
==== Front
Clin Transl Gastroenterol
Clin Transl Gastroenterol
CLTG
CT9
Clinical and Translational Gastroenterology
2155-384X
Wolters Kluwer Philadelphia, PA

38822801
CTG-24-0077
10.14309/ctg.0000000000000720
00004
3
Article
Inflammatory Bowel Disease
Interstitial Lung Disease as an Emerging Contributor to Mortality in Patients With Inflammatory Bowel Disease: A Population-Based Epidemiological Study
Vaezi Atefeh MD 1a.vaezi@ufl.edu

Ashby Tracy DO tracy.ashby@jax.ufl.edu
1
Schweitzer Michael MD 1michael.schweitzer@jax.ufl.edu

Ghali Peter MD 2maged.ghali@jax.ufl.edu

https://orcid.org/0000-0001-5298-8442
Mirsaeidi Mehdi MD, MPH 1
1 Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine-Jacksonville, University of Florida, Jacksonville, Florida, USA;
2 Division of Gastroenterology, University of Florida, Jacksonville, Florida, USA.
Correspondence: Mehdi Mirsaeidi, MD, MPH. E-mail: m.mirsaeidi@ufl.edu.
9 2024
1 6 2024
15 9 e107 3 2024
21 5 2024
© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

INTRODUCTION:

We aim to investigate the contribution of interstitial lung disease (ILD) to mortality in patients with inflammatory bowel disease (IBD).

METHODS:

We performed a comprehensive retrospective, population-based epidemiological study across the United States from 2001 to 2020, using the Wide-ranging Online Data for Epidemiologic Research database. Mortality data were classified according to the International Classification of Diseases, Tenth Revision, with the codes J84 for ILD, K50 for Crohn's disease, and K51 for ulcerative colitis. To discern patterns, age-adjusted mortality rates (AMR) were computed, stratified by sex, geographic census region, and racial/ethnic demographics.

RESULTS:

From 2001 to 2020, there were 57,967 reported deaths among patients with IBD with an AMR per million significantly rising from 10.989 in 2001–2005 to 11.443 in 2016–2020 (P < 0.0001). ILD was a contributor to death in 1.19% (692/57,967) of these cases, with AMR rising from 0.092 to 0.143 per million (P = 0.010). The percentage of ILD-related deaths in the IBD population increased from 1.02% to 1.30% over 2 decades. ILD was a more common cause of death in patients with Crohn's disease than with ulcerative colitis (54.6% vs 45.4%), with a significant increase for both conditions from 2001 to 2020 (P < 0.05). An upward trend in ILD-related mortality was observed in both sexes (P < 0.05) and within the White population (P = 0.010).

DISCUSSION:

The observed increase in mortality rates due to ILD among patients with IBD is concerning and highlights a critical need for systematic ILD screening protocols within the IBD patient population to facilitate early detection and management.

KEYWORDS:

diffuse parenchymal lung disease
interstitial lung disease
interstitial pneumonia
OPEN-ACCESSTRUE
SDCT
==== Body
pmcINTRODUCTION

Inflammatory bowel disease (IBD) is characterized with chronic and recurrent inflammatory involvement of gastrointestinal tract with unpredictable clinical course. It comprises 2 distinct diseases of ulcerative colitis (UC) and Crohn's disease (CD). Between 1990 and 2019, there was a notable rise in the prevalence, disability adjusted life years, and years lived with disabilities related to IBD and it is predicted to rise until 2025 (1). Both CD and UC have been experiencing a global rise in incidence and prevalence through previous decades (2). In North America, the incidence of UC and CD stands at 19.2 and 20.2 per 100,000 person-year, respectively (3), and the prevalence of IBD surpasses 0.3% (4). Patients with IBD face higher risk of death from gastrointestinal problems, infection, respiratory diseases, nonalcoholic liver diseases, cardiovascular diseases, and cancers (5–7).

Patients with IBD are at a greater likelihood of having other chronic inflammatory conditions such as arthritis, asthma, bronchitis, psoriasis, and pericarditis compared with general population (8). Respiratory involvement in patients with IBD is frequently overlooked, as it may develop insidiously with no specific or noticeable respiratory symptoms (9). Interstitial lung disease (ILD), an inflammatory disease of respiratory system, is an extraintestinal manifestation in patients with IBD and it is more common than previously perceived (10,11). Underdiagnosis of ILD in patients with IBD may result in irreversible destruction of the lung and significant morbidities (12,13).

Recognizing the avoidable factors contributing to the mortality of patients with IBD is critical for shaping forthcoming strategies in both prevention and management and might result in improved outcome of these patients. Hence, in this study, we aimed to investigate the risk of mortality due to ILD in patients with IBD using a nationwide database.

METHODS AND MATERIALS

Study design and data collection

We conducted this population-based epidemiological survey to evaluate contribution of ILD as a cause of death of patients with IBD in the United States, from 2001 to 2020. Data were obtained on September 7, 2023, from Wide-ranging Online Data for Epidemiologic Research (WONDER) database provided by the Center for Disease Control and Prevention. WONDER is an interactive, public, web-based tool. It includes data from death certificates of US citizens in all 50 states and the District of Columbia (14). Underlying cause of death reported in the death certificates is coded in accordance with the International Classification of Diseases, 10th Revision (ICD-10), since 1999. In WONDER, when a category contains fewer than 10 individuals, the data are suppressed for confidentiality reasons. Rates are labeled as unreliable when the death count is less than 20.

Study variables and outcomes

We defined population groups based on age at death (grouped as 15–24, 25–34, 35–44, 45–54, 55–64, 65–74, 75–84, and 85+ years old), sex (female, male), race/ethnicity (American Indian/Alaska Native, Asian-pacific islanders, Black or African American, and White), residential census region (Northeast, Midwest, South, and West), and year of death (grouped into 2000–2005, 2006–2010, 2011–2015, and 2016–2020). To access data on the cause of death, we used ICD-10 code J84 indicating ILD, ICD-10 code K50 for CD, and ICD-10 code K51 for UC. As our study spans to 2020, we use ICD-10 code U07.1 to specify the coronavirus disease 2019 (COVID-19) as a cause of death.

For evaluation of mortality, we generate number of deaths, age-adjusted mortality rates (AMR) per 1,000,000 population, with 95% confidence intervals (CIs) for groups of population based on demographic variables. The crude mortality rates were also obtained and reported but excluded from the analysis because they could potentially provide misleading information when comparing rates across different periods and age groups. The AMRs are calculated in WONDER by creating a weighted average of the age-specific death rates. For the calculation of AMR, the population of year 2000 US standard is used. The equation for calculating the AMR is R′=∑i(Psi/Ps)Ri, where Psi is the standard population for a specific age group i, Ps refers to the total US standard population, and Ri is the age-specific death rate.

Statistical analysis

The all-cause and ILD-related mortality rates for IBD, CD, and UC were extracted from WONDER. Crude and AMR with 95% CI were presented regarding sex, residential census region, and race/ethnicity. For age groups, the crude mortality rate with 95% CI was presented. Linear regression analysis was conducted to evaluate the trend in AMR from 2001 to 2020. The AMR future trend until the year 2030 was predicted using the linear regression model. To assure the fitness of models, a polynomial regression analysis with an order of 3 was also performed. Mortality rates through the last period and the first period were compared with determine percent change among population groups. A P value < 0.05 was considered as significant.

RESULTS

From 2001 through 2020, IBD was responsible for 57,967 deaths with an AMR of 10.9 (95% CI, 10.810–10.989) per 1,000,000 population. Considering 5-year intervals, the AMR of IBD increased from 10.989 (95% CI, 10.796–11.181) in 2001–2005 to 11.443 (95% CI,11.271–11.615) within 2016–2020 per 1,000,000 population. The average IBD-related AMR increased by 39.9% from 2001 to 2005 to 2016–2020 (Supplementary Digital Content, http://links.lww.com/CTG/B135).

ILD is defined as the contributor in cause of death for 692 patients with IBD from 2001 to 2020, with an AMR of 0.11 per 1,000,000 population (95% CI, 0.10–0.12). The share of ILD as a cause of mortality in patients with IBD increases from 1.02% in 2001–2005 to 1.30% in 2016–2020, with an increase in the number of deaths by almost 44% from 129 deaths in 2001–2005 to 229 deaths in 2016–2020. The average AMR per 1,000,000 population increased from 0.092 (95% CI, 0.075–0.109) in 2001–2005 to 0.143 (95% CI, 0.123–0.162) in 2016–2020 (P value, 0.01, r2, 0.795). Female patients and male patients with IBD died due to ILD at an average AMR of 0.111 (95% CI, 0.099–0.124) and 0.132 (95% CI, 0.117–0.147) per 1,000,000 population through 2001 to 2020, respectively. Male patients experienced a similar upward trend as the whole population with a fluctuation through 2011–2015 (P value, 0.01), while female patients had a steady rise (P value, 0.01). The average AMR increased by 89.9% among male patients and 67.1% among female patients (Table 1, Figure 1).

Table 1. ILD-related age adjusted mortality rate of patients with IBD per 1,000,000 US citizens (2001–2020)

	2001–2005	2006–2010	2011–2015	2016–2020	P value for trend of AMR	
No. of deaths	Age-adjusted rate per 1,000,000 (95% CI)	No. of deaths	Age-adjusted rate per 1,000,000 (95% CI)	No. of deaths	Age-adjusted rate per 1,000,000 (95% CI)	No. of deaths	Age-adjusted rate per 1,000,000 (95% CI)	
All-cause mortality of patients with IBD	12,562	10.989 (10.796–11.181)	13,218	10.550 (10.369–10.731)	14,609	10.547 (10.374–10.720)	17,578	11.443 (11.271–11.615)	<0.0001	
ILD-related mortality in patients with IBD	129	0.092 (0.075–0.109)	160	0.117 (0.098–0.136)	174	0.110 (0.092–0.128)	229	0.143 (0.123–0.162)	0.010	
Sex										
 Female	70	0.108 (0.083–0.138)	82	0.118 (0.093–0.149)	92	0.119 (0.094–0.148)	117	0.129 (0.104–0.153)	0.010	
 Male	59	0.108 (0.080–0.142)	78	0.147 (0.115–0.184)	82	0.122 (0.096–0.154)	112	0.160 (0.129–0.191)	0.010	
Census region										
 Northeast	22	0.082 (0.049–0.128)	25	0.095 (0.060–0.143)	28	0.118 (0.074–0.178)	41	0.150 (0.105–0.208)	0.010	
 Midwest	46	0.163 (0.118–0.219)	43	0.138 (0.098–0.189)	31	0.108 (0.072–0.155)	47	0.129 (0.094–0.172)	0.010	
 South	30	0.062 (0.040–0.091)	48	0.106 (0.077–0.142)	61	0.102 (0.077–0.134)	69	0.119 (0.092–0.152)	0.009	
 West	31	0.118 (0.077–0.173)	44	0.156 (0.111–0.213)	54	0.176 (0.130–0.231)	72	0.209 (0.163–0.265)	0.011	
Race/ethnicity										
 American Indian or Alaska Native	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	NA	
 Asian-pacific islanders	Suppressed	Suppressed	Suppressed	Suppressed	0	Unreliable	Suppressed	Suppressed	NA	
 Black or African American	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	10	Unreliable (0.018–0.083)	NA	
 White	122	0.119 (0.097–0.142)	148	0.125 (0.104–0.146)	168	0.139 (0.115–0.162)	214	0.167 (0.143–0.190)	0.010	
AMR, age-adjusted mortality rate; CI, confidence interval; IBD, inflammatory bowel disease; ILD, interstitial lung disease; NA, not applicable.

Figure 1. Interstitial lung disease-related age-adjusted mortality rate per 1,000,000 patients with inflammatory bowel disease, Crohn's disease, and ulcerative colitis (2001–2020) in the United States, and prediction up to 2030, with a regression equation of y = 0.0146x + 0.079 (r2 = 0.795). AMR, age-adjusted mortality rate; CD, Crohn's disease; IBD, inflammatory bowel disease; ILD, interstitial lung disease; UC, ulcerative colitis.

The ILD-related AMR of patients with IBD per 1,000,000 citizens of Northeast rises by approximately 86.3% from 0.082 (95% CI, 0.049–0.128) in 2001–2005, 0.095 (95% CI, 0.060–0.143) in 2006–2010, 0.118 (0.074–0.178) in 2011–2015, and ultimately to 0.150 (95% CI, 0.105–0.208) in 2016–2020 (P value, 0.01). Midwest citizens experienced a decline from 0.163 (95% CI, 0.118–0.219) in 2001–2005 to 0.108 (95% CI, 0.072–0.155) in 2011–2015 and then an incline to 0.129 (95% CI, 0.094–0.172) in 2016–2020 (P value, 0.01). Most deaths (30%) happen in the South census region with an overall increase in AMR from 0.062 (95% CI, 0.040–0.091) in 2001–2005 to 0.119 (95% CI, 0.092–0.152) in 2016–2020. The highest increase was in the mortality of West citizens who experienced a 132.2% rise from 31 deaths in 2001–2005 to 72 deaths in 2016–2020 (P-value, 0.011) (Figure 2).

Figure 2. Interstitial lung disease-related age-adjusted mortality rate per 1,000,000 patients with inflammatory bowel disease in the United States census regions. (a) 2001–2020; (b) 2001–2005; (c) 2006–2010; (d) 2011–2015; (e) 2016–2020.

Among different race and ethnicities, the ILD-related AMR of patients with IBD in American Indian or Alaska Native, Asian-pacific islanders, and Black or African American was not calculated due to the low number of deaths in these groups. White population accounted for a total of 652 deaths (94%) with an AMR of 0.119 (95% CI, 0.097–0.142) in 2001–2005, 0.125 (95% CI, 0.104–0.146) in 2006–2010, 0.139 (95% CI, 0.115–0.162) in 2011–2015, and 0.167 (95% CI, 0.143–0.190) in 2016–2020. Table 1 and Figure 1 present more details on ILD-related mortality of patients with IBD. The crude numbers and graphs of polynomial regression analysis are provided in Supplementary Digital Content (see Supplementary File, http://links.lww.com/CTG/B135).

The crude death rate was not calculated for age groups of 15–24, 25–34, 34–44, and 45–54 years due to low number of deaths in these age groups, which together was 65 deaths from 2001 to 2020. For other age groups, an upward trend in the crude death rate was observed. Table 2 is presenting details of death distribution among age groups.

Table 2. ILD-related crude mortality rates per 1,000,000 patients with IBD among age groups (2001–2020)

	2001–2005
N = 129	2006–2010
N = 160	2011–2015
N = 174	2016–2020
N = 229	
Death
N (%)	Crude rate per 1,000,000 (95% CI)	Death
N (%)	Crude rate per 1,000,000 (95% CI)	Death
N (%)	Crude rate per 1,000,000 (95% CI)	Death
N (%)	Crude rate per 1,000,000 (95% CI)	
Age groups									
 15–24	0	Unreliable	0	Unreliable	0	Unreliable	0	Unreliable	
 25–34	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	
 35–44	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	
 45–54	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	Suppressed	13 (5.67)	Unreliable (0.033–0.107)	
 55–64	19 (14.72)	Unreliable (0.082–0.212)	30 (18.75)	0.175 (0.118–0.250)	21 (12.06)	0.107 (0.066–0.163)	24 (10.48)	0.114 (0.073–0.170)	
 65–74	32 (24.80)	0.345 (0.236–0.487)	41 (25.62)	0.401 (0.287–0.543)	49 (28.16)	0.390 (0.289–0.516)	68 (29.69)	0.445 (0.345–0.564)	
 75–84	45 (34.88)	0.700 (0.510–0.936)	55 (34.37)	0.842 (0.634–1.096)	52 (29.88)	0.770 (0.575–1.010)	72 (31.44)	0.938 (0.734–1.181)	
 +85	19 (14.72)	Unreliable (0.511–1.325)	21 (13.12)	0.809 (0.501–1.236)	30 (17.24)	0.996 (0.672–1.422)	49 (21.39)	1.500 (1.110–1.984)	
CI, confidence interval; N, number.

COVID-19 as a cause of death in patients with IBD in 2020

From 17,578 deaths in patients with IBD through 2016–2020, COVID-19 counts for 296 deaths, all recorded in 2020. None of the patients with IBD who have ILD as a cause of mortality in 2020 had concurrent COVID-19. We also perform an additional analysis by removing 2020 data (Supplementary Digital Content, http://links.lww.com/CTG/B135).

Ulcerative colitis vs Crohn disease

From 2001 to 2020, 35,409 US citizens died due to CD, which compromised approximately 61% of IBD deaths. The AMR of patients with CD (per 1,000,000) was 6.714, 6.476, 6.462, and 6.916, in 2001–2005, 2006–2010, 2011–2015, and 2016–2020, respectively. For UC, it was 4.296, 4.123, 4.129, and 4.544, respectively, in the same periods.

Adding the ILD as a cause of death, the crude number of deaths in 2016–2020 (134 deaths) is almost twice the number of deaths in 2001–2005 (68 deaths), with an increase in AMR from 0.051 (95% CI, 0.039–0.066) in 2001–2005 to 0.087 (95% CI, 0.071–0.104) in 2016–2020 (P value, 0.009). For patients with UC, an upward trend was observed in the ILD-related AMR of them (P value, 0.009), with a rise from 0.052 (95% CI, 0.039–0.068) in 2001–2005 to 0.061 (95% CI, 0.049–0.075) in 2016–2020 (Table 3, Figure 3).

Table 3. ILD-related age adjusted mortality per 1,000,000 patients with CD and UC (2001–2020)

	2001–2005	2006–2010	2011–2015	2016–2020	P value for trend of AMR	
No. of deaths	Age-adjusted rate per 1,000,000 (95% CI)	No. of deaths	Age-adjusted rate per 1,000,000 (95% CI)	No. of deaths	Age-adjusted rate per 1,000,000 (95% CI)	No. of deaths	Age-adjusted rate per 1,000,000 (95% CI)	
Population with CD	7,691	6.714 (6.563–6.864)	8,141	6.476 (6.335–6.618)	8,957	6.462 (6.326–6.598)	10,620	6.916 (6.782–7.050)	0.0007	
Population with UC	4,898	4.296 (4.176–4.416)	5,101	4.123 (4.009–4.236)	5,685	4.129 (4.021–4.238)	7,006	4.544 (4.436–4.652)	0.03	
Population with CD/ILD	68	0.051 (0.039–0.066)	79	0.053 (0.041–0.067)	98	0.059 (0.046–0.073)	134	0.087 (0.071–0.104)	0.009	
Population with UC/ILD	62	0.052 (0.039–0.068)	81	0.064 (0.051–0.080)	76	0.052 (0.040–0.066)	95	0.061 (0.049–0.075)	0.009	
AMR, age-adjusted mortality rate; CD, Crohn's disease; CI, confidence interval; ILD, interstitial lung disease; UC, ulcerative colitis.

Figure 3. Trend of death in patients with Crohn's disease and ulcerative colitis comparing interstitial lung disease and other causes (2001–2020). CD, Crohn's disease; ILD, interstitial lung disease; UC, ulcerative colitis.

DISCUSSION

From 2001 to 2020, the United States experienced an overall 44% increase in the ILD-related mortality of patients with IBD. Our results also revealed an upward trend in the mortality of patients with UC and patients with CD due to ILD. Both sexes had experienced an upward trend in the ILD-related mortality. We demonstrated that most of the ILD-related mortality in patients with IBD have occurred in the South US census region, with the West region experiencing the highest change.

To the best of our knowledge, the share of ILD in the outcome of patients with IBD has not been explored previously. Studies focusing on ILD in patients with IBD are mostly case reports which may be due to lack of defined protocol to screen for ILD in patients with IBD, presentation of patients with unspecific symptoms, and mostly asymptomatic involvement (15). While keeping in mind that we do not have incidence and prevalence rate of ILD in patients with IBD through WONDER database, 2 hypotheses warrant investigation; first, we may be observing a higher rate of ILD diagnosis in patients with IBD due to improved coding of causes of death. Second, alongside the rising AMR of ILD in both the general population and among patients with IBD, there might also be an increasing incidence rate of ILD in patients with IBD. Involvement of the respiratory system in patients with IBD has been reported since the 1970s. However, there was a debate whether ILD in patients with IBD is an extraintestinal complication of the disease, a side effect of medications, or a coincidence of 2 unrelated diseases (16–19). Given the shared embryological origin of the gastrointestinal and respiratory systems, the involvement of lung in IBD is not surprising. Individuals who have a genetic tendency toward IBD, have a higher likelihood of developing ILD (20). Moreover, a common pathophysiologic pathway, proinflammatory fibroblasts, is involved in the pathogenic activation of both diseases (21). Smoking is another factor which may be involved in the pathogenesis of pulmonary involvement in patients with IBD. Smoking exhibits contrary effect on CD and UC, elevating the risk of CD while providing a protective effect against UC (22). In nonsmoking female patients with UC, a higher prevalence of lower airway involvement is documented which may precede the manifestation of IBD in younger patients (23). In this study, we lack data on the prevalence of smoking in our study population; hence, we cannot define the contribution of smoking in the trend of ILD-related AMR.

Pulmonary manifestations are more prevalent in adults (24) and include airway inflammation and obstruction, bronchiectasis, bronchiolitis obliterans organizing pneumonia, vasculitis, pleurisy, and ILD (25–28). Symptoms of respiratory involvement are unspecific including productive cough, chest pain, and dyspnea (29). Parenchymal disease frequently develops regardless of the activity level of IBD (30). Latent involvement is more prevalent than apparent respiratory symptoms (31). Zhao et al (32) conducted pulmonary function test (PFT) for 74 patients with IBD; abnormal PFT and decreased residual volume were observed in 75% and 51% of patients, respectively. They reported that only as few as 2.7% of patients with IBD had respiratory symptoms. Except for decrease in diffusing capacity of the lungs for carbon monoxide (DLCO), there is no specific PFT pattern in patients with IBD. The impairment includes obstructive and/or restrictive pattern or isolated reduction in forced expiratory volume in second one and forced vital capacity (33).

Patients with IBD have an overall 1.4 times higher risk of death compared with the general population. Respiratory involvement accounts for the second cause of death in patients with IBD and is responsible for 13.2% and 14.2% of the mortality of patients with CD and patients with UC, respectively (34). Studies have demonstrated an increasing trend in the risk of death from respiratory diseases among patients with CD and patients with UC (35–37). In this study, we found that the share of ILD as a cause of death of patients with IBD has been doubled through 2001 to 2020. However, as we used the WONDER database, which is based on death certificate, we cannot make any statement about the incidence of ILD in the population of patients with IBD. Indeed, we hope our study could raise the question about the prevalence and incidence of ILD in this population of patients with IBD as it seems to contribute to their death.

In this study, we explore the contribution of ILD to the mortality of patients with IBD, in a population-based epidemiological study through a time span of 20 years. This wide range data could reveal the rising proportion of ILD in the mortality of patients with IBD and added to the significance of our results. However, this study encounters some limitations. The database we used in this study relies on death certificates, which may be biased toward underreporting or overreporting of causes of death by clinicians. This also may have happened for recording the COVID-19 as a cause of death in 2020. Moreover, as many cases of pulmonary involvement in patients with IBD remains undiagnosed, it is probable that the actual rate of ILD-related mortality in patients with IBD is higher than what is reported in the death certificates. This study evaluates AMR among all patients with IBD; however, it fails to evaluate it in ethnic/race groups other than White patients. While it seems to be related to the lower number of mortality in these ethnic/race groups, we cannot rule out the possibility of underreporting. Finally, considering smoking as a potential confounding factor in this study, we used ICD-10 code F17.2 to define tobacco consumption as a cause of death, which identifies 113 patients with IBD between 2001 and 2020. This underscores the likelihood of underreporting regarding the impact of smoking on the study's outcomes.

Contribution of ILD in the outcome of IBD as a cause of mortality reveals the probability of underdiagnosis and high prevalence of ILD in patients with IBD. Moreover, the rising trend of ILD-related mortality of patients with IBD underscores the importance of considering and managing lung involvement, as a preventable cause of death in these patients to reduce mortality rate. This insight could lead to the development of screening programs, ultimately enhancing outcomes of patients with IBD.

CONFLICTS OF INTEREST

Guarantor of the article: Mehdi Mirsaeidi, MD, MPH.

Specific author contributions: A. Vaezi: conceptualization, formal analysis, drafting the manuscript, she has approved the final draft submitted; T. Ashby: interpreting data, validation, she has approved the final draft submitted; M. Schweitzer: interpreting data, validation, he has approved the final draft submitted; P. Ghali: interpreting data, validation, he has approved the final draft submitted; M. Mirsaeidi: conceptualization, methodology, validation, supervision, drafting the manuscript, he has approved the final draft submitted.

Financial support: None to report.

Potential competing interests: None to report.Study Highlights

WHAT IS KNOWN

✓ Patients with Inflammatory Bowel Disease (IBD) experience higher risk of having other chronic inflammatory conditions.

✓ Interstitial Lung Disease (ILD) is an extraintestinal manifestation of IBD, however, little is known about its contribution to the mortality of these patients.

WHAT IS NEW HERE

✓ ILD has been accountable for 692 deaths in IBD patients from 2001 to 2020, with an Age-Adjusted Mortality Rate of 0.11 per 1,000,000 population.

✓ The contribution of ILD as a cause of death of patients with IBD is on the rise from 1.02% in 2001-2005 to 1.30% in 2016-2020.

TRANSLATIONAL IMPACT

✓ There is a need to develop and implement systematic ILD screening protocols for early detection of ILD in patients with IBD.

Supplementary Material

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/CTG/B135
==== Refs
REFERENCES

1. Wang S Dong Z Wan X . Global, regional, and national burden of inflammatory bowel disease and its associated anemia, 1990 to 2019 and predictions to 2050: An analysis of the global burden of disease study 2019. Autoimmun Rev 2024;23 (3 ):103498.38052263
2. Ponder A Long MD . A clinical review of recent findings in the epidemiology of inflammatory bowel disease. Clin Epidemiol 2013;5 :237–47.23922506
3. Molodecky NA Soon IS Rabi DM . Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142 (1 ):46–e30. quiz e30.22001864
4. Ng SC Shi HY Hamidi N . Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet 2017;390 (10114 ):2769–78.29050646
5. Kassam Z Belga S Roifman I . Inflammatory bowel disease cause-specific mortality: A primer for clinicians. Inflamm Bowel Dis 2014;20 (12 ):2483–92.25185685
6. Bewtra M Kaiser LM TenHave T . Crohn's disease and ulcerative colitis are associated with elevated standardized mortality ratios: A meta-analysis. Inflamm Bowel Dis 2013;19 (3 ):599–613.23388544
7. Li F Ramirez Y Yano Y . The association between inflammatory bowel disease and all-cause and cause-specific mortality in the UK Biobank. Ann Epidemiol 2023;88 :15–22.38013230
8. Bernstein CN Wajda A Blanchard JF . The clustering of other chronic inflammatory diseases in inflammatory bowel disease: A population-based study. Gastroenterology 2005;129 (3 ):827–36.16143122
9. Karadag F Ozhan MH Akçiçek E . Is it possible to detect ulcerative colitis-related respiratory syndrome early? Respirology 2001;6 (4 ):341–6.11844126
10. Black H Mendoza M Murin S . Thoracic manifestations of inflammatory bowel disease. Chest 2007;131 (2 ):524–32.17296657
11. Ephgrave K . Extra-intestinal manifestations of Crohn's disease. Surg Clin North Am 2007;87 (3 ):673–80.17560419
12. Ceyhan B . Inflammatory bowel disease and lung [in Turkish]. Tuberk Toraks 2006;54 (3 ):292–8.17001550
13. Eliadou E Moleiro J Ribaldone DG . Interstitial and granulomatous lung disease in inflammatory bowel disease patients. J Crohns Colitis 2020;14 (4 ):480–9.31602473
14. CDC WONDER. Available at: https://wonder.cdc.gov. Accessed December 14, 2023.
15. Xu L Xiao W Ma D . Ulcerative colitis combined with acute interstitial lung disease and airway disease: A case report and literature review. Exp Ther Med 2014;8 (4 ):1229–36.25187830
16. Balestra DJ Balestra ST Wasson JH . Ulcerative colitis and steroid-responsive, diffuse interstitial lung disease. A trial of N = 1. JAMA 1988;260 (1 ):62–4.3379724
17. Janower ML . Ulcerative colitis and diffuse interstitial lung disease: Rare association or complete coincidence? JAMA 1989;261 (3 ):381–2.
18. Balestra DJ Balestra ST . Ulcerative colitis and diffuse interstitial lung disease: Rare association or complete coincidence?-reply. JAMA 1989;261 (3 ):382.2909775
19. Hesselmann J Kuhn M Ostendorf PC Acute alveolitis in ulcerative colitis: Extra-intestinal organ complication or drug side effect [in German]. Leber Magen Darm. 1991;21 (1 ):26–8, 31.2027303
20. Luo Q Zhou P Chang S . The gut-lung axis: Mendelian randomization identifies a causal association between inflammatory bowel disease and interstitial lung disease. Heart Lung 2023;61 :120–6.37247539
21. Korsunsky I Wei K Pohin M . Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med 2022;3 (7 ):481–518.e14.35649411
22. Ananthakrishnan AN . Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol 2015;12 (4 ):205–17.25732745
23. Papanikolaou I Kagouridis K Papiris SA . Patterns of airway involvement in inflammatory bowel diseases. World J Gastrointest Pathophysiol 2014;5 (4 ):560–9.25400999
24. Peradzyńska J Krenke K Lange J . Low prevalence of pulmonary involvement in children with inflammatory bowel disease. Respir Med 2012;106 (7 ):1048–54.22516040
25. Camus P Piard F Ashcroft T . The lung in inflammatory bowel disease. Medicine (Baltimore) 1993;72 (3 ):151–83.8502168
26. Marvisi M Fornasari G . Is the lung a target organ in inflammatory bowel disease? [in Italian]. Recenti Prog Med 2001;92 (12 ):774–7.11822102
27. Majewski S Piotrowski W . Pulmonary manifestations of inflammatory bowel disease. Arch Med Sci 2015;11 (6 ):1179–88.26788078
28. Casella G Villanacci V Di Bella C . Pulmonary diseases associated with inflammatory bowel diseases. J Crohns Colitis 2010;4 (4 ):384–9.21122533
29. Bachmann O Länger F Rademacher J . Pulmonary manifestations of inflammatory bowel disease [in German]. Internist (Berl) 2010;51 (S1 ):264–8.20107759
30. Rothfuss KS Stange EF Herrlinger KR . Extraintestinal manifestations and complications in inflammatory bowel diseases. World J Gastroenterol 2006;12 (30 ):4819–31.16937463
31. Kuzela L Vavrecka A Prikazska M . Pulmonary complications in patients with inflammatory bowel disease. Hepatogastroenterology 1999;46 (27 ):1714–9.10430329
32. Zhao Y Xia Y Liu Z . Clinical evaluation of lung function in 74 patients with inflammatory bowel disease. Chin J Digestion 2014:379–83.
33. Georgakopoulou VE Tarantinos K Papalexis P . Role of pulmonary function testing in inflammatory bowel diseases (Review). Med Int (Lond) 2022;2 (4 ):25.36699508
34. Chu TPC Moran GW Card TR . The pattern of underlying cause of death in patients with inflammatory bowel disease in England: A record linkage study. J Crohns Colitis. 2016;11 (5 ):578–85.
35. Duricova D Pedersen N Elkjaer M . Overall and cause-specific mortality in Crohn's disease: A meta-analysis of population-based studies. Inflamm Bowel Dis 2010;16 (2 ):347–53.19572377
36. Höie O Schouten LJ Wolters FL . Ulcerative colitis: No rise in mortality in a European-wide population based cohort 10 years after diagnosis. Gut 2007;56 (4 ):497–503.17028127
37. Jussila A Virta LJ Pukkala E . Mortality and causes of death in patients with inflammatory bowel disease: A nationwide register study in Finland. J Crohns Colitis 2014;8 (9 ):1088–96.24630486
