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201807-1258LE
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Increasing Hypersensitivity Pneumonitis-Related Mortality in the United States

from 1988 to 2016

Evans R. Fernández Pérez MD, MS;1 David Sprunger, MD;2 Pailin Ratanawatkul;3 Lisa A. Maier,

MD, MSPH,4 Tristan J. Huie, MD;1 Jeffrey J. Swigris, DO, MS;1 Joshua J. Solomon, MD;1 Michael

Mohning, MD;1 Rebecca C. Keith, MD;1 Kevin K. Brown, MD1

Institutional Affiliations:

1. Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver,

CO, USA.

2. Division of General Surgery, University of Colorado, Aurora, CO, USA.

3. Division of Pulmonary and Critical Care Medicine, Faculty of Medicine, Khon Kaen

University, Thailand.

4. Division of Occupational Health and Environmental Health Sciences, National Jewish

Health, Denver, CO, USA.

Correspondence to:
Evans R. Fernández Pérez, M.D., M.S.
Associate Professor of Medicine
Division of Pulmonary, Critical Care and Sleep Medicine
Interstitial Lung Disease Program and Autoimmune Lung Center
National Jewish Health; Southside Building, Office #G12
1400 Jackson Street, Denver, CO 80206
E-mail: Fernandezevans@njhealth.org

ARTICLE TYPE: Research letter

FUNDING: none
KEY WORDS: hypersensitivity pneumonitis; clinical epidemiology

Conception and design: EFP; Analysis: EFP, DS, PR; Interpretation and drafting the manuscript
for important intellectual content: EFP, DS, PR, LM, TH, JSw, JSol, MM, RK, KB

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To the Editor,

Hypersensitivity pneumonitis (HP) is an immunologically mediated form of diffuse lung disease,

and results from an inhaled exposure to a large variety of antigens. While some patients

develop acute disease, with resolution after removal from exposure, in a significant subgroup of

patients, persistent disease complicated by progressive pulmonary fibrosis, occurs.(1, 2)

Population-level mortality from HP, in the United States, has not been well-characterized.(3) By

evaluating the National Center for Health Statistics multiple cause-of-death (MCOD) database,

we aimed to determine the overall burden of HP by describing temporal trends in HP-related

mortality across population subgroups and by examining the underlying cause-of-death (UCD).

Some of the results of this study have been previously reported in an abstract.(4)

METHODS

Data sources and case definitions

We analyzed the files for 1988-2016 stored in the MCOD database.(5) MCOD data designates

one UCD (defined by the World Health Organization as “the disease or injury which initiated the

train of events leading to death”) and up to 20 additional contributing causes-of-death. Deaths

from HP as the underlying or contributing cause-of-death were coded according to the 9th

International Classification of Diseases (ICD) for 1988-1998 and the 10th ICD after 1999.

We captured all HP-related mortality as death with ICD-9 495.x or ICD-10 J67.x (HP) and ICD-9

506.x or ICD-10 J68.x (pneumonitis due to inhalation of chemicals, gases, fumes or vapors). The

latter diagnosis code was included since limited data exist regarding the epidemiological burden

of HP cause by low-molecular-weight compounds. For example, chemical manufacturing and

processing, especially when isocyanates and anhydrides are used for paint spraying and epoxy

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manufacture are well described causal agents.(6, 7) We excluded other causes known to cause

interstitial lung disease, including connective tissue diseases, radiation fibrosis,

pneumoconiosis, and sarcoidosis.

The yearly mortality rate from HP was calculated stratified by sex, race, age-groups and

geography.

Statistical analysis

The years in the study period at which change in mortality trend occurred and was statistically

significantly different (i.e. increased or decreased trend) or remained stable, the annual

percentage change (APC), and the average APC from 1988 to 2016 was computed with the

Joinpoint software (version 4.6.0). Incidence rate ratios were calculated using Poisson

regression. Age-adjusted rates were computed by the direct method(8) to the projected year

2000 U.S. population. Years of potential life lost to age 75 were calculated using the method

described by the Centers for Disease Control.(9) Data was analyzed using JMP 13.1 (SAS

Institute, Cary, NC).

RESULTS

There were 69,316,867 deaths in the United States during the study period, and 1,904 MCOD

records contained a code for HP (UCD 88%, 1680/1904; contributing cause-of-death 12%,

224/1904). Decedents with HP were predominantly male (60%) and white (87%, table), with an

average age of 7013 years.

The age-adjusted HP-related mortality rate increased from 0.12 per 1,000,000 in 1988 to 0.68

per 1,000,000 persons in 2016 (figure). The average annual percent increase in the age-

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adjusted HP-related mortality rate was about 0.8% per year from 1988 through 1999 but

increased to 7.6% per year from 1999 through 2016.

The age-adjusted HP-related mortality rate increased among women (from 0.06 per 1,000,000

in 1988 to 0.52 per 1,000,000 women in 2016, P<0.01) and men (from 0.18 per 1,000,000 in

1988 to 0.59 per 1,000,000 men in 2016, P<0.01). The greatest increase in HP-related deaths

was among non-Hispanic whites (P<0.01). The overall crude mortality rate was 0.28 per

1,000,000 under age 75 (95% CI, 0.22-0.34). HP decedents lost 15,557 (mean/year 66, CI 55-78)

years of life to age 75.

Overall, HP mortality rates by region were higher in the Midwestern U.S. and increased with

age, in particular among adults 65 years (table).

DISCUSSION

These results demonstrate that over nearly three decades, the recognized mortality rate of HP

in the United States has grown significantly. The age-adjusted mortality rate was higher in

whites than in other racial groups suggesting that genetic differences between-ethnic/racial-

groups may play a role in susceptibility to HP and/or disease behavior, although we cannot

exclude a contribution in exposure. Also, we identified notable differences in HP by age and

gender. Although this study is meant to describe population-level phenomena, our results

align with others implicating aging-related mechanisms in HP pathogenesis.(10) Our data also

highlight the impact of HP on premature death.

The reason for the difference in mortality rates between men and women is unknown, but we

speculate that it might reflect potential differences in exposures. Region-specific variations in

HP mortality could reflect differences in occupational exposure across states. Farm- and

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agricultural-related antigens are common causes of HP,(7) probably explaining why Vermont,

South Dakota and Wisconsin had the highest mortality rates (table legend).

This study has limitations. First, as with any other study that includes death certificate data,

inaccuracies on death certificates or in the coding of information on the certificate are possible.

There is no way to assess the fidelity of either; thus, results should be considered best

estimates. Second, despite increased HP awareness in recent years, the absence of evidence-

based diagnostic guidelines, a variable case definition, and the myriad clinical phenotypes of HP

may promote coding inconsistencies and favor disease underestimation. Third, the study

period covered trends in mortality between ICD–9 and ICD–10 possibly resulting in the sudden

artificial changes in mortality rates from 1998-1999 (figure). However, from 1988 to 2016, we

found one Joinpoint in the trends of HP mortality at 2012 (figure) and not during the ICD

transition. Furthermore, while mortality rates remained stable from 1988 through 1999, it

increased from 1999 through 2016. Fourth, the increasing trend in the number of reported

deaths may reflect an aging population or increased disease recognition rather than true

patterns in mortality rates. However, we observed increasing mortality rates from HP even

when adjusting for the age distribution of the population.

Recognizing the limitations, these data suggest that age-adjusted HP-related mortality rate

increased from 1998 through 2016, and that mortality rates rise with increasing age. Rates

were highest in men, in non-Hispanic whites, and predominantly in the Midwestern United

States.

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REFERENCES

1. Fink JN, Ortega HG, Reynolds HY, Cormier YF, Fan LL, Franks TJ, Kreiss K, Kunkel S, Lynch D,

Quirce S, Rose C, Schleimer RP, Schuyler MR, Selman M, Trout D, Yoshizawa Y. Needs

and opportunities for research in hypersensitivity pneumonitis. Am J Respir Crit Care

Med 2005; 171: 792-798.

2. Fernandez Perez ER, Brown KK. Fibrotic hypersensitivity pneumonitis. Curr Resp Care Rep

2014; 3: 170-178.

3. Fernandez Perez ER, Kong AM, Raimundo K, Koelsch TL, Kulkarni R, Cole AL. Epidemiology of

Hypersensitivity Pneumonitis among an Insured Population in the United States: A

Claims-based Cohort Analysis. Ann Am Thorac Soc 2018; 15: 460-469.

4. Fernández Pérez ER, Sprunger D, Olson AL, Swigris JJ. Hypersensitivtiy Pneumonitis

Associated Mortality in the U.S. Am J Respir Crit Care Med 2017; 195: A1565.

5. CDC - National Center for Health Statistics. Accessed 2018 June 14. Available from:

http://www.cdc.gov/nchs/.

6. Selman M, Pardo A, King TE, Jr. Hypersensitivity pneumonitis: insights in diagnosis and

pathobiology. Am J Respir Crit Care Med 2012; 186: 314-324.

7. Bang KM, Weissman DN, Pinheiro GA, Antao VC, Wood JM, Syamlal G. Twenty-three years of

hypersensitivity pneumonitis mortality surveillance in the United States. Am J Ind Med

2006; 49: 997-1004.

8. Klein RJ, Schoenborn CA. Age adjustment using the 2000 projected U.S. population. Healthy

People 2010 Stat Notes 2001: 1-10.

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9. Premature mortality in the United Sates: public health issues in the use of years of potential

life lost. Accessed 2018 June 14. Available from:

https:/www.cdc.gov/mmwr/preview/mmwrhtml/00001773.htm.

10. Selman M, Rojas M, Mora AL, Pardo A. Aging and interstitial lung diseases: unraveling an old

forgotten player in the pathogenesis of lung fibrosis. Semin Respir Crit Care Med 2010;

31: 607-617.

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Table. Average annual age-adjusted hypersensitivity pneumonitis–related mortality, incidence

rate ratios and average annual percent change in mortality rates by demographic characteristic

in the United States, 1988–2016.

Age-adjusted Rate
Number of Incidence Rate Average Annual Percent Change (95% CI) II
Variable Per 1,000,000
Decedents *, †, ‡ Ratio (95% CI) 1988-1999 1999-2016 1988-2016
(95% CI)
Overall 1,904 (100%) 0.23 (0.18, 0.28) - 0.8 (-5.1, 7.0) 7.6 (4.2, 11.1) 5.6 (3.8, 7.4)
Gender
Male 1138 (60%) 0.28 (0.22, 0.34) 1.55 (1.24, 1.86) -0.60 (-4.8, 3.8) 7.5 (3.3, 11.9) 4.8 (2.9, 6.7)
Female 766 (40%) 0.18 (0.13, 0.22) Referent 0.94 (-10.8, 14.3) 7.8 (3.6, 12.1) 5.5 (2.7, 8.3)
Race ll
Non-Hispanic White 1,663 (87%) 0.29 (0.23, 0.36) 4.14 (2.46, 5.82) 1.70 (-3.4, 7.1) 7.6 (3.9, 11.3) 5.8 (4.0, 7.6)
Hispanic 133 (7%) 0.10 (0.07, 0.14) 1.43 (0.57, 2.29) 0.20 (-8.6, 9.9) 6.9 (-1.0, 15.4) 4.1 (0.6, 7.8)
Black (non-Hispanic) 73 (4%) 0.07 (0.04, 0.10) Referent -10.3 (-55.9, 82.7) 8.6 (3.7, 13.6) 3.8 (0.2, 7.5)
Census Region **
Northeast 332 (17%) 0.34 (0.24, 0.44) 2.12 (1.60, 2.64) -6.06 (-14.6, 3.4) 8.0 (3.6, 12.6) 3.9 (1.8, 6.1)
South 498 (26%) 0.16 (0.13, 0.20) Referent 0.24 (-14.0, 16.6) 6.3 (-0.5, 13.6) 3.1 (-0.4, 6.7)
Midwest 592 (31%) 0.42 (0.33, 0.52) 2.62 (2.07, 3.17) -1.55 (-7.4, 4.7) 7.4 (3.7, 11.2) 4.8 (2.8, 6.9)
West 482 (25%) 0.27 (0.20, 0.34) 1.69 (1.30, 2.08) 5.37 (-1.7, 13.0) 5.6 (0.6, 11.0) 4.4 (1.6, 7.4)
Age Groups, years §
44 82 (4%) 0.01 (0.01, 0.02) Referent -2.10 (-7.3, 3.4) 1.24 (-1.5, 4.0) 0.1 (-1.2, 1.3)
45-54 162 (8%) 0.03 (0.02, 0.03) 3.00 (2.09, 3.91) 6.11 (-2.6, 15.6) 6.0 (1.3, 11) 4.4 (1.5, 7.4)
55-64 352 (18%) 0.08 (0.06, 0.10) 8.00 (5.93, 10.07) -2.88 (-9.4, 4.1) 9.8 (4.9, 15.0) 6.8 (3.9, 9.7)
65-74 540 (28%) 0.18 (0.14, 0.22) 18.00 (13.26, 22.74) 0.30 (-3.6, 4.3) 7.0 (2.8, 11.3) 5.9 (3.7, 8.2)
75-84 534 (28%) 0.30 (0.25, 0.35) 30.00 (23.51, 36.49) 1.42 (-2.1, 5.1) 6.0 (3.3, 8.8) 4.6 (3.1, 6.2)
85 234 (12%) 0.38 (0.22, 0.54) 38.00 (26.18, 49.82) -0.18 (-9.5, 10.1) 13.0 (9.0, 17.2) 7.4 (4.6, 10.3)
* To avoid misclassification of hypersensitivity pneumonitis (HP) exclusionary codes included: diffuse connective tissue disease
[ICD-9 710; ICD-10 M30-M36], rheumatoid arthritis and other inflammatory polyarthropathies [ICD-9 714; ICD-10 M05, M06,
M08], radiation fibrosis [ICD-9 508.1; ICD-10 J70.1], pneumoconiosis [ICD-9 500; ICD-10 J60], asbestosis [ICD-9 501; ICD-10 J61],
silicosis or talcosis [ICD-9 502; ICD-10 J62], berylliosis and other inorganic dusts [ICD-9 503; ICD-10 J63], unspecified
pneumoconiosis [ICD-9 505; ICD-10 J64], sarcoidosis [ICD-9 135; ICD-10 D86], pulmonary alveolar proteinosis/other interstitial
pulmonary diseases [ICD-9 code 516; ICD-10 J84.0], other specified interstitial pulmonary diseases ICD-9 code 516.8; ICD-10
J84.2; J84.8], and respiratory conditions due to other external agents [ICD-9 508.9; ICD-10 J70]. From a total of 1,927
hypersensitivity pneumonitis cases, 23 contained one of these codes and were excluded (final N = 1,904).
† Hypersensitivity pneumonitis was a contributing cause of death in 224 cases. The underlying-cause-of-death in these cases
included: cardiovascular (ICD-9 390-459, ICD-10 I00-I99; 52 [23%]), malignancy (ICD-9 140-239, ICD-10 C00-D49; 44 [20%]),
pulmonary fibrosis (ICD-9 515, IC-10 J84.1; 38 [17%]), chronic obstructive pulmonary disease (ICD-9 490-492, ICD-10 J40-J44; 19
[8%]), infection (ICD-9 001-139, ICD-10 A00-B99; 17 [8%]), renal (ICD-9 580-629, ICD-10; N00-N99; 94 [2%]), and miscellaneous
causes 50 (22%).
‡ The most common sub-classifications of HP were unspecified HP 1,380 (72%), farmer’s lung (ICD-9 495.0, ICD-10 J67.0;369
[19%]), avian-related HP (ICD-9 495.2, ICD-10 J67.2; 63 [3%]) and pneumonitis due to inhalation of chemicals, gases, fumes or
vapors (ICD9 506.0, 506.2-506.9, ICD-10 J68.0, J68.2-J68.9; 58 [3%]). Excluding the latter group produced similar HP estimates.
§ Unable to calculate age-adjusted rates for age groups. These numbers represent crude rates and CIs. To compute annual
crude mortality rates, the total number of decedents with HP coded in a given year was divided by the corresponding mid-
interval population in the same year (July 1st intercensal population estimates). All population estimates were obtained from
the U.S. Bureau of the Census (https://www.census.gov/en.html).
ll Other race groups excluded because of small population size and large variance, making rate estimates unreliable.
** States with the highest mean age-adjusted mortality rate (per million population) by Census Region included: Northeast

(Vermont 1.52 [0.8-2.3], Maine 0.33 [0.15-0.51], Pennsylvania 0.29 [0.21-0.37]), South (North Carolina 0.39 [0.30-0.48], South

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Carolina 0.27 [0.17-0.38], West Virginia 0.21 [0.08-0.33]), Midwest (South Dakota 0.92 (0.43-1.41) Wisconsin 0.87 (0.61-1.5),
Iowa 0.58 [0.37-0.80].), and in the West (Wyoming 0.69 [0.28-1.10], Idaho 0.53 [0.17-0.90], Oregon 0.49 [0.23-0.76]).
II These time periods were selected in order to assess trends before and after the ICD-9 to ICD-10 transition. The Joinpoint

software (Version 4.6.0) was run with a minimum of three observed time points in the beginning and ending line segments
(including the joinpoint), and a minimum of four observed time points in a middle line segment (including the two joinpoints). A
maximum of two joinpoints were searched for using the Grid search algorithm, the permutation test, and an overall alpha level
of 0.05.

Figure. Age-adjusted mortality rates in decedents with hypersensitivity pneumonitis by race

and gender per 1,000,000 population, 1988–2016.*

*Mortality rates are standardized for age to the 2000 United States Census population.
The figure includes the temporal trends of the overall HP age-adjusted mortality as multiple cause-of-death in the United States
(0.23; 95% CI 0.18 to 0.28). From 1988 through 2016, two periods were identified by the joinpoint program: 1988-2012 (APC
1.8%; 95% CI 0.2% to 3.3%) and 2012-2016 (APC 31.8%;95% CI 20.9% to 43.7%). Average APC from 1988 to 2016: 5.6%; 95% CI
3.8% to 7.4%.
The overall age-adjusted mortality rate from HP as the underlying cause-of-death (0.19; 95% CI 0.16 to 0.24) also showed
similar trends: 1988-2010 (APC 1.3%; 95% CI -0.5% to 3.3%) and 2010-2016 (APC 19.0%; 95% CI 11.7% to 26.9%. Average APC
from 1988 to 2016: 4.9%; 95% CI 2.9% to 6.9%.
APC, annual percent change.

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1.00

0.90

0.80
Mortality Rate per 1,000,000 Population

0.70

0.60

0.50 ICD-9 to ICD-10 transition

0.40

0.30

0.20

0.10

0.00
1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016
Year
Mortality Rates, non-Hispanic White Mortality Rates, Hispanic
Mortality Rates, non-Hispanic Black Mortality Rates, Males
Mortality Rates, Females Copyright © 2019 by the American Thoracic Society Mortality Rates, Overall