Bronchoscopy Post Lung Transplantation
The post-operative care of lung transplant patients is complex with the main goal of management being the preservation of allograft function. Being able to perform bronchoscopy with bronchoalveolar lavage as well as trans-bronchial biopsy (TBBX) as part of the routine investigation of a drop in lung function greater than 20% is a vital skill for clinicians caring for lung transplant recipients. Bronchoscopy provides clinicians with a rich source of microbiological, cytological, and histological sampling thereby enhancing the ability to make an accurate diagnosis, particularly the differentiation of rejection from infection or the presence of both. The following chapter aims to provide an insight into the use of bronchoscopy post lung transplantation.
KeywordsBronchoscopy Lung transplantation Trans-bronchial biopsy Rejection Infection
10.1 Surveillance Bronchoscopy versus Clinically Mandated
When discussing bronchoscopy post transplantation we refer to either surveillance or clinically mandated bronchoscopies . Surveillance bronchoscopy is performed as part of a routine predefined protocol regardless of whether the patient is symptomatic, whether there is allograft dysfunction, or radiological change. Clinically mandated bronchoscopy is performed when a patient presents with new symptoms of cough, dyspnoea and reduction in lung function by greater than 10% from baseline forced expiratory volume in 1 s (FEV1), or if there is any radiological change. Bronchoscopies performed as part of surveillance or clinically mandated procedures may involve bronchoalveolar lavage to diagnose infection as well as detect any airway complications, or may involve more invasive procedures such as trans-bronchial biopsies (TBBX) to diagnose rejection.
The role of surveillance bronchoscopy after lung transplantation, and the value of surveillance bronchoscopy versus clinically mandated bronchoscopy remains controversial, with some clinicians questioning the risk versus benefit ratio of performing the procedure and arguing that it exposes patients to unnecessary procedural risk, which would include bleeding, pneumothorax, cardiac arrhythmias, sedation related complications and even post procedural pneumonia [3, 4, 5, 6, 7, 8, 9, 10, 11]. Therefore individual centres vary widely in their practices particularly since there is no consensus on the frequency in which we should be performing surveillance TBBX or whether we should be performing them at all .
In support of surveillance bronchoscopy is the association between episodes of acute rejection and the development of CLAD [13, 14, 15, 16, 17]. One aim of routine surveillance bronchoscopy is early detection of clinically ‘silent’ episodes of acute cellular rejection that would otherwise have been missed by routine clinical monitoring using non-invasive methods such as spirometry and radiology that if left untreated could result in an increased risk of developing CLAD [18, 19, 20].
Clinicians who do not support surveillance bronchoscopy consider spirometry to be a non-invasive, cheap and easily reproducible method by which to monitor graft function in patients post LTX. A drop in FEV1 of greater than 10% from baseline, has traditionally been used by physicians to trigger investigations, including TBBX, in an attempt to find and treat any reversible causes [21, 22].
At our unit we perform the first bronchoscopy within the first 24 h post lung transplantation just prior to the patient being extubated in order to assess the anastomosis, clear secretions or clot that may have accumulated during the procedure, and provide early microbiological and virological samples to guide early therapy. We then follow up with a surveillance bronchoscopy at 1 week post-transplant to once again evaluate the anastomosis, airways, and ensure that our targeted microbiological therapies have been successful prior to cessation of antimicrobial treatment. Subsequent surveillance bronchoscopies with bronchoalveolar lavage and TBBX are performed at 3 weeks, 6 weeks, 9 weeks and 12 weeks. The 9-week surveillance bronchoscopy may be omitted if all other bronchoscopies have been normal and there has not been any rejection. Beyond the 3 months surveillance bronchoscopy +/− TBBX only clinically mandated bronchoscopies are performed. As already mentioned, large variations in monitoring practice exist amongst centres with some centres following a similar protocol to ours, others performing annual surveillance bronchoscopy and TBBX, whilst others only do clinically mandated procedures.
10.2 Diagnosis of Infections
The risk of infection is much higher after lung transplantation than in any other solid organ transplant, and early detection of occult infection may lead to better outcomes [23, 24, 25]. Anastomotic infections can be secondary to necrosis, colonization, or aspiration. Due to their state of immune suppression patients are susceptible to both common airway pathogens as well as numerous rarer bacterial, viral, and fungal infections that often arise from the normal flora of the donor or recipient airway , with bacterial infections most likely in the first few weeks after lung transplantation . With increasing population movement we may see the increased incidence of donor-derived infections such as tuberculosis which may be detected during surveillance bronchoscopies prior to clinical sequelae . Although most patients undergoing bronchoscopy for diagnosis of infection will be doing so in order to obtain microbiological samples and would be clinically symptomatic at the time of bronchoscopy, up to one third of patients may be asymptomatic and harbouring infection . This is most common in the 3–12 month period post lung transplantation .
10.3 Diagnosis of Acute Cellular Rejection
An international grading system for pulmonary allograft rejection was first adopted by the ISHLT in 1990 , modified in 1996  and then again in 2007 , and is based on the presence of perivascular and interstitial mononuclear infiltrates, Grade A0 (no rejection), Grade A1 (minimal rejection), Grade A2 (mild rejection), Grade A3 (moderate rejection) and Grade A4 (severe rejection). Lymphocytic bronchiolitis is classified according to the presence and severity of mononuclear inflammation in the airways and graded as Grade B0 (none), Grade B1R (low grade, which in the 1996 guidelines were described as grade B1 and B2), Grade B2R (high grade, which in the 1996 guidelines were described as grade B3 and B4) and BX (ungradeable). Obliterative bronchiolitis (Grade C), is described as present (C1) or absent (C0), without reference to presence of inflammatory activity. Chronic vascular rejection is unchanged as Grade D diagnosis of acute rejection .
It is important to consider the fact that acute cellular rejection is a heterogeneous process with some parts of the lung being affected and others being entirely normal which means that one can miss an episode of rejection simply because there has been inadequate sampling of lung parenchyma . As a result of this potential for sampling error The Lung Rejection Study Group (LRGS) has provided guidelines which recommend a minimum of 5 pieces of evaluable (2–3 mm; containing a minimum of 100 alveoli per high power field), well-expanded alveolar parenchyma from two separate lobes to provide adequate sensitivity for diagnosing ACR [31, 32].
The interpretation of the samples by individual pathologists has also been shown to be variable with studies showing only moderate agreement between two pathologists reading the same samples in determining the same grade of rejection (i.e. A0, A1, A2, A3, A4) although there is consistency with intra-reader agreement .
10.4 Diagnosis of Antibody Mediated Rejection
Antibody mediated rejection (AMR) is increasingly being recognised as a cause of acute lung allograft dysfunction as well as CLAD [32, 34, 35, 36, 37], with a recent consensus document on pulmonary AMR being published by the ISHLT . Histopathological samples obtained via bronchoscopy and TBBX provides essential information which enables the clinician to upgrade their diagnostic accuracy according to the current diagnostic classification.
10.5 Diagnosis and Management of Airway Complications
Direct visualisation of the airways via bronchoscopy allows us to not only assess for airway complications but also provides a therapeutic option e.g. balloon dilatation of anastomotic strictures . With approximately 1/3 of airway complications post lung transplantation being asymptomatic  one must always consider that failure to achieve normal lung function post transplantation may be due to an undiagnosed stricture. Hence direct visualisation of the airways via bronchoscopy is critical to obtain optimal results for the patient. The direct mortality related to airway complications in the first year is approximately 2.3% , and overall 1 and 5 year survival rate of 88% and 73% as compared with 91% and 79% in the control group respectively .
In the early postoperative days we can assess anastomotic integrity and grade anastomotic ischaemia which arises due to the disruption of the usual blood supply to the bronchus which loses the antegrade bronchial artery component post-operatively and therefore relies on retrograde flow from the pulmonary arteries to the bronchial arteries via the capillary network and collaterals. Sputum plugs and blood clots which may obstruct the anastomosis or other parts of the bronchial tree can also therapeutically be removed.
Anastomotic stricture is the most commonly reported long term airway complication post-transplant . Therapeutic options for airway strictures include balloon dilatation and the insertion of stents. When performing balloon dilatation the patient often requires to return for multiple dilatations to obtain a long lasting result but the management of the strictures not only improves airflow, it enhances airway secretion clearance and reduces the risk of post stricture infections in patients who are already at an increased risk due to their immune suppressed status . Potential complications are mucosal bleeding, airway tear, partial or complete rupture of the airway, and prolonged hypoxia. Other methods described include cryotherapy, electrocautery, laser, brachytherapy, bougie dilatation with rigid bronchoscopy, and stent placement.
When considering the insertion of stents to manage anastomotic strictures care must be exercised in choosing patients appropriate for stent insertion as there is significant morbidity associated with stents particularly stent migration and recurrent infections as a result of reduced sputum clearance. Ongoing inflammation at the site of stent insertion may also lead to the formation of granulation tissue resulting in within-stent stenosis .
The importance of bronchoscopy in the post-operative care of the lung transplant patient cannot be underestimated. As discussed in this chapter it provides clinicians with vital information required to make an accurate diagnosis in what are complex patients in whom the cause of allograft dysfunction may be multifactorial. Although often considered a diagnostic tool, advancements in interventional bronchoscopy have resulted in an increasing use of bronchoscopy as a therapeutic tool in complications such as those within the airway.