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Respiratory Research

, 20:182 | Cite as

Myelodysplastic syndromes and idiopathic pulmonary fibrosis: a dangerous liaison

  • Spyros A. Papiris
  • Panagiotis Tsirigotis
  • Caroline Kannengiesser
  • Lykourgos Kolilekas
  • Konstantinos Gkirkas
  • Andriana I. Papaioannou
  • Patrick Revy
  • Paschalina Giouleka
  • Georgia Papadaki
  • Konstantinos Kagouridis
  • Vassiliki Pappa
  • Raphael Borie
  • Catherine Boileau
  • Demosthenes Bouros
  • Bruno Crestani
  • Effrosyni D. ManaliEmail author
Open Access
Letter to the Editor

Abstract

Previous studies have shown that the co-existence of bone marrow failure and pulmonary fibrosis in a single patient or in a family is suggestive of telomere related genes (TRG) germline mutations. This study presents the genetic background, clinical characteristics, and outcome of a group of five Greek patients co-affected with IPF and MDS. Four out of five patients developed an IPF acute exacerbation that was not reversible. We failed to detect any mutation in the TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 genes in any patient. Moreover, telomere length was normal in the two patients tested. This could suggest that although the co-occurence of IPF and MDS are suggestive of TRG mutation in patients < 65 years old, in the elderly it may occur without germline mutations and could negatively affect prognosis. Physicians should be aware for possible IPF deterioration and therapeutic options for MDS should be wisely considered.

Abbreviations

ACD

Adrenocortical dysplasia

AML

Acute myeloid leukemia

CRP

C-reactive protein

DKC1

Dyskeratosis congenita 1

DLCO

Diffusing capacity for carbon monoxide

FVC

Forced vital capacity

GAP

Gender, age, lung physiology score

Ht

Hematocrit

IPF

Idiopathic pulmonary fibrosis

IPSS

International prognosis system score

MCV

Mean corpuscular volume

MDS

Myelodysplastic syndromes

NA

Not available

NAF1

Nuclear Assembly Factor 1 Ribonucleoprotein

NHP2

H/ACA ribonucleoprotein complex subunit 2

NOP10

H/ACA ribonucleoprotein complex subunit 3

PARN

Poly(A)-specific ribonuclease

PLTs

Platelets

PO2/FiO2

Ratio of arterial pressure of oxygen to fraction of inspired oxygen

RA

Refractory anemia

RAEB

Refractory anemia with excess blasts

RARS

Refractory anemia ring sideroblasts

RTEL1

Regulator of telomere length 1

TERC

Telomerase RNA component

TERT

Telomerase reverse transcriptase

TINF2

TERF1-interacting nuclear factor 2

TRG

Telomeres related genes

UIP

Usual interstitial pneumonia

WBC

White blood count

Both myelodysplastic syndromes (MDS) and idiopathic pulmonary fibrosis (IPF) constitute irreversible diseases of the elderly, and both share comorbidities that adversely affect their prognosis [1, 2]. Their co-occurrence exists and may relate to several factors including aging, but the impact of this type of liaison on each other’s prognosis has not yet received adequate attention [3, 4]. MDS presents with peripheral blood cytopenia, occasionally bone marrow fibrosis [1, 5] and encompasses a heterogeneous group of myeloid disorders that present increased risk to malignant transformation mainly to acute myeloid leukemia (AML) [1]. IPF is an irreversibly progressive fibrotic lung disorder [2]. Besides aging, the co-occurence of IPF and MDS has been reported in telomeropathies associated to telomeres related genes (TRG) [as telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC)] germline mutations [6, 7] and short-telomeres [8]. Mutations in TRG are identified in 30% of patients with familial pulmonary fibrosis [9]. Furthermore, mutations in TRG have been shown to carry an unfavorable prognosis for IPF patients undergoing lung transplantation since TRG mutations increase the risk of severe bone marrow suppression and infections, eventually related to immunosuppression [7]. This study aims to present the genetic background, clinical characteristics, and outcome of a group of five consecutive Greek patients co-affected with IPF and MDS. All patients were diagnosed and followed-up at the Hematology and Pulmonary Medicine Department of a tertiary university hospital in Athens from March 2015 to March 2016 and all of them were included in the study due to clinical suspicion of telomeropathy based on the conjunction of pulmonary fibrosis and myelodysplasia [10]. The study has been approved by the decision No 937/22–7-15 of the “Attikon” hospital’s bioethics committee.

After written informed consent, all patients diagnosed with both IPF and MDS, underwent genetic testing for TERT, TERC, Dyskeratosis congenita 1 (DKC1), TERF1-interacting nuclear factor 2 (TINF2), Regulator of telomere length 1 (RTEL1), poly(A)-specific ribonuclease (PARN), Nuclear Assembly Factor 1 Ribonucleoprotein (NAF1), Adrenocortical dysplasia (ACD), H/ACA ribonucleoprotein complex subunit 2 (NHP2) and H/ACA ribonucleoprotein complex subunit 3 (NOP10) by next generation sequencing. Two of the five patients had their telomere lengths measured in peripheral blood cells by the telomeric restriction fragment (TRF) assay as already described [11]. IPF was diagnosed according to international consensus criteria [2] and MDS diagnosis was documented based on the World Health Organization 2016 classification criteria [5]. Autoimmune rheumatic diseases were excluded based on the absence of signs and symptoms of collagen vascular disease as well as on negative serological examination [2]. Patients’ data are reported in Table 1.
Table 1

Epidemiological, clinical, pulmonary function, hematology parameters, outcome and genetic background of 5 Greek patients with IPF and MDS

Parameters

#1

#2

#3

#4

#5

Gender

F

M

M

M

M

Age at IPF diagnosis (years)

74

82

74

78

84

Age at MDS diagnosis (years)

78

81

80

79

83

Age at death (years)

82

81

79

84

Duration of treatment with azacytidine (months)

0

14

9

1

0

Status

Alive

Dead

Dead

Dead

Dead

Time to death from diagnosis of IPF (months)

3

77

24

1

HRCT pattern

UIP

UIP

Probable UIP

Probable UIP

Probable UIP

Lung histology

UIP

UIP

Serology for CTD

negative

negative

negative

negative

negative

FVC % pred

88.6

80.8

70.5

68

DLCO % pred

59.2

58.3

77

65

GAP stage

I

III

I

II

II

WHO 2008 classification

RARS

RAEB II

RAEB I

RAEB I

RA

IPSS score

Low

Intermediate 2

Very high

Intermediate 1

Low

Treatment

Azacytidine

Azacytidine

Azacytidine

Cycles azacytidine

6

2

6

PO2/FiO2

357

118

137.5

142

73

Ht %

33.9

26.2

29.4

37.9

34.3

MCV (fL)

109.4

78.2

116.5

105.6

90.3

Neutrophils (G/L)

3210

600

540

1210

6700

PLT (G/L)

300

91

171

137

365

CRP (mg/L)

< 3

49.5

100

94.8

100

Family history

Yesa

No

No

No

No

TRG mutation

No

No

No

No

No

Telomere length (Kb)

10.9

NA

NA

NA

9.1

IPF idiopathic pulmonary fibrosis, CTD collagen vascular disease, HRCT high resolution computed tomography, MDS myelodysplastic syndrome; #: patient, UIP usual interstitial pneumonia, RARS refractory anemia ring sideroblasts, RAEB refractory anemia with excess blasts, RA refractory anemia, FVC forced vital capacity, DLCO diffusing capacity for carbon monoxide, GAP gender, age, lung physiology score, PO2/FiO2 ratio of arterial pressure of oxygen to fraction of inspired oxygen, IPSS international prognosis scoring system, Ht hematocrit, WBC white blood count, MCV mean corpuscular volume, PLT platelets, CRP C-reactive protein, NA not available, TRG telomere related gene. Family history: aMother died from liver cirrhosis. PO2/FiO2, Ht%, MCV, Neutrophils, PLT, Temperature, CRP regard the time point of the final respiratory event; the rest of the measurements regard baseline values

Five patients, with both IPF and MDS, four males, with a mean age of 80 (+/− 6) years, 60% ex- smokers were studied. Pulmonary function and hematology parameters are reported in Table 1. IPF diagnosis predated MDS diagnosis in three patients by 48, 77 and 18 months respectively. No patient received any anti-fibrotic or immunosuppressive agent. (Table 1). TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 germline mutations were not detected in any patient. The telomere length was not pathologically reduced in the two patients tested (Table 1). MDS was classified as refractory anemia (RA) and RA with ring sideroblasts (RARS) in two patients both presenting low values for the international prognosis system score (IPSS). MDS was classified as RA with excess blasts (RAEB) in three patients presenting intermediate-1, intermediate-2 and high values for IPSS respectively (Table 1). RAEB patients were treated with azacytidine 75 mg/m2 subcutaneously for 7 days every 4 weeks [1, 5] and two of them developed acute leukemia. Four patients (including the three patients who received azacytidine) developed a fatal IPF acute exacerbation despite intensive supportive care, 12 (1–77) months post IPF diagnosis, 13 [9, 10, 11, 12, 13, 14] months post MDS diagnosis and 9 [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14] months post MDS treatment initiation with azacytidine.

Based on this case-series four out of five patients with the co-existence of IPF and MDS developed an IPF acute exacerbation that was not reversible. An extensive work-up was performed to exclude obvious causes of the deterioration such as infection, aspiration or drug toxicity [12]. Although azacytidine has been used safely in elderly patients and has been shown to significantly improve survival and quality of life [13], our observations suggest that this drug may not be as effective in patients with both IPF and MDS. Azacytidine is a hypomethylating agent and re-expression of tumor-suppressor genes has been suggested as a possible mechanism of action. However, hypomethylating activity is global and Azacytidine has a pleotropic effect on the immune system and could trigger the development of diffuse alveolar damage upon usual interstitial pneumonia through either an eventual toxicity of the drug to the lungs [1, 13] or infection because of the increased immunosuppression upon the vulnerable lungs of IPF patients [12, 14, 15, 16].

Despite previous studies showing that the co-existence of bone marrow failure and pulmonary fibrosis in a single patient or in a family is very suggestive of TRG germline mutations [6, 7], we failed to detect any mutation in the TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 genes in any patient. Moreover, telomere length was normal in the two patients tested. In the study of Parry and co-workers [6] all patients were much younger compared to our patients with 6 out of 10 presenting with aplastic anemia in childhood or early adulthood and 4 out of them presenting with pulmonary fibrosis at an age younger than 61 years. Furthermore, all patients had a positive family history of either pulmonary fibrosis and MDS or aplastic anemia. The patients of the present study were much older and only one of them had a positive family history suggestive of short telomere syndrome.

Therefore, although the co-occurrence of IPF and MDS are suggestive of TRG mutation in patients < 65 years old, in the elderly it may develop without germline mutations or may relate to mutations in other genes that are still unknown. Both IPF and MDS are diseases of the elderly and may be triggered by physiologic aging processes affecting both the lungs and the bone marrow, such as stem cell exhaustion, mitochondrial dysfunction, epigenetic alterations and disturbances of DNA methylation [3, 4].

Conclusion

This case series suggests that in the elderly patients the co-occurrence of IPF and MDS may develop without germline mutations and could negatively affect prognosis. Physicians should be aware for possible IPF deterioration and therapeutic options for MDS should be wisely considered.

Notes

Acknowledgments

Not applicable.

Authors’ contributions

SAP designed the study, contributed significantly to the interpretation of data and wrote the manuscript, PT contributed significantly to the collection and interpretation of data and wrote part of the manuscript, CK performed the genetic testing for all patients, contributed significantly at the interpretation of data and wrote part of the manuscript, LK contributed significantly to the collection and interpretation of data and critically revised the final version of the manuscript, KG contributed significantly to the collection and interpretation of data and wrote part of the manuscript, AIP performed the statistical analysis and significantly contributed to the interpretation of data, PR performed the measurement of telomere length, contributed significantly to the interpretation of data and wrote part of the manuscript, PG, GP, KK, VP, RB, CB, DB contributed significantly to the interpretation of data and critically revised the final version of the manuscript, BC and EDM participated at the design of the study, contributed significantly to the collection and interpretation of data, coordinated the whole team and wrote with SAP the final version of the manuscript. All authors read and approved the final manuscript.

Funding

1. F.Hoffmann-La Roche, 2. Chancellerie des Universités de Paris (Legs Poix)

Ethics approval and consent to participate

All patients gave written informed consent to participate in the study. The study has been approved by the decision No 937/22–7-15 of the “Attikon” hospital’s bioethics committee.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

  1. 1.
    Garcia-Manero G. Myelodysplastic syndromes: 2015 update on diagnosis, risk stratification and management. Am J Hematol. 2015;90:831–41.CrossRefGoogle Scholar
  2. 2.
    Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824.CrossRefGoogle Scholar
  3. 3.
    Selman M, Buendía-Roldán I, Pardo A. Aging and Pulmonary Fibrosis. Rev Investig Clin. 2016;68:75–83.Google Scholar
  4. 4.
    Visconte V, Tiu RV, Rogers HJ. Pathogenesis of myelodysplastic syndromes: an overview of molecular and non-molecular aspects of the disease. Blood Res. 2014;49:216–27.CrossRefGoogle Scholar
  5. 5.
    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.CrossRefGoogle Scholar
  6. 6.
    Parry EM, Alder JA, Qi X, Chen JJ, Armanios M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood. 2011;117:5607–11.CrossRefGoogle Scholar
  7. 7.
    Borie R, Kannengiesser C, Hirschi S, Le Pavec J, Mal H, Bergot E, et al. Severe hematologic complications after lung transplantation in patients with telomerase complex mutations. J Heart Lung Transplant. 2015;34:538–46.CrossRefGoogle Scholar
  8. 8.
    Alder JK, Hanumanthu VS, Strong MA, DeZern AE, Stanley SE, Takemoto CM, et al. Diagnostic utility of telomere length testing in a hospital-based setting. Proc Natl Acad Sci U S A. 2018;115:E2358–65.CrossRefGoogle Scholar
  9. 9.
    Borie R, Kannengiesser C, Nathan N, Tabèze L, Pradère P, Crestani B. Familial pulmonary fibrosis. Rev Mal Respir. 2015;32:413–34.CrossRefGoogle Scholar
  10. 10.
    Borie R, Tabèze L, Thabut G, Nunes H, Cottin V, Marchand-Adam S, et al. Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis. Eur Respir J. 2016;48:1721–31.CrossRefGoogle Scholar
  11. 11.
    Kannengiesser C, Borie R, Ménard C, Réocreux M, Nitschké P, Gazal S, et al. Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis. Eur Respir J. 2015;46:474–85.CrossRefGoogle Scholar
  12. 12.
    Papiris SA, Manali ED, Kolilekas L, Kagouridis K, Triantafillidou C, Tsangaris I, et al. Clinical review: idiopathic pulmonary fibrosis acute exacerbations--unravelling Ariadne’s thread. Crit Care. 2010;14:246.CrossRefGoogle Scholar
  13. 13.
    Ritchie EK. Safety and efficacy of azacitidine in the treatment of elderly patients with myelodysplastic syndrome. Clin Interv Aging. 2012;7:165–73.CrossRefGoogle Scholar
  14. 14.
    Toma A, Fenaux P, Dreyfus F, Cordonnier C. Infections in myelodysplastic syndromes. Haematologica. 2012;97:1459–70.CrossRefGoogle Scholar
  15. 15.
    Molyneaux PL, Cox MJ, Willis-Owen SA, Mallia P, Russell KE, Russell AM, et al. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2014;190:906–13.CrossRefGoogle Scholar
  16. 16.
    Wolff F, Leisch M, Greil R, Risch A, Pleyer L. The double-edged sword of (re) expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation. Cell Commun Signal. 2017;15:13.CrossRefGoogle Scholar

Copyright information

© The Author(s). 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Spyros A. Papiris
    • 1
  • Panagiotis Tsirigotis
    • 2
  • Caroline Kannengiesser
    • 3
    • 4
    • 8
  • Lykourgos Kolilekas
    • 5
  • Konstantinos Gkirkas
    • 2
  • Andriana I. Papaioannou
    • 1
  • Patrick Revy
    • 4
    • 6
  • Paschalina Giouleka
    • 1
  • Georgia Papadaki
    • 1
  • Konstantinos Kagouridis
    • 1
  • Vassiliki Pappa
    • 2
  • Raphael Borie
    • 7
    • 8
  • Catherine Boileau
    • 3
    • 4
  • Demosthenes Bouros
    • 9
  • Bruno Crestani
    • 4
    • 7
    • 8
  • Effrosyni D. Manali
    • 1
    Email author
  1. 1.2nd Pulmonary Medicine DepartmentGeneral University Hospital “Attikon” Medical School, National and Kapodistrian University of AthensAthensGreece
  2. 2.2nd Department of Internal Medicine, Hematology UnitGeneral University Hospital “Attikon” Medical School, National and Kapodistrian University of AthensAthensGreece
  3. 3.APHP Service de GénétiqueHôpital BichatParisFrance
  4. 4.Université de ParisParisFrance
  5. 5.7th Pulmonary DepartmentAthens Chest Hospital “Sotiria”AthensGreece
  6. 6.INSERM UMR 1163, Laboratory of GenomeDynamics in the Immune System, Imagine Institute, labéllisé Ligue contre le cancerParisFrance
  7. 7.APHP, Hôpital Bichat, Service de Pneumologie ADHU FIRE Centre de référence des maladies pulmonaires raresParisFrance
  8. 8.Inserm U1152ParisFrance
  9. 9.1st Department of Pneumonology, Athens Chest Hospital “Sotiria”, Athens, Medical SchoolNational and Kapodistrian University of AthensAthensGreece

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