differential diagnosis of f-ILDs, even though such patterns are non-specific. Increased lymphocytes suggest an alternative diagnosis to IPF15, 16 and may be observed in idiopathic NSIP (mainly in cellular NSIP or in NSIP where alveolar opacifications are present in the HRCT scan), cryptogenic-organizing pneumonia, hypersensitivity pneumonitis (HP) and lymphocytic interstitial pneumonia.1 Smoking-related ILDs, mainly desquamative interstitial pneumonia (DIP), are characterized by the presence of ‘smoker's’ macrophages and increased eosinophils, often at levels as high as seen in eosinophilic pneumonia.17 BAL lymphocyte subsets have been examined extensively in sarcoidosis and HP: a CD4/CD8 ratio >3.5 was reported to be very specific for sarcoidosis in a characteristic clinical-radiologic context;18, 19 subacute HP usually presents with a reduced CD4/CD8 ratio.1 Recent guidelines from the American Thoracic Society/European Respiratory Society on IPF suggest avoiding BAL in subjects with suspected IPF.20 This suggestion is however open to criticism: in a minority of cases with HRCT scan typical for UIP, an alternative diagnosis such as chronic HP or idiopathic NSIP may be considered after the detection of an increased lymphocyte count in BAL;16 when atypical clinical-radiological features are predominant, alternative diagnoses need to be considered and BAL could contribute to the collection of useful information with low risk for the patients. BAL is also useful to indicate unexpected diagnoses in cases mimicking f-ILDs such as disseminated lung malignancies including lymphomas, eosinophilic pneumonia, alveolar proteinosis, Langerhans cell histiocytosis, chronic alveolar haemorrhage, exogenous lipoidic pneumonia, dust exposure (asbestos exposure) and bronchiolitis.1, 19, 21-23 BAL has also a role in the diagnostic work-up of patients with f-ILD and may provide additional information in patients who cannot, or will not agree to, be subjected to more invasive procedures—in a minority of cases, the procedure may suggest an alternative diagnosis. BAL may also have a prognostic value:24 increased neutrophils with a low lymphocyte count suggest a bad prognosis in chronic HP and increased neutrophils have been reported to predict mortality in IPF.

TBB and transbronchial cryobiopsy

Andersen et al.25 are credited with the first description of TBLB following their observation that bronchial biopsy specimens of small airways harvested during rigid bronchoscopy often contained lung parenchyma. The forceps used in conventional TBLB reach lung tissue through the bronchial routes and specimens come from the centrilobular regions.1 The disorders that are centred around terminal and respiratory bronchioles or significantly involve these structures (OP) or are distributed along the lymphatic routes (sarcoidosis, carcinomatous lymphangitis) may be easily sampled by the forceps. In ‘lymphangitic’ disorders, bronchial biopsies may also contribute to increasing diagnostic accuracy. TBLB specimens may contain very specific and informative lesions (also using immunohistochemical staining) that are diagnostic by themselves (e.g. carcinomatous lymphangitis, other neoplasms, lymphangioleiomyomatosis or Langerhans cell histiocytosis). Alternatively, TBLB specimens may show characteristic, but not specific, features that may be considered diagnostic only after discussion of the clinico-radiologic context (e.g. OP, sarcoidosis, HP). Finally, they may not be informative when morphologic findings are completely incongruous with the clinical-radiologic context.26, 27 The diagnostic role of conventional TBLB in IPF and other idiopathic fibrotic interstitial pneumonias is extremely important. Berbescu et al.28 reported that the hallmarks of UIP (honeycombing, patchy fibrosis and fibroblastic foci) may be identified in TBLB samples. Tomassetti et al.29 confirmed this observation but showed that the sensitivity of the procedure is very low and that other patterns such as NSIP and DIP provide a very low negative predictive value (i.e. when these patterns are identified in tiny TBB specimens, the probability remains high of a diagnosis of UIP in larger samples). The procedure has a low complication rate: pneumothorax occurs in up to 8% of cases,1, 29 major bleeding in less than 1% of cases and other complications (acute exacerbation of fibrotic lung disease, air embolism) even more rarely.30

More recently, cryoprobes have been used to obtain lung tissue4 and studies of their clinical role in f-ILDs are starting to show promising results. Samples obtained through c-TBB are usually 40–50 mm² in size and contain peripheral structures of the secondary pulmonary lobules.31 Recognition of UIP pattern on these large specimens has good inter-observer variability index and may be recognized by pathologists with high confidence (Fig. 3).5 Immunohistochemical analysis may be carried out easily in samples obtained by cryobiopsy. In the near future new markers such as laminin-5-gamma2-chain, fascin, heat shock protein 27, beta-cateninn and MUC5b (Fig. 4) will provide additional useful information on the morphological background of IPF.13, 14 Less high-quality evidence studies are available for other patterns such as NSIP and DIP, but the combination of morphological information provided by c-TBB and BAL profiles might be considered diagnostic and thereby avoid a SLB. Indeed the value of c-TBB, in combination with other clinical findings in the context of a multidisciplinary discussion, was found to be similar to that reported for SLB.32

It is clear that transbronchial cryobiopsy instead of regular TBB can be considered a potential alternative to SLB. However, studies on the standardization of the procedure are still absent.31 The bioptic sample size is many times greater than that obtained by regular TBB and is representative also of the periphery of the secondary pulmonary lobule. Improved results are seen in ‘intubated patients’ and when biopsies are taken within 1 cm of the pleura. In studies to date, the sample size appears to be larger when larger cryoprobes or a freezing time >4 s are used. The routine use of bronchial blockers (e.g. Fogarty balloon or another blocker) appears to prevent the potentially dangerous effects of any major bleeding.33 The rate of pneumothorax varies in different studies and seems to be higher when biopsies are obtained just beneath the pleura or in subjects with the UIP pattern (a higher pneumothorax rate of 28% was reported by Casoni and coworkers, but in this study the biopsies were obtained at a maximum of 1 cm distance from the pleura and samples showed a UIP pattern in 75% of cases).5 The strategies used to collect samples are not yet standardized,31 with the majority of studies to date having retrieved lung tissue from one segment and only a minority have collected lung samples from different segments of the same lobe.4 No prospective studies have yet been published comparing these two approaches in terms of diagnostic yield and rate of complications. Even less information is available on biopsies performed in different ipsilateral lobes, although this approach seems reasonable in cases in which the CT scan pattern differs greatly in different lobes (i.e. pleuroparenchymal fibroelastosis in the upper lobes and reticulation in the lower lobes).

Mediastinal biopsies/aspiration and transcutaneous approach

Endobronchial ultrasonographic fine needle aspiration (FNA) and endo-oesophageal ultrasound FNA have good test performance for diagnosis of sarcoidosis, even in clinically unselected cohorts of patients with intrathoracic lymphadenopathy.6, 34, 35 Other ILDs that may present with hilar/mediastinal adenopathies may have a morphological confirmatory diagnosis through these approaches (mycobacterioses, fungal infections, lymphoproliferative disorders).36, 37 Interestingly, EUS may allow the sampling of subdiaphragmatic organs and thus lymphomatoid granulomatosis or other kinds of lymphoproliferative disorders may be diagnosed with biopsies performed in liver, spleen or even adrenal glands.38 Blinded FNA using 19-G needles is still useful in the same clinico-radiologic context, although its diagnostic yield appears significantly lower.39 The diagnostic role of these procedures in f-ILD is however irrelevant or minimal. In the majority of cases, enlarged hilar and mediastinal adenopathies may be found in CT scan films of patients with f-ILD, but such moderate enlargement is almost always due to non-specific inflammation.40 Biopsy of these lymph nodes is therefore of little clinical value except in cases of suspected cancer (as occurs in patients with IPF).41

The transcutaneous approach guided by imaging techniques (CT or ultrasound) is used in pulmonary nodules with a very high diagnostic yield in neoplastic lesions even when these lesions measure less than 1 cm. This approach is rarely used in the diagnostic work-up of patients with ILDs, although case reports and a few case series have reported good results mainly in alveolar opacification or when core biopsies with large needles are performed.42, 43

SLB

According to current guidelines, SLB is still recommended for diagnostic confirmation in a proportion of patients with suspected f-ILD, in particular in the diagnosis of IPF when the HRCT scan pattern is not typical.3, 20 However, two important points need to be considered. Firstly, SLB represents only a small sample of the whole lung and the minimal quantity of lung necessary to guarantee the maximum morphological information compared with the whole lung or lungs remains unknown. Secondly, surgical biopsy may be associated with a significant mortality at 90 days, mainly related to acute exacerbation. Kondoh et al. reported that 5 of 236 consecutive patients who underwent SLB experienced an acute exacerbation of IPF following the procedure, with two patients dying within 30 days of the SLB.44 Utz et al. reported a VATS 30-day mortality of 18.8%, with all deaths occurring in patients with UIP/IPF.45 In a meta-analysis conducted by Nguyen and Myer, a total of 1188 patients undergoing VATS were evaluated and, collectively, 24 patients (2.1%) died within 30 days of the procedure.46 Another meta-analysis showed that the median diagnostic yield was 95% (range, 42–100%), with IPF as the most frequent diagnosis (33.5%).46 Notably, neither biopsy site, biopsy number or SLB method were associated with diagnostic accuracy. The pooled post-operative mortality rate for included studies was 3.6% (95% confidence interval, 2.1–5.5), with significant heterogeneity observed. Subgroup analysis revealed that exclusion criteria based on immunocompromised status, mechanical ventilation and severe respiratory dysfunction (diffusing capacity of lung for carbon monoxide <35% or forced vital capacity <55% predicted), but not SLB technique or underlying interstitial lung disease subtype, were possible sources of heterogeneity. Other complications related to SLB are prolonged air leak, persisting pain, fistula and empyema.47 Given these potential risks and complications, performing a SLB is not always possible due to age, pulmonary disease severity, comorbidities or patient disinclination to undergo the procedure. However, new less surgical invasive approaches are under investigation, with reduced or no assisted ventilation and with expected reduction of acute lung injury mainly related to the lack of requirement for invasive ventilation.48