Better survival in combined pulmonary fibrosis and emphysema than in lone pulmonary fibrosis: bias or reality? A response to Centrilobular emphysema combined with pulmonary fibrosis results in improved survival by Todd et al., Fibrogenesis & Tissue Repair 2011, 4:6

Athol U Wells

Jean-François Cordier

KM Antoniou

L Kiakouama

M Akira

M Mejia

NW Todd

V Cottin

Vincent Cottin

Fibrogenesis & Tissue Repair

English

PubMed

Crossref

Centrilobular emphysema combined with pulmonary fibrosis results in improved survival: a response

International audienceBetter survival in combined pulmonary fibrosis and emphysema than in lone pulmonary fibrosis: bias or reality? A response to Centrilobular emphysema combined with pulmonary fibrosis results in improved survival by Todd et al., Fibrogenesis & Tissue Repair 2011, 4:6. Please see related letter http://fibrogenesis.com/content/4/1/17

Cottin, Vincent

Cordier, Jean-François

Wells, Athol U.

HAL-HCL

Springer - Publisher Connector

LETTER TO THE EDITORS Open Access
Centrilobular emphysema combined with
pulmonary fibrosis results in improved survival: a
response
Vincent Cottin1,2*, Jean-François Cordier1,2 and Athol U Wells3
Abstract
Better survival in combined pulmonary fibrosis and emphysema than in lone pulmonary fibrosis: bias or reality? A
response to Centrilobular emphysema combined with pulmonary fibrosis results in improved survival by Todd et
al., Fibrogenesis & Tissue Repair 2011, 4:6.
Please see related letter http://fibrogenesis.com/content/4/1/17
We read with great interest the somewhat thought-pro-
voking article by Todd et al. [1], which addressed the
prognosis of patients with combined pulmonary fibrosis
and emphysema (CPFE). The authors found that survival
in CPFE was better than that of patients with idiopathic
pulmonary fibrosis (IPF) without emphysema or with
minimally extensive emphysema (’lone fibrosis’), in strik-
ing contrast to previous results [2-4]. From these coun-
terintuitive results, it is argued that tobacco-smoking-
induced pulmonary inflammation may be protective
against the progression of fibrosis. However, in reaching
this conclusion, we feel the authors have failed to suffi-
ciently consider a number of potential biases that are
evident from the stated data.
Firstly, amongst biopsied patients, fibrotic non-specific
interstitial pneumonia (NSIP) was more prevalent in
association with CPFE (6 of 20, 30%) than in the
remaining groups (7 of 53, 13%). If these proportions
are extrapolated to the whole cohort, including non-
biopsied cases, the prevalence of fibrotic NSIP was sig-
nificantly higher in the CPFE cases. Furthermore, this
imbalance may have been amplified by the inclusion of
non-biopsied cases: it is well recognized that NSIP when
combined with emphysema may mimic honeycombing
and can, therefore, be confused with genuine IPF [5]. A
bias towards NSIP would also explain the unexpectedly
higher female rate in the CPFE group.
Secondly, the way in which transplantation was
handled in the survival analysis is very open to question.
It has been usual to censor at date of transplantation,
and not to handle a transplant event as a death. The
authors point out that the rate in transplantation did
not differ between groups. However, as at least a third
of ‘deaths’ (n = 34) were transplant episodes, it is likely
that this way of handling transplant events as deaths dis-
torted the Kaplan-Meier curves.
Thirdly, potential lead-time bias was a significant con-
cern in this study. For example, patients with CPFE
were more frequently ever-smokers than their counter-
parts with lone fibrosis, and conceivably were more
likely to suffer from chronic bronchitis and thus to seek
medical advice or to draw medical attention. A better
outcome in patients with CPFE compared with patients
with lone fibrosis may therefore reflect earlier identifica-
tion of disease.
Lastly and most importantly, patients with CPFE (pul-
monary fibrosis with significant emphysema) and those
with lone fibrosis had comparable carbon monoxide dif-
fusion capacity (DLco) in the study by Todd et al. [1].
As DLco reflects the combined impact of emphysema
and fibrosis [6], it follows that patients with more exten-
sive emphysema must have had less extensive fibrosis, to
end up with the same average level of DLco. In other
words, based on DLco levels, patients with CPFE must
have had significantly less extensive fibrosis than the
lone fibrosis group.
In essence, Todd et al. report better survival, using a
highly controversial outcome analysis, in a patient sub-
* Correspondence: vincent.cottin@chu-lyon.fr
1Hospices Civils de Lyon, Hôpital Louis Pradel, Service de Pneumologie -
Centre de Référence National des Maladies Pulmonaires Rares, Lyon, France
Full list of author information is available at the end of the article
Cottin et al. Fibrogenesis & Tissue Repair 2011, 4:16
http://www.fibrogenesis.com/content/4/1/16
© 2011 Cottin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
group (CPFE) with a higher prevalence of fibrotic NSIP
and much less extensive fibrosis. These confounding
factors would seem to adequately account for the
observed group differences. Thus, whilst Todd et al.
should be commended for addressing the question of
the relative prognosis of CPFE versus IPF, the biases dis-
cussed here make it difficult to reach clear conclusions.
Such studies stimulate research by suggesting unreliable
yet intriguing conclusions. Adequately conducted studies
with adjustment for severity, and extent of fibrosis, and
control of confounding factors are now needed to
address the unresolved issue of whether CPFE and lone
IPF may differ in outcome.
Author details
1Hospices Civils de Lyon, Hôpital Louis Pradel, Service de Pneumologie -
Centre de Référence National des Maladies Pulmonaires Rares, Lyon, France.
2Université de Lyon, Université Lyon I, INRA, UMR754 INRA-Vetagrosup EPHE
IFR 128, Lyon, France. 3Royal Brompton Hospital, London, UK.
Authors’ contributions
VC conceived the study and drafted the manuscript; AW designed the study
and contributed to draft the manuscript; JFC designed the study and
contributed to draft the manuscript; all authors read and approved the final
manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 27 April 2011 Accepted: 25 July 2011 Published: 25 July 2011
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doi:10.1186/1755-1536-4-16
Cite this article as: Cottin et al.: Centrilobular emphysema combined
with pulmonary fibrosis results in improved survival: a response.
Fibrogenesis & Tissue Repair 2011 4:16.
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Hal-Diderot

Atamas SP: Centrilobular emphysema combined with pulmonary fibrosis results in improved survival. Fibrogenesis Tissue Repair

Groupe d’Etude et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM&quot;O&quot;P): Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J

Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension. Chest

Idiopathic pulmonary fibrosis: outcome in relation to smoking status. Am J Respir Crit Care Med

JF: Conditions associated with severe carbon monoxide diffusion coefficient reduction. Respir Med

Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color ﬁgure charges • Immediate publication on acceptance

Tissue Repair

Toyokawa K: Usual interstitial pneumonia and nonspecific interstitial pneumonia with and without concurrent emphysema: thin-section CT findings. Radiology

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3160364

Centrilobular emphysema combined with pulmonary fibrosis results in improved survival: a response

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