To the Editor:
Interstitial lung diseases (ILDs) are a group of diseases characterized by chronic fibrotic parenchymal remodeling leading to respiratory failure and, commonly, death. A subset of ILDs occur in patients with autoimmune or connective tissue disease (CTD) disease. However, some patients with ILD may have features of an autoimmune disease without meeting established diagnostic criteria for a specific CTD (1). Recently, consensus was achieved proposing nomenclature for these patients under the research classification of interstitial pneumonia with autoimmune features (IPAF) (2). Studies have now characterized features in patients classified with IPAF (3). However, prognostication remains challenging, and there is a lack of well-defined markers of mortality risk (4). Recent clinical observations in two common forms of ILD, namely idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP) have demonstrated an association between the presence of hypothyroidism and increased mortality (5, 6). IPAF classification is associated with features of autoimmunity and hypothyroidism is commonly the result of autoimmune mediated thyroid dysfunction (7). The impact of hypothyroidism on mortality in patients classified with IPAF is not known. We hypothesized that in patients meeting criteria for IPAF, a diagnosis of concomitant hypothyroidism would be associated with increased mortality.
To test our hypothesis, we reviewed electronic health records and abstracted clinical data from patients who were presented at the Multidisciplinary ILD Conference from February 2009 to August 2018 at the University of Michigan. This research was conducted with approval by the Institutional Review Board. All diagnoses were made by consensus with clinical–radiologic–pathologic review following American Thoracic Society and European Respiratory Society guidelines (8). In cases of suspected underlying rheumatologic disease, patients were evaluated by a rheumatologist and then re-presented at ILD conference for final diagnosis. If patients were not formally diagnosed with a CTD and met serologic, radiologic, and/or morphologic classification criteria for IPAF by American Thoracic Society/European Respiratory Society criteria (2), they were included in the cohort. A diagnosis of hypothyroidism was made based on a retrospective review of the clinical and medication record. All cases of hypothyroidism were identified before the Multidisciplinary ILD meeting, and no cases were identified by retrospective review of follow-up data. Categorical variables are presented as counts and percentages. Overall survival was assessed by evaluation of Kaplan-Meier curves with the log-rank test. Variables predictive of all-cause mortality were identified using a priori knowledge and univariable and multivariable Cox proportional hazards analysis using previously published reporting guidelines (9). The total survival time of subjects was defined as the observed time from multidisciplinary diagnosis to death, transplant, loss of follow-up, or end of study period. Lung transplantation was included with mortality as a composite endpoint. All analyses were performed with R version 4.0.3 (The R Foundation for Statistical Computing).
We identified 319 patients with IPAF who were discussed at the University of Michigan Multidisciplinary ILD conference from 2009 to 2018. The mean (standard deviation) age of the IPAF cohort was 62.5 (±11.3) years, with a female preponderance (53%:47% female:male). We identified by medical record review 62 (19.4%) patients with a clinical diagnosis of hypothyroidism and 257 (80.6%) patients without a clinical diagnosis of hypothyroidism at the time of multidisciplinary meeting. Demographics, clinical characteristics, IPAF domain classification, and relevant therapies are reported in Table 1. In our IPAF cohort, features confirming IPAF in most patients (n = 181, 57%) came from the serologic and morphologic domain. Surgical lung biopsy was performed in 118 (36.9%) patients, and most patients (n = 63) demonstrated a usual interstitial pneumonia (UIP) histologic pattern (Table 1). Most patients with a surgical biopsy of UIP were classified as having IPAF based on meeting criteria in the serological and morphological domain with similar frequency as patients without UIP (58.7% vs. 56.3%). A diagnosis of hypothyroidism was associated with an increased hazard ratio (HR) for mortality (HR, 2.31; 95% confidence interval [CI], 1.38–3.87; P = 0.001) in univariate analysis (Figure 1 and Table 2) that remained significant when the analysis was adjusted for patient age, sex, baseline forced vital capacity, diffusion capacity for carbon monoxide, and smoking history (HR, 2.02; 95% CI, 1.04–3.93; P = 0.037) (Table 2). This association was particularly strong in patients with IPAF aged 64 years or older (population median; unadjusted HR, 2.33; 95% CI, 1.21–4.47; P = 0.01; adjusted HR, 2.41; 95% CI, 1.04–5.59; P = 0.04). In the 118 patients with surgical lung biopsies, the association between hypothyroidism and mortality was significant in univariate analysis (HR, 2.81; 95% CI, 1.16–6.73; P = 0.02) and significance was maintained after adjusting for age, sex, baseline forced vital capacity, diffusion capacity of carbon monoxide, smoking history, and the presence of UIP on biopsy (HR, 4.29; 95% CI, 1.35–13.62; P = 0.01). Our results support our hypothesis that hypothyroidism is associated with increased mortality in IPAF and risk appears greater in older patients.
Table 1.
Characteristics of study participants in patient cohort classified as having interstitial pneumonia with autoimmune features
| All | Hypothyroidism | No Hypothyroidism | |
|---|---|---|---|
| Number (%) | 319 | 62 (19.4) | 257 (80.6) |
| Mean age at diagnosis, y (±SD) | 63.3 (11.1) | 66.5 (9.6) | 62.6 (11.3) |
| Sex, n (%) | |||
| Male | 149 (46.9) | 14 (23.8) | 135 (52.5) |
| Female | 170 (53.1) | 48 (76.2) | 122 (47.5) |
| Smoking history, n (%) | |||
| Nonsmoker | 180 (56.6) | 34 (55.5) | 146 (56.8) |
| Ever-smoker | 139 (43.4) | 28 (44.5) | 111 (43.2) |
| FVC, % predicted (±SD) | 68.3 (18.5) | 68.8 (18.0) | 68.0 (18.5) |
| DlCO, % predicted (±SD) | 48.9 (17.5) | 50.7 (16.0) | 48.5 (17.8) |
| IPAF Domains | |||
| All 3 | 90 (28.2) | 17 (27.0) | 73 (28.4) |
| Serological + clinical | 21 (6.5) | 3 (4.8) | 18 (7.0) |
| Serological + morphological | 181 (56.7) | 37 (60.3) | 144 (56.0) |
| Clinical + morphological | 27 (8.4) | 4 (7.9) | 23 (8.6) |
| Clinical, no, n (%) | |||
| Digital fissuring | 2 (0.6) | 0 (0) | 2 (0.8) |
| Digital ulceration | 2 (0.6) | 1 (1.6) | 1 (0.4) |
| Inflammatory arthritis | 77 (24.1) | 12 (19.4) | 65 (25.3) |
| Palmar telangectasia | 3 (0.9) | 1 (1.6) | 2 (0.8) |
| Raynauds phenomenon | 63 (19.7) | 13 (20.9) | 50 (19.4) |
| Digital edema | 11 (3.4) | 3 (4.8) | 8 (3.1) |
| Serological, no, n (%) | |||
| Anti-nuclear Ab | 146 (45.7) | 31 (50.0) | 115 (44.7) |
| Rheumatoid Factor | 44 (13.7) | 8 (12.9) | 36 (14.0) |
| Anti-CCP | 50 (15.6) | 8 (12.9) | 42 (16.3) |
| Anti-dsDNA | 28 (8.7) | 6 (9.6) | 22 (8.7) |
| Anti-SSa | 53 (16.6) | 11 (17.7) | 42 (16.3) |
| Anti-SSb | 6 (1.8) | 0 (0) | 6 (2.33) |
| Anti-RNP | 52 (16.3) | 7 (11.2) | 45 (17.5) |
| Anti-Sm | 10 (3.13) | 3 (4.8) | 7 (2.7) |
| Anti-Scl70 | 11 (3.4) | 2 (3.2) | 9 (3.5) |
| Anti-tRNA | 25 (7.8) | 5 (8.0) | 20 (7.7) |
| ANCA | 12 (3.8) | 3 (4.8) | 9 (3.5) |
| Morphological, no, n (%) | |||
| Radiographic NSIP | 234 (73.3) | 46 (74.2) | 188 (73.2) |
| Radiographic UIP | 61 (19.1) | 9 (14.5) | 52 (20.2) |
| Radiographic OP | 7 (2.3) | 2 (3.2) | 5 (1.9) |
| Radiographic LIP | 3 (0.9) | 0 (0) | 3 (1.2) |
| Other | 14 (4.) | 5 (8.1) | 9 (3.5) |
| Surgical lung biopsy | 118 (36.9) | 25 (40.3) | 93 (36.2) |
| UIP (Yes, %) | 63 (19.7) | 17 (26.9) | 46 (17.8) |
| Comorbidities, no, n (%) | |||
| COPD | 24 (7.5) | 3 (4.8) | 21 (8.2) |
| Asthma | 23 (7.2) | 4 (6.4) | 19 (7.4) |
| Obstructive Sleep Apnea | 81 (25.3) | 13 (20.9) | 68 (26.5) |
| Pulmonary HTN | 64 (20.0) | 13 (20.9) | 51 (19.8) |
| Diabetes Mellitus | 55 (17.2) | 11 (17.7) | 44 (17.1) |
| Cardiovascular disease | 33 (10.3) | 6 (9.7) | 27 (10.5) |
| GERD | 147 (46.0) | 28 (45.1) | 119 (46.3) |
| Cancer | 29 (9.1) | 5 (8.0) | 24 (9.33) |
| Therapy, no, n (%) | |||
| PPI therapy | 173 (54.2) | 34 (54.8) | 139 (54.1) |
| CSs | 137 (42.9) | 26 (41.9) | 111 (43.2) |
| CS duration, mean (range) | — | 8.8 (0–65) | 9.9 (0–100) |
| Azathioprine | 37 (11.6) | 7 (11.2) | 30 (11.6) |
| Mycophenolate | 87 (27.2) | 14 (22.5) | 73 (28.4) |
| Methotrexate | 2 (0.6) | 0 (0) | 2 (0.7) |
| CS + immunosuppression | 69 (21.6) | 15 (24.2) | 54 (21.0) |
| Pirfenidone | 21 (6.6) | 3 (4.8) | 18 (7.0) |
| Nintedanib | 22 (6.8) | 2 (3.2) | 20 (7.7) |
| Duration, mean (range) | — | 1.6 (0–38) | 2.3 (0–54) |
Definition of abbreviations: ANCA = antineutrophil cytoplasmic; CCP = cyclic citrullinated peptide; COPD = chronic obstructive pulmonary disease; CS = corticosteroid; DlCO = diffusion capacity for carbon monoxide; dsDNA = double-stranded deoxyribonucleic acid; FVC = forced vital capacity; GERD = gastroesophageal reflux disease; HTN = hypertension; IPAF = interstitial pneumonia with autoimmune features; LIP = lymphocytic interstitial pneumonia; NSIP = non-specific interstitial pneumonia; OP = organizing pneumonia; PPI = proton pump inhibitor; RNP = ribonucleoprotein; SSa = Sjögren’s syndrome–related antigen A; SSb = Sjögren's syndrome–related antigen B; Scl70 = scleroderma/70 kD extractable immunoreactive fragment or anti-topoisomerase I; SD = standard deviation; Sm = Smith; tRNA = aminoacyl-tRNA synthetase; UIP = usual interstitial pneumonia.
CS and Antifibrotic duration: mean months and range in months (minimum to maximum). No data were imputed. FVC missing data: n = 7 (n = 1 hypothyroidism cohort and n = 6 no hypothyroidism cohort). DlCO missing data: n = 15 hypothyroidism cohort and n = 42 no hypothyroidism cohort.
Figure 1.
Mortality is increased in patients meeting interstitial pneumonia with autoimmune features (IPAF) classification criteria with concomitant hypothyroidism. A total of 319 patients with IPAF were identified from the interstitial lung disease (ILD) multidisciplinary meeting records at the University of Michigan Medical Center from 2009 to 2018. A diagnosis of hypothyroidism was recorded from the medical record. Survival time was defined as the time from ILD multidisciplinary meeting to death, transplant, censored by end of study period, or loss of follow-up. Kaplan-Meier survival estimates above demonstrate increased mortality in patients classified as having IPAF with hypothyroidism (log-rank P = 0.001).
Table 2.
Association of hypothyroidism and mortality in patients meeting interstitial pneumonia with autoimmune features classification criteria
| Hazard Ratio | 95% Confidence Interval | P Value | |
|---|---|---|---|
| Univariable Analysis | |||
| Hypothyroidism | 2.31 | 1.38–3.87 | 0.001 |
| Age | 1.57 | 1.23–2.01 | <0.001 |
| Sex | 0.89 | 0.55–1.44 | 0.63 |
| FVC % predicted | 0.86 | 0.75–0.99 | 0.04 |
| DlCO % predicted | 0.92 | 0.78–1.07 | 0.27 |
| History of smoking | 1.05 | 0.69–1.60 | 0.82 |
| Multivariable Analysis | |||
| Hypothyroidism | 2.02 | 1.04–3.93 | 0.04 |
Definition of abbreviations: DlCO = diffusion capacity for carbon monoxide; FVC = forced vital capacity.
Cox proportional hazards model, hypothyroidism (reference) versus no hypothyroidism, male (reference) versus female, nonsmoker (reference) versus ever-smoker. Two-sided P values of less than 0.05 were considered significant (shown in bold). FVC and DlCO percent predicted at study baseline. Hazard ratio calculated by age per 10-yr increments, FVC per 10% increment increase, and DlCO per 10% increment increase. Multivariable model is adjusted for age, sex, baseline FVC percent predicted, baseline DlCO percent predicted, and smoking status.
Thyroid function is crucial to the maintenance of physiological homeostasis. Thyroid dysfunction is common in patients with lung fibrosis, thyroid antibodies are found at high concentrations in idiopathic interstitial pneumonia, and hypothyroidism is associated with an increased risk of mortality in IPF and CHP (5, 6, 10). A key finding in pulmonary fibrosis is features of metabolic stress at the alveolar epithelium correlating with mitochondrial dysfunction and epithelial cell loss with aberrant pulmonary wound healing and fibrosis (11). Recent work has identified mechanistic links between thyroid hormone signaling and aberrant mitochondrial function and morphology in type 2 transitional alveolar epithelial cells, key cellular contributors to progressive lung fibrosis (12). Indeed, recent findings point toward hypothyroidism as a possible causal determinant of pulmonary fibrosis (13). Given our limited understanding of IPAF, the observation that hypothyroidism is associated with mortality in our cohort suggests shared mechanistic pathways that require further study.
This study has notable limitations. The study is retrospective and may be subject to bias, and a single-center approach may not be relevant to common practice. We used the original IPAF proposal diagnostic criteria to render IPAF classifications; however, the study cohort was accrued over a prolonged period and includes recruitment before the original consensus publication. To partially address this limitation, data were reviewed in a multidisciplinary fashion to decrease inaccuracies in IPAF classification after completion of retrospective review of medical records and/or rheumatology review and multidisciplinary discussion. Our subgroup analysis is limited by sample size. The etiology of hypothyroidism was not able to be determined in all cases, and the effectiveness of treatment for hypothyroidism was not captured. The effects of etiology and therapy in relation to IPAF and mortality require further study. It is also possible that cases of hypothyroidism were not all recorded, as most are diagnosed and managed through primary care and may not have been captured by our retrospective medical record review.
Hypothyroidism is a relatively common comorbidity in ILD and may have a significant impact on outcomes. Our data suggest that patients with IPAF with hypothyroidism may be at increased risk of mortality, implying shared pathological mechanisms in progressive fibrotic lung diseases (14). Clinicians should be aware of the potential prognostic impact of hypothyroidism in IPAF and other forms of ILD.
Footnotes
Supported by National Heart, Lung, and Blood Institute grants R00HL139996 (D.N.O’D.) and R56HL155055 (D.N.O’D.) and National Institute of Arthritis and Musculoskeletal and Skin Diseases grant K24AR063120 (D.K.).
Author Contributions: P.V.M. and E.S.W. collected data and contributed to manuscript. D.N.O’D. and E.S.W. conceived manuscript and analyzed data. B.R.W., V.N., K.R.F., S.M., and D.K. contributed to data collection, analysis, and manuscript drafting. All authors have read and approved of the final manuscript submission.
Author disclosures are available with the text of this letter at www.atsjournals.org.
References
- 1. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest . 2011;140:1292–1299. doi: 10.1378/chest.10-2662. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. “ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD” An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J . 2015;46:976–987. doi: 10.1183/13993003.00150-2015. [DOI] [PubMed] [Google Scholar]
- 3. Sambataro G, Sambataro D, Torrisi SE, Vancheri A, Pavone M, Rosso R, et al. State of the art in interstitial pneumonia with autoimmune features: a systematic review on retrospective studies and suggestions for further advances. Eur Respir Rev . 2018;27:170139. doi: 10.1183/16000617.0139-2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Graney BA, Fischer A. Interstitial pneumonia with autoimmune features. Ann Am Thorac Soc . 2019;16:525–533. doi: 10.1513/AnnalsATS.201808-565CME. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Oldham JM, Kumar D, Lee C, Patel SB, Takahashi-Manns S, Demchuk C, et al. Thyroid disease is prevalent and predicts survival in patients with idiopathic pulmonary fibrosis. Chest . 2015;148:692–700. doi: 10.1378/chest.14-2714. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Adegunsoye A, Oldham JM, Husain AN, Chen L, Hsu S, Montner S, et al. Autoimmune hypothyroidism as a predictor of mortality in chronic hypersensitivity pneumonitis. Front Med (Lausanne) . 2017;4:170. doi: 10.3389/fmed.2017.00170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet . 2017;390:1550–1562. doi: 10.1016/S0140-6736(17)30703-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med . 2018;198:e44–e68. doi: 10.1164/rccm.201807-1255ST. [DOI] [PubMed] [Google Scholar]
- 9.Lederer DJ, Bell SC, Branson RD, Chalmers JD, Marshall R, Maslove DM, et al. Control of confounding and reporting of results in causal inference studies. Guidance for authors from editors of respiratory, sleep, and critical care journals. Ann Am Thorac Soc. 2019;16:22–28. doi: 10.1513/AnnalsATS.201808-564PS. [DOI] [PubMed] [Google Scholar]
- 10. Sato Y, Tanino Y, Nikaido T, Togawa R, Kawamata T, Wang X, et al. Clinical significance of thyroid hormone and antibodies in patients with idiopathic interstitial pneumonia. J Thorac Dis . 2020;12:522–537. doi: 10.21037/jtd.2020.01.02. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Mora AL, Bueno M, Rojas M. Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis. J Clin Invest . 2017;127:405–414. doi: 10.1172/JCI87440. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Yu G, Tzouvelekis A, Wang R, Herazo-Maya JD, Ibarra GH, Srivastava A, et al. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med . 2018;24:39–49. doi: 10.1038/nm.4447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Zhang Y, Zhao M, Guo P, Wang Y, Liu L, Zhao J, et al. Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis. EBioMedicine . 2021;73:103669. doi: 10.1016/j.ebiom.2021.103669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Varone F, Sgalla G, Iovene B, Richeldi L. Progressive fibrosing interstitial lung disease. A proposed integrated algorithm for management. Ann Am Thorac Soc . 2020;17:1199–1203. doi: 10.1513/AnnalsATS.202003-214PS. [DOI] [PubMed] [Google Scholar]