Restrictive chronic lung allograft dysfunction: where are we now?
Stijn E Verleden, David Ruttens, Elly Vandermeulen, Hannelore Bellon, Dirk E Van
Raemdonck, Lieven J Dupont, Bart M Vanaudenaerde, Geert Verleden and Robin Vos
Department of clinical and experimental medicine, Lab of Pneumology, Lung transplant Unit,
Katholieke Universiteit Leuven and University Hospitals Leuven
Word count 2872
Number of figures: 0
Number of tables: 2
Running title: an update on restrictive CLAD
Keywords: chronic lung allograft dysfunction, lung transplantation, bronchiolitis obliterans syndrome,
restrictive allograft syndrome, restriction
Address for correspondence:
Dr Stijn Verleden
K U Leuven
Lung Transplantation Unit
49 Herestraat, B-3000 Leuven, Belgium
Tel: + 32 16 330194 Fax: + 32 16 330806
E-mail: stijn.verleden@med.kuleuven.be
1
Summary
Chronic lung allograft dysfunction (CLAD) remains a frequent and troublesome complication after
lung transplantation. Apart from bronchiolitis obliterans syndrome (BOS), a restrictive phenotype of
CLAD (rCLAD) has recently been recognized, which occurs in approximately 30% of CLAD patients.
The main characteristics of rCLAD include a restrictive pulmonary function pattern with a persistent
decline in lung function (FEV1, FVC, and TLC), persistent parenchymal infiltrates and (sub)pleural
thickening on chest CT scan, as well as pleuroparenchymal fibro-elastosis and obliterative
bronchiolitis on histopathological examination. Once diagnosed, median survival is only 6 - 18
months compared to 3-5 years in BOS. We will review the historical evidence for rCLAD and describe
the different diagnostic criteria and prognosis. Furthermore, we will elaborate on the typical
radiological and histopathological presentations of rCLAD and highlight risk factors and mechanisms.
Lastly, we will summarize some opportunities for further research including the urgent need for
adequate therapy. This mini-review will thus not only assess the current knowledge, but also clarify
the existing gaps in understanding this increasingly recognized complication after lung
transplantation.
Word count 173
2
Introduction
Chronic lung allograft dysfunction (CLAD) remains one of the major hurdles hampering long term
survival in lung transplant (LTx) recipients. Recently, different phenotypes of CLAD were recognized,
with important clinical and scientific implications. The term CLAD encompasses all forms of chronic
lung dysfunction with a FEV1 decrease ≥20% compared to the mean of the two best post-operative
values that persists over a period of at least 3 weeks after ruling out specific causes of allograft
dysfunction such as persistent acute rejection, infection, anastomotic stricture, disease recurrence,
pleural disease, diaphragm dysfunction, native lung hyperinflation and possible other specific causes
of allograft failure [1]. Recently, several groups have provided evidence for the existence of a
restrictive phenotype of CLAD, with a prognosis limited to 6-18 months. Herein, we will review
current and historic evidence and specifically focus on diagnosis, characteristics, mechanisms,
prevalence, and prognosis of rCLAD.
History
In 1984, Burke et al. were the first to describe the presence of obliterative bronchiolitis (OB) in
patients with a ventilatory defect after heart-lung transplantation. OB is a fibroproliferative
obliteration of the small airways and, for the next decades, it was considered to be the hallmark of
chronic rejection. However, these patients did not show a typical, purely obstructive, ventilatory
defect and suffered at least partially from restrictive physiology; a decrease in total lung capacity
(TLC) was seen in a number of these patients. Radiographic imaging at that time revealed interstitial
infiltrates with variable pleural thickening [2]. Subsequent pathological examination showed diffuse
interstitial fibrosis and, focally, a fibrotic and thickened pleura [3]. These findings were later
confirmed by both animal and biopsy studies. In one study, rhesus monkeys that underwent heartlung transplantation developed interstitial fibrosis and focal scarring of the allograft [4]. Another
study examining pulmonary function evolution in 9 patients transplanted for pulmonary
3
hypertension, demonstrated restrictive alterations in the early post-transplant phase for which the
reason was unknown [5]. Lastly, two histological studies demonstrated fibrotic alterations; one
showing marked interstitial and pleural fibrosis on open lung biopsy and autopsy [3], the other
demonstrated diffuse alveolar damage (DAD) in 2 of 3 long term survivors without OB and 1 of 6
survivors with OB [6]. However, in an expert panel report on chronic rejection, a restrictive
pulmonary function was considered more likely to be due to confounding factors rather than a
manifestation of chronic allograft failure [7]. Consequently, only forced expiratory volume in 1
second (FEV1) was used to evaluate Bronchiolitis Obliterans Syndrome (BOS), which was defined as
the clinical correlate of pathological OB with a persistent decrease in FEV1 of at least 20% compared
to the mean of the best 2 post-operative values in the absence of other confounding factors [7]. In
subsequent studies, several investigators described interstitial fibrosis on transbronchial biopsies,
occurring in almost 37% of patients 2 years after LTx, and questioned its relevance [8]. One study, in
particular, demonstrated the presence of severe interstitial changes in 16% of patients suffering from
end-stage CLAD who underwent redo-LTx [9]. Moreover, upper lobe fibrosis and associated
restrictive pulmonary function defects was noted in 13 of 686 patients by the Duke and Toronto
groups [10]. Still, these findings were regarded as atypical and no attempts were made to further
characterize the fate of these patients. It is only recently that several studies have attempted to use
different diagnostic criteria in order to investigate a chronic and primarily progressive restrictive
pulmonary function defect after LTx.
Diagnosing rCLAD
There is currently no internationally approved definition of rCLAD; however, several groups
attempted to discriminate a form of rCLAD by using different diagnostic criteria. Woodrow et al.
made a distinction within CLAD patients (both single and double LTx) based on the presence of
pleuro-parenchymal infiltrates on chest CT scan and the pattern of FVC decline. First, they made a
4
division between ‘non-specific’ CLAD (pleuroparenchymal infiltrates present) and ‘specific’ CLAD
(pleuroparenchymal infiltrates absent) patients [11], followed by an additional subdivision within the
‘specific’ CLAD patients between restrictive (FVC decline ≥20%) and obstructive (FVC decline <20%).
Sato et al. defined a group of LTx patients with restrictive pulmonary function decline (a decrease in
TLC ≥10% compared to the best post-transplant baseline together with a decrease in FEV1 ≥20%
[12]), as having restrictive allograft syndrome or RAS. This definition, however, was only applied to
double lung recipients with regular TLC measurements available and remains questionable as to
whether this definition can be applied to single lung transplant recipients. This is due to the decline
in native lung function influencing and confounding the results of the pulmonary function tests. This
observation was confirmed in a second independent cohort, which used the FEV1/FVC ratio as an
additional measure, for those patients for which TLC measurements were not available. A FEV1/FVC
index that remained normal or increased above normal with a FVC decline of at least 20% from
baseline (in conjunction with an FEV1 decline of at least 20%) was considered restrictive, whereas a
FEV1/FVC index of less than 0.7 was considered obstructive [13]. A subsequent study implementing
spirometry alone to diagnose a form of rCLAD, was performed by Todd et al. [14]. In their study, the
pattern of FVC decline at CLAD diagnosis was used to make a distinction between patients with
restrictive (FVC/FVCbest <0.80) and obstructive (FVC/FVCbest ≥0.80) CLAD. The main advantage of using
this method for diagnosis is its universal applicability. However, patients with a decline in FEV1 may
also have a concordant decrease in FVC as a results of air trapping and whether this reflects
restriction may only become clear during further follow up of the patients. One noticeable
discrepancy between this study and the others is that only spirometry at CLAD diagnosis was used to
assess outcome after diagnosis. Also of note is that some patients can evolve from a strictly
obstructive to a restrictive pulmonary function defect throughout the disease [12; 15].
Biopsy findings could also help in diagnosing patients with rCLAD [16]. A recent study implemented
histopathological examination of transbronchial biopsies in combination with spirometry (FEV1
decrease ≥20% and FEV1/FVC >0.70) and imaging (CT not showing signs of OB, being airtrapping,
5
mosaic attenuation and bronchiectasis). Indeed, acute fibrinoid organizing pneumonia (AFOP) was
diagnosed on transbronchial biopsies, which was characterized by patent bronchioles with
peribronchial and alveolar fibrin deposition, with little or no concomitant inflammation. These AFOP
patients presented with a non-obstructive pulmonary function defect and bilateral infiltrates. Further
investigation will be needed to link the histopathological concept of AFOP with rCLAD. Since there
are clear clinical similarities (non-obstructive pulmonary function and interstitial abnormalities on CT)
between AFOP and rCLAD patient, there likely is a large degree of overlap between both entities. In
this respect, one has to remark that some of these patients deteriorate so quickly that pulmonary
function testing is not possible and hence adequate phenotyping cannot be performed in which case
biopsy can suggest rCLAD. However, a decrease in FEV1 usually precedes the biopsy procedure by
several weeks/months, therefore it is possible that the patients are diagnosed only at a later stage of
the disease. Table 1 provides a summary of the different studies that have defined a restrictive form
of CLAD along with their respective diagnostic criteria. One has to be aware of the advantages and
disadvantages that each of these diagnostic tools entail such as a higher cost for routine TLC
measurements, perhaps lower specificity for spirometry, exposure to radiation for CT and inherent
risk for taking biopsies and outweigh these with advantages such as direct evidence (biopsy), low
cost (spirometry), easy criterion (TLC) and separate assessment of native and transplant lungs
(imaging). A summary of the advantages and disadvantages of the different tools is shown in table 2.
A multimodal approach, using both radiological, histopathological, and functional (i.e. lung function)
evaluation of the allograft is however probably necessary to diagnose and further phenotype CLAD.
Prevalence and prognosis of rCLAD
The study by Woodrow et al. was an important study investigating non-specific CLAD patients using a
combination of imaging and spirometry [11]. Patients with persistent pleuro-parenchymal infiltrates
on CT were denominated ‘non-specific’ CLAD (35%), while ‘specific’ CLAD patients (no pleuro6
parenchymal infiltrates) were divided into restrictive BOS (28%) and obstructive BOS (37%). However,
there was no survival difference between ‘non-specific’ and ‘specific’ CLAD patients and no
difference between the restrictive and obstructive patients in the ‘specific’ CLAD group [11]. The
study by Sato et al., using TLC decline as diagnostic criteria for rCLAD, demonstrated that 30% of all
CLAD patients were suffering from a restrictive lung function decline but more importantly, survival
after diagnosis was significantly worse in rCLAD compared to BOS patients (1.5 vs. 4 years after
diagnosis) [12]. The study by Verleden et al., using a combination of FEV1/FVC and TLC, demonstrated
a similar prevalence of rCLAD (28%) with a median survival of 0.7 years vs. 3 years in BOS [13]. Todd
et al. found that 30% of the investigated CLAD patients experienced a FVC decline >20% at diagnosis
(i.e. rCLAD), which resulted in a survival of 0.8 years compared to 3 years in BOS patients [14]. Lastly,
the study by Paraskeva et al. implementing AFOP on biopsy to phenotype patients, similarly showed
a prevalence of 25% with a prognosis of only 0.3 years after diagnosis (vs. 0.8 years) [16]. Together,
these studies clearly demonstrate a worse prognosis in patients diagnosed with rCLAD compared to
patients suffering from obstructive CLAD. However, additional studies are necessary to confirm these
findings. Large monocentric studies and ideally multicentric, prospective studies are needed to
confirm the worse prognosis of rCLAD compared to BOS. One possible reason for the worse
prognosis in these patients may be that acute exacerbations, defined as respiratory distress needing
oxygen supplementation, hospital admission, or mechanical ventilation, are a typical characteristic of
the disease. Indeed, all rCLAD patients underwent at least 1 to a maximum of 4 exacerbations, and,
in almost all cases, this led to death or necessitated urgent redo transplantation [17].
Radiology of rCLAD
All reports on rCLAD demonstrated radiological alterations of interstitial lung disease [12-14]. Typical
characteristics include (traction-)bronchiectasis, central and peripheral consolidation, pleural
thickening and volume loss; while most patients showed an upper-lobe dominant fibrotic pattern
7
[12;14]. One surprising finding was that half of the rCLAD patients already demonstrated
parenchymal alterations on chest CT scan before CLAD onset. This demonstrates that patients with
persistent infiltrates deserve a closer clinical follow-up before the FEV1 and/or FVC declines. In
contrast to FVC at diagnosis, none of the observed chest CT scan alterations correlated with survival
after diagnosis. This might indicate that CT is an useful aid in diagnosing rCLAD, but less useful in
predicting patient prognosis [18]. Additionally, 18F-fluorodeoxyglucose positron emission tomography
could be helpful in diagnosing rCLAD as hypermetabolic activity can be observed in the (sub)pleural
region [19]. However, further evidence for its diagnostic and eventual prognostic utility is lacking.
Pathology of rCLAD
Histopathological analysis of explanted lungs and open lung biopsies of patients with rCLAD revealed
pleuro-parenchymal fibro-elastosis, which is characterized by hypocellular collagen deposition with
thickening of the septa [20]. This collagen accumulation was mainly situated in the subpleural space,
but centrilobular and paraseptal collagen distribution was also observed. A sharp demarcation
between ‘healthy’ and diseased zones was present. Remarkably, almost all studied specimens also
showed OB lesions, indicating that part of the airflow limitation is probably due to those lesions that
are typically associated with BOS. Another noticeable finding in almost all specimens was diffuse
alveolar damage (DAD), which tended to merge with areas of pleuro-parenchymal fibro-elastosis
suggesting a continuous process [20]. DAD is a rather nonspecific finding, but is considered to be the
most severe form of acute lung injury. Two recent studies confirmed the role of late onset (>3
months post LTx) DAD in the development of CLAD and more specifically rCLAD [21;22]. As
mentioned previously, the exact role of AFOP in the pathology of rCLAD remains to be investigated.
8
Risk factors and mechanism
The risk factors and mechanisms of rCLAD remain mostly elusive as no comprehensive studies have
been performed to date. Females were more predisposed to develop rCLAD in the study by Todd et
al. [14], but none of the other studies could confirm this. Similarly, patients developing rCLAD were
also younger in the study by Verleden et al. and tended to be younger in the study by Sato et al.
[12;13], but this was not confirmed in the other studies [14;16]. Equally, CMV mismatch seemed to
predispose to rCLAD in one study but not in the others [12]. This all alludes to coincidental findings,
not reflecting the general population but a consequence of the single center approach with most of
the studies performed by the same centers with a similar patient cohort, which implies that drawing
conclusions is difficult. Therefore, larger studies using uniform diagnostic criteria are necessary to
shed more light on the exact pathophysiological risk factors.
There might be a role for inflammation in rCLAD as patients experience more episodes of severe
lymphocytic inflammation (grade B2R) prior to rCLAD diagnosis compared to BOS patients [23].
Similar to the development of BOS, acute rejection, Pseudomonal colonization, and pulmonary
infection were identified as risk factors for later development of rCLAD [23]. There could also be a
role for eosinophils in the disease process of rCLAD [23;24]. Indeed, 82% of the rCLAD patients
experienced an episode of increased BAL eosinophils (≥2%) during follow-up, which was associated
with a rapid evolution towards rCLAD and ultimately death [24]. At the moment of diagnosis of
rCLAD, BAL concentrations of IL-6 and IP-10 were upregulated compared to BOS and control, while
VEGF was downregulated. Interestingly, these mediators correlated with survival after diagnosis [25].
Intriguingly, donor biopsy levels of several inflammatory cytokines (IL-1β, IL-6, IL-8, IL-10, interferon-γ
and TNF-α) did not predispose to later development of rCLAD, while donor IL-6 levels predisposed to
BOS, suggesting that pre-transplant insults might not play an important role [26]. Two studies
demonstrated that late-onset DAD is a risk factor for rCLAD (in contrast to early-onset DAD which
predisposes to BOS) and further established that the CXCR3 axis, as a potent chemoattractant for
9
mononuclear cells, is involved. Indeed, increased concentrations of CXCL9, CXCL10 and CXCL11
(CXCR3 ligands) were found in BAL when DAD was diagnosed on biopsy and prolonged increased
levels of these chemokines predicted subsequent CLAD development [22]. Recently, a role for
alveolar alarmins, important pro-inflammatory molecules, in rCLAD has also been demonstrated as
levels of S100 proteins were significantly upregulated in BAL fluid of rCLAD patients compared to BOS
and control [27].
Treatment
Pirfenidone is an anti-fibrotic drug and is in some countries approved as the first treatment option
for IPF [28]. Recently, a case report demonstrated the potential of pirfenidone to slow down the
evolution of rCLAD [19]. Another drug that could be beneficial is alemtuzumab (campath-1H), which
is an antagonist of CD52, a protein expressed on B cells, lymphocytes, dendritic cells, and monocytes.
This drug was found to improve interstitial changes and lung function in 4 patients who were likely
suffering from rCLAD [29] Extracorporeal photophoresis (ECP) is probably not a good treatment
option as ECP in rCLAD patients did not lead to a stabilization or increase in pulmonary function [30].
At present, these treatment options remain anecdotal, and other treatment options are necessary as
preliminary evidence shows that re-transplantation might not be an adequate therapeutic solution
for patients with rCLAD, with a 3-year survival after re-transplantation limited to 34% compared to
68% in patients with BOS [31].
Phenotyping CLAD: the end is near or just started?
There is a clear need for studies confirming the prognosis of rCLAD as well as internationally
approved diagnostic criteria for rCLAD. This would spur the initiation of multi-center trials to
investigate risk factors and mechanisms in more depth. Additionally, there is a need for studies
10
comparing spirometric evolution (FEV1, FVC, FEV1/FVC and TLC) with radiology and pathology to
establish the degree of overlap between the different diagnostic criteria for rCLAD. Indeed, we are
only in the phase of clinically defining this disease and most of the pathophysiological mechanisms
remain elusive.
One has to be aware of the idiosyncratic post-transplant trajectory for each LTx patient, bearing in
mind that not all patients may fit perfectly within a single phenotype. Moreover, there are many
factors that may confound accurate classification of these patients. Retrospective judgment is
extremely difficult as full pulmonary functions testing (including TLC measurements) and chest CT
scans are not always routinely performed. Patients who received a single LTx may be difficult to
assess due to the confounding effects of the native lung on pulmonary function tests and imaging
could be more appropriate in those cases as the native and transplanted lung can be investigated
separately. Some patients can also evolve from one phenotype to another without clear cause or
explanation, so one should always be careful when classifying a patient at a given moment in time
[1].
Future research should focus on a better definition of the disease, confirmation of the natural history
and a further understanding of the pathophysiological mechanisms of rCLAD. Only by doing so, we
can have a basis for therapeutic trials. This is the only hope to win the battle against CLAD after lung
transplantation and to achieve a long-term survival that matches that of other solid-organ
transplants [32].
11
Acknowledgements
SEV is a post-doctoral fellow of the FWO (12G8715N). RV is supported by the Research Foundation
Flanders (FWO) (KAN2014 1.5.139.14) and Klinisch Onderzoeksfonds (KOF) KULeuven. BMV is senior
research fellows of the FWO. GMV is supported by the FWO (G.0723.10, G.0679.12 and G.0679.12)
and Onderzoeksfonds KULeuven (OT/10/050).
None of the funding sources had an influence on the content of this manuscript
12
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15
LTx center
Diagnostic criteria used*
patients, n
CLAD, n
rCLAD, n (%)
Mean Age
Male (%)
Type LTx
timing post LTx
Median survival post diagnosis
Risk factors associated with rCLAD
Virginia [11]
CT (persistent infiltrates)
241
96
34 (35%)
53
50
S+SS
2Y
2.8Y(0.9-4.6)
None reported
FVC decline ≥20%
241
96
27(28%)
53
56
S+SS
3.1Y
4.0Y
Native disease of sarcoidosis
Toronto [12]
TLC decline ≥10% compared to baseline
468
156
47 (30%)
42
49
Leuven [13]
TLC decline >10% or FEV1/FVC>0.70
294
71
20 (28%)
38
54
SS
NA
1.5Y
Donor+/recipient- CMV mismatch
S+SS
2.7Y
0.7Y
Severe LB,
Duke [14]
FVC/FVC best <0.80 from best value
566
216
65 (30%)
55
45
SS
2.8Y
0.8Y(0.6-1.3)
Female gender
Melbourne [16]
FEV1/FVC index>0.7, CT (atypical) and AFOP
194
87
22 (25%)
40
59
S+SS
1.6Y
0.3Y(0.1-0.78)
Native interstitial lung disease
BAL eosinophils, younger
Table 1: Summary of different criteria used to diagnose rCLAD. All studies reported here, evaluated their total patient cohort using their specific
diagnostic criteria. Values are shown as mean, median (IQR) or median(CI)(survival for Virginia patients) according to values found in the manuscripts.
An atypical CT in [16], is a CT not showing signs of mosaic attenuation and airtrapping. S: single lung transplantation, SS: sequential single lung
transplantation.* all criteria also require a drop in FEV1≥20% compared to the mean of the 2 best post-operative values. The different diagnostic tools
with their respective advantages and disadvantages are outlined in more detail in table 2.
16
Tool
Criterion
Advantage
Disadvantage
Plethysmography
TLC decline ≥10% (12)
Easy to use criterion
Higher cost for repeat measurement
Patient claustrophobia and additional oxygen requirement may
prohibit TLC measurement
In retrospect a lot of centers have no TLC data available. Prospective
follow up of TLC necessary
Spirometry
FEV1/FVC≥0.70 (13)
Serial measurements available
Specificity unclear
FVC/FVCbest>0.80 (14)
Low cost
e.g. FVC drop may allude to gas trapping
Implicated in regular patient follow-up
Imaging
Persistent infiltrates and pleural thickening (11,18)
Phenotyping possible in single lung Tx
Radiation exposure
Possible in sicker patients
Specificity unclear
Easy to perform
Histopathology
AFOP (16) and late onset (>3months) DAD on TBB (21,22)
Very direct evidence
e.g. differential diagnosis with infections
Representative biopsy is necessary
Risk of complications
Interpretation by experienced pathologist
Specificy of AFOP for rCLAD not clear
Table 2: Overview of the different tools that can be used to diagnose rCLAD such as TLC measurement, spirometry, imaging and histopathology with
their advantages and disadvantages. All tools require an additional decline in FEV1≥20%. Abbreviations: AFOP: acute fibrinoid organizing pneumonia;
DAD: diffuse alveolar damage; TBB: transbronchial biopsy; Tx: transplantation
17