Position Paper
Antacid therapy in idiopathic pulmonary fibrosis:
more questions than answers?
Kerri A Johannson*, Irina Strâmbu*, Claudia Ravaglia, Jan C Grutters, Claudia Valenzuela, Nesrin Mogulkoc, Fabrizio Luppi, Luca Richeldi,
Athol U Wells, Carlo Vancheri*, Michael Kreuter* for the Erice ILD Working Group†
Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal Lancet Respir Med 2017;
reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but 5: 591–98
robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy *Contributed equally
(proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal †Members listed in the appendix
reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and Department of Medicine,
IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through University of Calgary, Calgary,
AB, Canada (K A Johannson MD);
which the guideline recommendation was achieved and aim to contextualise the recommendation for providers Pulmonology Department,
caring for patients with IPF. University of Medicine and
Pharmacy Carol Davila,
Introduction Ettore Majorana Foundation and Centre for Scientific Bucharest, Romania
(I Strâmbu MD); Pulmonology
Idiopathic pulmonary fibrosis (IPF) is a progressive Culture in Erice, Italy, to discuss priority clinical and Unit, Department of Thoracic
parenchymal lung disease of unclear origin, associated research issues in ILD. Participants represented Diseases, G B Morgagni L
with a median survival of 3–5 years from the time of 17 countries from Europe and North America. Among Pierantoni Hospital, Forli, Italy
diagnosis.1 At present, two IPF-specific pharmacological the topics of discussion was the current conditional (C Ravaglia MD); Interstitial
Lung Diseases Center of
therapies are available that slow disease progression, but to guideline recommendation for antacid therapy in IPF. Excellence, Department of
date there is no known cure.2,3 Patients with IPF have In pro–con debates and round-table discussions, the Pulmonology, St Antonius
frequent comorbid conditions, including a high reported evidence supporting this recommendation was presented Hospital, Nieuwegein,
for consideration. Given the current controversies, this Netherlands
prevalence of gastro-oesophageal reflux (GER) and gastro-
(Prof J C Grutters MD); Division
oesophageal reflux disease (GERD).4–6 The potential role of Position Paper was prepared by the primary participants of Heart and Lungs, University
GER in the pathogenesis or progression of disease has (authors) who discussed this issue while incorporating Medical Center Utrecht,
been an important focus of research, in an effort to find input from all other participants of the Erice ILD Working Netherlands (Prof J C Grutters);
Pulmonology Department,
effective therapeutic approaches to patient management. Group (appendix).
Hospital Universitario de la
GER and consequent microaspirations have been proposed In recent literature on IPF, symptomatic GER has been Princesa, Madrid, Spain
as pathogenic in IPF and there are data to suggest that termed GERD. However, in the current perspective, we (C Valenzuela MD);
treatment with antacid therapy might be of clinical benefit discuss the hypothesis that asymptomatic reflux might Pulmonology Department,
University of Ege,
in terms of slowing chronic disease progression, and be pathogenic in IPF and is, for that reason, a form of
Bornova-İzmir, Turkey
possibly even survival.7–9 Conversely, other reports10,11 GERD. Therefore, to avoid confusion, we have adopted (Prof N Mogulkoc MD); Center
question the efficacy of antacid therapy in IPF and have the following two concepts. First, when appropriate, for Rare Lung Diseases,
suggested that possible harm cannot be excluded. GER (referring to acid or non-acid reflux) will be sub- University Hospital of Modena,
Modena, Italy (F Luppi MD);
The most recent international guideline statement on divided into asymptomatic and symptomatic GER, with
UOC Pneumologia, Università
the treatment of IPF12 attempted to address the role for symptoms categorised as oesophageal or non-oesophageal. Cattolica del Sacro Cuore,
antacid therapy in the management of IPF, with the non- Rome, Italy (Prof L Richeldi MD);
conflicted voting members of the committee making a Interstitial Lung Disease Unit,
Key messages Royal Brompton Hospital,
conditional recommendation for the use of antacid London, UK (Prof A U Wells MD);
therapy in the treatment of patients with IPF. From the • Gastro-oesophageal reflux (GER) is proposed as Regional Referral Centre for
outset, this recommendation has been controversial in pathogenic in the development or progression of Rare Lung Diseases,
light of the absence of data generated from any placebo- idiopathic pulmonary fibrosis (IPF) Department of Clinical and
Experimental Medicine,
controlled trial. We believe that there is equipoise • To date, international guidelines conditionally recommend University of Catania, Catania,
regarding the pathogenic role of GER in IPF,13 and it is the use of antacid therapy for patients with IPF Sicily, Italy
unclear whether the guideline recommendation should • There is a paucity of high-quality data supporting a (Prof C Vancheri MD); Center for
be interpreted to suggest that the majority of patients pathogenic role of GER in IPF, or a benefit of antacid Interstitial and Rare Lung
Diseases, Pneumology and
with IPF with no symptoms of GER might reasonably be therapy in patients with IPF Respiratory Critical Care
offered regular antacid therapy, in the hope of slowing • Given the clinical equipoise, we have aimed to Medicine, Thoraxklinik,
disease progression. In this perspective, we have contextualise the guideline recommendation for University of Heidelberg,
summarised the evidence addressing the association Heidelberg, Germany
practitioners caring for patients with IPF
(Prof M Kreuter MD); and
between GER and IPF, and have sought to contextualise • Moving forward, consistent terminology must be adopted Translational Lung Research
the current conditional guideline recommendation for and prospective randomised trials of antireflux therapy Center Heidelberg, German
practitioners caring for these patients. must be completed to meaningfully address the question Center for Lung Research,
In December, 2015, a working group of 48 international Heidelberg, Germany
of antacid therapy use for patients with IPF
(Prof M Kreuter)
interstitial lung disease (ILD) experts assembled at the
www.thelancet.com/respiratory Vol 5 July 2017 591
, Position Paper
Correspondence to: Second, for reflux of gastric contents (acid or non-acid) which GER contributes to the development or exacerbation
Prof Athol U Wells, into the airways (excluding aspiration pneumonia) of pulmonary disease. Several reports suggest associations
Interstitial Lung Disease Unit,
Royal Brompton Hospital,
causing pulmonary symptoms or complications we use between reflux and respiratory diseases including chronic
London SW3 6NP, UK the term microaspiration, which could be symptomatic or cough, severe asthma, chronic obstructive pulmonary
asymptomatic. disease (COPD), IPF, and other interstitial lung diseases.20
The term airway reflux has been proposed to account for
See Online for appendix What is GER? the syndrome of non-oesophageal reflux symptoms and
GER is the reflux of gastric contents into the oesophagus subsequent respiratory effects.21 However, this term might
with some degree of GER occurring physiologically. GER over-attribute pulmonary symptoms such as cough and
can be acidic or non-acidic with oesophageal pH below or dyspnoea to gastric reflux, and careful future work is
above 4·0, respectively. GERD is termed as a condition needed to characterise these associations.
that develops when the reflux of stomach contents causes For these extra-oesophageal diseases, it is presumably
symptoms or complications,14 a definition adopted in the not the GER itself that would be considered harmful, but
field of gastroenterology. It is important to recognise that rather the subsequent physiological effects of refluxate
GERD is not synonymous with GER or simple heartburn, microaspiration on the airways and lung parenchyma.
and that the GERD syndrome requires consequent It remains unclear whether these adverse effects are
adverse downstream effects from the reflux. Whether the mitigated by the use of antacid therapy or whether any
development of IPF can be considered a consequent interventions are effective in reducing or eliminating
downstream effect of reflux is at the heart of the current microaspiration.
controversy.
Overall, symptomatic oesophageal GER is common with What is the recommended treatment for GER?
an estimated prevalence of 10–20% in North America and The recommended approach to managing a patient with
Europe, with a lower prevalence in Asia.15 GER can be symptomatic GER is multifaceted and should be
diagnosed in the presence of typical oesophageal based on disease severity according to symptoms and
symptoms (heartburn, acidic reflux, chest pain), non- consequences. This approach applies to all individuals
oesophageal symptoms (cough, laryngitis), or through the with symptomatic GER, including patients with IPF
use of invasive diagnostic techniques. These include with documented symptoms or sequelae. Potential
oesophageal manometry to measure the competence of interventions range from lifestyle modification to
the lower oesophageal sphincter and ambulatory 24 h surgical fundoplication, with the latter reserved for
catheter pH monitoring to identify excessive acid reflux severe and refractory disease. Clinical practice guide-
events. The combination of pH plus impedance lines from gastroenterological societies recommend a
monitoring is recommended to identify both acid and non- step-wise approach to therapy, starting with oral antacids
acid reflux events in the oesophagus, as well as the height for intermittent mild symptoms and lifestyle modifi-
and volume of the reflux. Upper endoscopy might show cations as initial therapy, as needed.16,22 Although many
oesophagitis, erosions, Barrett’s oesophagus, or the lifestyle modifications have been proposed in the
development of adenocarcinoma, though this procedure is conservative management of GER, a systematic review
not routinely recommended for all patients with reflux of 16 randomised trials23 found that only weight loss and
symptoms.16 Importantly, reflux-causing non-oesophageal elevation of the head end of the bed were effective in
symptoms might not be identified using standard improving GER symptoms. For persistent symptoms,
oesophageal tests, which have low sensitivity for gaseous histamine 2 receptor antagonists (H2RAs) taken once a
or aerosolised reflux.17 Newer investigations, including day can be used as pharmacological therapy, and can be
high-resolution manometry, appear better able to identify increased to twice a day as needed for symptom control.
subtle defects in oesophageal motility, which are associated If there is no response to usual dose H2RAs twice a day,
with an increased propensity towards reflux.18 Given the a proton pump inhibitor (PPI) once a day should be
differences between oesophageal and non-oesophageal started. PPIs competitively bind to an adenosine
reflux, distinct diagnostic algorithms might be necessary triphosphatase pump on the gastric parietal cell
to characterise the pathogenic mechanisms of reflux providing sustained inhibition of acid secretion into the
associated with chronic pulmonary diseases such as IPF. stomach. Although the definition of severe or refractory
disease is variable, most patients with persistent
How is GER related to microaspiration? symptoms despite use of PPIs once a day should be
The refluxate content of GER is not only gastric acid but referred to a gastroenterologist for the consideration of
also bile salts; pepsin, trypsin, and other enzymes; food more aggressive management such as PPIs twice a day
particles; and bacteria or their products; all of which can or surgical fundoplication. This step-wise management
be potentially harmful.19 The reflux of gastric contents into approach is recommended by gastrointestinal prac-
the proximal oesophagus can lead to aspiration of these titioners, with treatment titration based on the presence
contents into the airways, leading to direct toxic injury. of symptoms or erosive oesophagitis or other com-
This microaspiration is proposed as a mechanism by plications, such as Barrett’s oesophagus. This approach
592 www.thelancet.com/respiratory Vol 5 July 2017
Antacid therapy in idiopathic pulmonary fibrosis:
more questions than answers?
Kerri A Johannson*, Irina Strâmbu*, Claudia Ravaglia, Jan C Grutters, Claudia Valenzuela, Nesrin Mogulkoc, Fabrizio Luppi, Luca Richeldi,
Athol U Wells, Carlo Vancheri*, Michael Kreuter* for the Erice ILD Working Group†
Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal Lancet Respir Med 2017;
reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but 5: 591–98
robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy *Contributed equally
(proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal †Members listed in the appendix
reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and Department of Medicine,
IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through University of Calgary, Calgary,
AB, Canada (K A Johannson MD);
which the guideline recommendation was achieved and aim to contextualise the recommendation for providers Pulmonology Department,
caring for patients with IPF. University of Medicine and
Pharmacy Carol Davila,
Introduction Ettore Majorana Foundation and Centre for Scientific Bucharest, Romania
(I Strâmbu MD); Pulmonology
Idiopathic pulmonary fibrosis (IPF) is a progressive Culture in Erice, Italy, to discuss priority clinical and Unit, Department of Thoracic
parenchymal lung disease of unclear origin, associated research issues in ILD. Participants represented Diseases, G B Morgagni L
with a median survival of 3–5 years from the time of 17 countries from Europe and North America. Among Pierantoni Hospital, Forli, Italy
diagnosis.1 At present, two IPF-specific pharmacological the topics of discussion was the current conditional (C Ravaglia MD); Interstitial
Lung Diseases Center of
therapies are available that slow disease progression, but to guideline recommendation for antacid therapy in IPF. Excellence, Department of
date there is no known cure.2,3 Patients with IPF have In pro–con debates and round-table discussions, the Pulmonology, St Antonius
frequent comorbid conditions, including a high reported evidence supporting this recommendation was presented Hospital, Nieuwegein,
for consideration. Given the current controversies, this Netherlands
prevalence of gastro-oesophageal reflux (GER) and gastro-
(Prof J C Grutters MD); Division
oesophageal reflux disease (GERD).4–6 The potential role of Position Paper was prepared by the primary participants of Heart and Lungs, University
GER in the pathogenesis or progression of disease has (authors) who discussed this issue while incorporating Medical Center Utrecht,
been an important focus of research, in an effort to find input from all other participants of the Erice ILD Working Netherlands (Prof J C Grutters);
Pulmonology Department,
effective therapeutic approaches to patient management. Group (appendix).
Hospital Universitario de la
GER and consequent microaspirations have been proposed In recent literature on IPF, symptomatic GER has been Princesa, Madrid, Spain
as pathogenic in IPF and there are data to suggest that termed GERD. However, in the current perspective, we (C Valenzuela MD);
treatment with antacid therapy might be of clinical benefit discuss the hypothesis that asymptomatic reflux might Pulmonology Department,
University of Ege,
in terms of slowing chronic disease progression, and be pathogenic in IPF and is, for that reason, a form of
Bornova-İzmir, Turkey
possibly even survival.7–9 Conversely, other reports10,11 GERD. Therefore, to avoid confusion, we have adopted (Prof N Mogulkoc MD); Center
question the efficacy of antacid therapy in IPF and have the following two concepts. First, when appropriate, for Rare Lung Diseases,
suggested that possible harm cannot be excluded. GER (referring to acid or non-acid reflux) will be sub- University Hospital of Modena,
Modena, Italy (F Luppi MD);
The most recent international guideline statement on divided into asymptomatic and symptomatic GER, with
UOC Pneumologia, Università
the treatment of IPF12 attempted to address the role for symptoms categorised as oesophageal or non-oesophageal. Cattolica del Sacro Cuore,
antacid therapy in the management of IPF, with the non- Rome, Italy (Prof L Richeldi MD);
conflicted voting members of the committee making a Interstitial Lung Disease Unit,
Key messages Royal Brompton Hospital,
conditional recommendation for the use of antacid London, UK (Prof A U Wells MD);
therapy in the treatment of patients with IPF. From the • Gastro-oesophageal reflux (GER) is proposed as Regional Referral Centre for
outset, this recommendation has been controversial in pathogenic in the development or progression of Rare Lung Diseases,
light of the absence of data generated from any placebo- idiopathic pulmonary fibrosis (IPF) Department of Clinical and
Experimental Medicine,
controlled trial. We believe that there is equipoise • To date, international guidelines conditionally recommend University of Catania, Catania,
regarding the pathogenic role of GER in IPF,13 and it is the use of antacid therapy for patients with IPF Sicily, Italy
unclear whether the guideline recommendation should • There is a paucity of high-quality data supporting a (Prof C Vancheri MD); Center for
be interpreted to suggest that the majority of patients pathogenic role of GER in IPF, or a benefit of antacid Interstitial and Rare Lung
Diseases, Pneumology and
with IPF with no symptoms of GER might reasonably be therapy in patients with IPF Respiratory Critical Care
offered regular antacid therapy, in the hope of slowing • Given the clinical equipoise, we have aimed to Medicine, Thoraxklinik,
disease progression. In this perspective, we have contextualise the guideline recommendation for University of Heidelberg,
summarised the evidence addressing the association Heidelberg, Germany
practitioners caring for patients with IPF
(Prof M Kreuter MD); and
between GER and IPF, and have sought to contextualise • Moving forward, consistent terminology must be adopted Translational Lung Research
the current conditional guideline recommendation for and prospective randomised trials of antireflux therapy Center Heidelberg, German
practitioners caring for these patients. must be completed to meaningfully address the question Center for Lung Research,
In December, 2015, a working group of 48 international Heidelberg, Germany
of antacid therapy use for patients with IPF
(Prof M Kreuter)
interstitial lung disease (ILD) experts assembled at the
www.thelancet.com/respiratory Vol 5 July 2017 591
, Position Paper
Correspondence to: Second, for reflux of gastric contents (acid or non-acid) which GER contributes to the development or exacerbation
Prof Athol U Wells, into the airways (excluding aspiration pneumonia) of pulmonary disease. Several reports suggest associations
Interstitial Lung Disease Unit,
Royal Brompton Hospital,
causing pulmonary symptoms or complications we use between reflux and respiratory diseases including chronic
London SW3 6NP, UK the term microaspiration, which could be symptomatic or cough, severe asthma, chronic obstructive pulmonary
asymptomatic. disease (COPD), IPF, and other interstitial lung diseases.20
The term airway reflux has been proposed to account for
See Online for appendix What is GER? the syndrome of non-oesophageal reflux symptoms and
GER is the reflux of gastric contents into the oesophagus subsequent respiratory effects.21 However, this term might
with some degree of GER occurring physiologically. GER over-attribute pulmonary symptoms such as cough and
can be acidic or non-acidic with oesophageal pH below or dyspnoea to gastric reflux, and careful future work is
above 4·0, respectively. GERD is termed as a condition needed to characterise these associations.
that develops when the reflux of stomach contents causes For these extra-oesophageal diseases, it is presumably
symptoms or complications,14 a definition adopted in the not the GER itself that would be considered harmful, but
field of gastroenterology. It is important to recognise that rather the subsequent physiological effects of refluxate
GERD is not synonymous with GER or simple heartburn, microaspiration on the airways and lung parenchyma.
and that the GERD syndrome requires consequent It remains unclear whether these adverse effects are
adverse downstream effects from the reflux. Whether the mitigated by the use of antacid therapy or whether any
development of IPF can be considered a consequent interventions are effective in reducing or eliminating
downstream effect of reflux is at the heart of the current microaspiration.
controversy.
Overall, symptomatic oesophageal GER is common with What is the recommended treatment for GER?
an estimated prevalence of 10–20% in North America and The recommended approach to managing a patient with
Europe, with a lower prevalence in Asia.15 GER can be symptomatic GER is multifaceted and should be
diagnosed in the presence of typical oesophageal based on disease severity according to symptoms and
symptoms (heartburn, acidic reflux, chest pain), non- consequences. This approach applies to all individuals
oesophageal symptoms (cough, laryngitis), or through the with symptomatic GER, including patients with IPF
use of invasive diagnostic techniques. These include with documented symptoms or sequelae. Potential
oesophageal manometry to measure the competence of interventions range from lifestyle modification to
the lower oesophageal sphincter and ambulatory 24 h surgical fundoplication, with the latter reserved for
catheter pH monitoring to identify excessive acid reflux severe and refractory disease. Clinical practice guide-
events. The combination of pH plus impedance lines from gastroenterological societies recommend a
monitoring is recommended to identify both acid and non- step-wise approach to therapy, starting with oral antacids
acid reflux events in the oesophagus, as well as the height for intermittent mild symptoms and lifestyle modifi-
and volume of the reflux. Upper endoscopy might show cations as initial therapy, as needed.16,22 Although many
oesophagitis, erosions, Barrett’s oesophagus, or the lifestyle modifications have been proposed in the
development of adenocarcinoma, though this procedure is conservative management of GER, a systematic review
not routinely recommended for all patients with reflux of 16 randomised trials23 found that only weight loss and
symptoms.16 Importantly, reflux-causing non-oesophageal elevation of the head end of the bed were effective in
symptoms might not be identified using standard improving GER symptoms. For persistent symptoms,
oesophageal tests, which have low sensitivity for gaseous histamine 2 receptor antagonists (H2RAs) taken once a
or aerosolised reflux.17 Newer investigations, including day can be used as pharmacological therapy, and can be
high-resolution manometry, appear better able to identify increased to twice a day as needed for symptom control.
subtle defects in oesophageal motility, which are associated If there is no response to usual dose H2RAs twice a day,
with an increased propensity towards reflux.18 Given the a proton pump inhibitor (PPI) once a day should be
differences between oesophageal and non-oesophageal started. PPIs competitively bind to an adenosine
reflux, distinct diagnostic algorithms might be necessary triphosphatase pump on the gastric parietal cell
to characterise the pathogenic mechanisms of reflux providing sustained inhibition of acid secretion into the
associated with chronic pulmonary diseases such as IPF. stomach. Although the definition of severe or refractory
disease is variable, most patients with persistent
How is GER related to microaspiration? symptoms despite use of PPIs once a day should be
The refluxate content of GER is not only gastric acid but referred to a gastroenterologist for the consideration of
also bile salts; pepsin, trypsin, and other enzymes; food more aggressive management such as PPIs twice a day
particles; and bacteria or their products; all of which can or surgical fundoplication. This step-wise management
be potentially harmful.19 The reflux of gastric contents into approach is recommended by gastrointestinal prac-
the proximal oesophagus can lead to aspiration of these titioners, with treatment titration based on the presence
contents into the airways, leading to direct toxic injury. of symptoms or erosive oesophagitis or other com-
This microaspiration is proposed as a mechanism by plications, such as Barrett’s oesophagus. This approach
592 www.thelancet.com/respiratory Vol 5 July 2017
