Unmasking catamenial hemoptysis in the era of CFTR modulator therapy

TES is a rare entity that can affect women of child-bearing age and is defined by the presence of endometriosis implants in the lungs and/or pleural space [ 2 – 3 ]. The prevalence of TES in CF women is unknown. A retrospective chart review conducted at our adult CF center identified four women with documented catamenial hemoptysis in the prior 10 years. However, we suspect the prevalence of catamenial hemoptysis is underestimated due to lack of acquisition and documentation of menstrual history. Catamenial hemoptysis accounts for <7% of TES cases [ 3 ]. Additional clinical manifestations of TES include catamenial pneumothorax, catamenial hydropneumothorax, and/or pulmonary nodules.[ 3 ] Diagnostic evaluation of catamenial hemoptysis may include a chest CT and airway inspection with bronchial brushings and/or tissue biopsies. Ground-glass consolidations are the most common finding on chest imaging. Airway inspection with bronchoscopy performed within 24–48 hours of menstruation in case-series have demonstrated erythematous lesions with bronchial brushings confirming endometrial tissue. However, the diagnostic value of bronchial brushings and/or biopsies is unknown.[ 2 , 3 , 4 ]. Although the occurrence of catamenial hemoptysis is rare, this case demonstrates the importance of soliciting a menstrual history in any woman reporting hemoptysis. A patient’s underlying clinical presentation and symptoms can be diagnostic of TES, and extensive diagnostic work-up may not be needed. While estrogen is associated with a pro-inflammatory state [ 5 ] leading to potential airway inflammation and subsequent hemoptysis, estrogen levels are not at peak during menstruation. Therefore, we performed diagnostic evaluation to exclude arteriovenous malformation (AVM) or concomitant pulmonary infection in the setting of lung function decline. She had no evidence of AVM on her chest imaging and microbiology results from her bronchoalveolar lavage revealed chronic Pseudomonas aeruginosa infection. Additional etiologies to consider for recurrent hemoptysis include pulmonary infarction, bronchial carcinoid and lung cancer, and should be ruled out in the appropriate clinical context [ 6 ]. Standard pharmacologic treatment for catamenial hemoptysis targets ovulation and menstruation suppression, and can be achieved through administration of hormonal contraceptives, gonadotropin-releasing hormone analogs or synthetic androgen therapy. Ultimately, these agents suppress the growth of thoracic endometrial implants leading to cessation of hemoptysis [ 2 , 3 ]. Notably, our patient had resolution of hemoptysis while on oral contraceptive therapy until Lumacaftor/Ivacaftor was initiated. Lumacaftor/Ivacaftor has been associated with decreased effectiveness of hormonal contraceptive therapies, although the exact mechanism is not well-delineated [ 7 ]. This drug interaction is thought to be secondary to the Lumacaftor compound of the drug as Tezacaftor/Ivacaftor and Elexacaftor/Tezacaftor/Ivacaftor have not been shown to have interactions with hormonal contraception. Thus, we believe the initiation of Lumacaftor/Ivacaftor resulted in decreased effectiveness of her hormonal therapies resulting in impaired ovulation and menstruation suppression resulting in recurrent hemoptysis. When Tezacaftor/Ivacaftor was approved in 2017, she was transitioned to this therapy given the absence of known interactions with hormonal contraception, and she denied hemoptysis while on treatment. Similarly, when Elexacaftor/Tezacaftor/Ivacaftor was approved in 2019, she was transitioned to this therapy given the potential of further improvement in her lung function and decreased rate of pulmonary exacerbations. She denies episodes of catamenial hemoptysis since being on Elexacaftor/Tezacaftor/Ivacaftor and oral contraceptive therapy. With the approval of recent CFTR modulators, CF care-providers will need to continue to be mindful of the implications of possible drug interactions in this population.

We present the first documented case of catamenial hemoptysis recrudescence in a woman with CF in the setting of oral contraceptive therapy with concomitant Lumacaftor/Ivacaftor administration. Although catamenial hemoptysis is rare, we suspect the incidence is under- reported as health care providers do not frequently ask about menstrual history in the context of hemoptysis. Our case highlights the importance of obtaining a menstrual history when evaluating women with CF, particularly when hemoptysis is reported. While there are known drug interactions with Lumacaftor/Ivacaftor and hormonal contraception, Tezacaftor/Ivacaftor and Elexacaftor/Tezacaftor/Ivacaftor do not have such interactions suggesting that Lumacaftor contributes to decreased effectiveness of hormonal therapies. Thus, we propose that CF women with catamenial hemoptysis and a genetic mutation approved for Tezacaftor/Ivacaftor and/or Elexacaftor/Tezacaftor/Ivacaftor can be managed with simultaneous administration of either CFTR modulator and hormonal contraceptive therapy.

Hemoptysis is a well-known complication in people with cystic fibrosis (CF), which occurs in approximately 9% of CF individuals over a 5-year time period [ 1 ]. However, catamenial hemoptysis, expectoration of blood that coincides with menstruation, can be a unique manifestation in women with CF. Catamenial hemoptysis can be associated with thoracic endometriosis syndrome, (TES) which is estimated to occur in less than 6% of the general female population [ 2 ]. Studies examining catamenial hemoptysis in CF are limited. We present a case of catamenial hemoptysis in a woman with CF, and discuss therapeutic management with hormonal contraceptive therapy and implications of concomitant use of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. A 25-year-old nulligravid woman with CF (genotype F508del/F508del) had a history of catamenial hemoptysis since the age of 13. Prior guidelines have defined mild to moderate hemoptysis as 5–240 ml and massive hemoptysis as >240 ml [ 1 ]. She reported episodes of mild-moderate hemoptysis with no history of massive hemoptysis or bronchial artery embolization. Imaging and bronchoscopy were deferred, and she was started on combined oral contraceptive therapy at the age of 15 for a presumed diagnosis of TES with cessation of her hemoptysis over the subsequent 7 years. At the age of 22, she had a baseline lung function of 55% predicted with frequent pulmonary exacerbations requiring antibiotic treatment. The FDA approved Lumacaftor/Ivacaftor in 2015, and she was started on therapy with improvement in her lung function to 66% within the first year of treatment. However, she developed recrudescence of hemoptysis associated with irregular menses and menorrhagia. She had no known history of a bleeding diathesis, and no evidence of pelvic endometriosis, uterine fibroids or polyps. She was transitioned off oral contraceptives and had a levonorgestrel-releasing intrauterine device (IUD) inserted. Lumacaftor/Ivacaftor was continued as she otherwise had sustained improvement in her lung function and overall decrease in pulmonary exacerbations. Despite IUD insertion, she continued to have intermittent mild to moderate hemoptysis with irregular menstrual bleeding. A chest CT and bronchoscopy were performed during her next menstrual cycle. Her chest CT demonstrated bilateral bronchiectasis and right upper lobe ground glass opacities ( Figure 1A ). Her airways were inspected to the subsegmental level bilaterally and were normal except for tracheal hyperemia ( Figure 1B ) and multiple erythematous lesions. The largest of these lesions in the right upper lobe was biopsied ( Figure 1C ). Cytological analyses of the samples revealed pulmonary alveolar macrophages with acute inflammation. Although endometrial tissue was not found on biopsy, her presentation was consistent with TES. She was followed closely by our colleagues in reproductive endocrinology and completed 6 months of leuprolide acetate injections, a synthetic gonadotropin-releasing hormone agonist, given intermittent hemoptysis despite IUD insertion. Notably, her hemoptysis resolved while receiving leuprolide acetate. During this time frame, Tezacaftor/Ivacaftor was approved, and she was transitioned from Lumacaftor/Ivacaftor to Tezacaftor/Ivacaftor due to concerns of decreased effectiveness of hormonal therapies while on Lumacaftor/Ivacaftor. Upon completion of leuprolide acetate, her IUD was removed and she was restarted on combined oral contraceptive therapy. She had no episodes of hemoptysis while on oral contraception and Tezacaftor/Ivacaftor. When the FDA approved Elexacaftor/Tezacaftor/Ivacaftor in 2019, she was transitioned to this therapy with no episodes of hemoptysis since initiation.