CFDB - Cystic Fibrosis DataBase

Bronchopulmonary complications therapy

Hemoptysis in cystic fibrosis

Background

Hemoptysis occurs as a complication of lung disease in CF and is believed to result from erosion of abnormal bronchial vessels (Mingora CM, Flume PA, 2021). An increased risk of hemoptysis in Cf patients has been associated to several factors including older age, advanced lung disease (forced expiratory volume in 1s (FEV1) <70% predicted), airway colonisation by Pseudomonas aeruginosa, CF-related diabetes, portal hypertension, and liver cirrhosis . Recently (Pavaut G et al, 2020) an observational retrospective study including 85 adul patients with CF identified ABPA and diabetes as factors for the development of massive haemoptysis  in CF patients who have previously experienced an episode of mild-to-moderate haemoptysis.

Defining as minor or major is based on the amount of bleeding that generally occurs in more severely damaged lung regions. Hemoptysis can be an acute medical emergency, and region of erosion can be localized angiographically and controlled by therapeutic intervention. Recently (Bozkanat KM et al, 2021)  four cases (age range: 25–34 years) of catamenial haemoptysis have been described representing thoracic endometriosis related to hormonal variations in  airway inflammation or infection resulting in bronchial artery bleeding. Use of pro‐coagulants, hormone contraceptives, anti‐inflammatories, bronchial artery embolization, and use of modulators have been discussed as management strategies.

A classification of severity of haemoptysis is generally accepeted as massive (>240 ml/24h or >100 ml/day for ≥2 days), moderate-severe (>20 ml/24h) or mild (<20 ml/24h). Minor hemoptysis - that is, blood streaking in sputum - is relatively common and has been reported in up to 60% of adolescents and adults with CF. It usually requires no specific therapy other than treatment of a CF pulmonary exacerbation, correction of contributing factors such as coagulation abnormalities (for example vitamin K deficiency) and breaking the chronic use of medications which can promote hemorrhage.

Major hemoptysis is defined as the expectoration of gross blood, usually more than 240ml in 24h, or recurrent bleeding of less volume (>100 mL/day) for a few days or weeks.

Major hemoptysis is a life–threatening condition (because of asphyxiation or hypotension) requiring aggressive therapies to control the bleeding. It occurs in approximately 1% of all patients with CF and is rarely seen in children younger than 10 years. Observational studies show that major hemoptysis is more common as the patient aged and in patients with Staphylococcus aureus infection.

Bronchial Artery Embolization (BAE) has become an increasingly used therapeutic option for major hemoptysis, although conservative therapy has been demonstrated to be as effective. Multiple complications from embolization have been reported, including transverse myelitis, bronchoesophageal fistulas, systemic emboli, recurrent hemorrhage, bronchial necrosis, and paralysis. Concerning medical therapy of hemoptysis, anedoctal cases (Hurley M et al, 2011) report the successful use at low doses of tranexamic acid (TXA) , a synthetic derivative of the amino acid lysine, for controlling recurrent severe hemoptysis episodes in people with CF. which  has been used in patients with haemoptysis to reduce the amount of expectorated blood, ostensibly by decreasing the fibrinolytic activity and thereby improving the clinical outcomes.Tranexamic acid is a well-known antifibrinolytic drug with established efficacy in prohibiting connections between fibrin and plasmin, which is activated by t-PA release from endothelial cells derived  from ruptured bronchial arteries, which contain high levels of tissue plasminogen activator (t-PA) in their endothelial cells

Issues

  1. What is the best diagnostic tool to identify earlier the site of bleeding.
  2. What are both benefits and side effects or disadvantages for medical and surgical treatment of hemoptysis in people with CF
  3. whether  BAE is effective and safe.

What is known

Cystic Fibrosis Pulmonary Guidelines for Pulmonary Complications (Flume PA et al, 2010) have been previously published to help clinicians in clinical practice.

1 CDSR (Prutsky G et al, 2016) is available to evaluate the effectiveness and safety of antifibrinolytic agents in reducing the volume and duration of haemoptysis in adult and paediatric patients with different etiologies including CF. TXA did not affect remission of haemoptysis evaluated at seven days after the start of treatment. No significant difference in the incidence of mild side effects was registered  between active and placebo groups (OR 3.13, 95% CI 0.80; 12.24). There is insufficient evidence to judge whether antifibrinolytics should be used to treat haemoptysis from any cause, though limited evidence suggests they may reduce the duration of bleeding.  

However, in general (Moen CA et al, 2013)   tranexamic acid is indicated that may reduce both the duration and volume of bleeding, with low risk for short-term thromboembolic complications, in patients with haemoptysis.

A japanese study (Kinoshita T et al, 2019),  including almost 30000 subjects with hemoptysis for different etiologies covering also cystic fibrosis, showed that tranexamic acid may reduce in-hospital mortality among patients with haemoptysis requiring emergency admission compared with patients did not.

A study (Al-Samkari H et al 2019) was performed  to examine the use of antifibrinolytic agents in managing  adult  inpatients and outpatients with CF and hemoptsysis, and rates of admission for bleeding prior to and following implementation of these drugs. Effectiveness of the pathway was evaluated via comparison of annualized hemoptysis admission rates prior to and following pathway enrollment over 54 months period. Main results including 72 distinct episodes of hemoptysis treated with antifibrinolytic agents as tranexamic acid or epsilon aminocaproic acid in a total of 21 adult patients with CF showed that systemic antifibrinolytic therapy was associated with a reduction in hospital admissions. No serious adverse events were observed.

A series of four cases are consistent with other studies that propose inhaled TA as an alternative for hemoptysis treatment, reducing bleeding (Segrelles Calvo G et al, 2016).

In a previous study (Moua J et al, 2013), beta-blockade, particularly with atenolol, appears to successfully treat recurrent hemoptysis refractory to conservative therapy in a small group of patients with CF aged 13-40 years old. Reduction of intravenous antibiotics use, decreases in the frequency and the amount of hemoptysis were statistically found when comparing the pre- and post-treatment means observed.

Concerning BAE as safe  a case of temporary unilateral diaphragmatic paralysis associated to lung consolidation following BAE has been registered in a pediatric CF female patient. This complication worsened the lung function of the patient who underwent lung transplantation after 9 months (Terlizzi V et al, 2020) .

An observational study (Flight WG et al, 2017)  showed that among twenty-seven patients undergoing to 51 BAE procedures over a median follow-up period of 26 months BAE was effective in controlling haemoptysis, but it is associated with considerable morbidity and high recurrence rates.

Recently (Gavioli EM et al, 2021) a retrospective observational study including 38 adult patients with CF aimed to evaluate the use of vitamin K therapy at a average daily dose of 10 mg in the setting od hemoptysis during an acute pulmnary exacerbation was performed. The median lenght of stay, the median time until next hospital admision and the 30-day readmission rates were evaluated . Results on the potential role of vitamin K in the setting of hemoptysis were inconclusive.

 

Unresolved questions

A  proposed clinical trial (NCT01496196) started in 2011  should be  relevant to have information about  the potential therapeutic role of inhaled tranexamic acid in patients with non massive major hemoptysis  in  adult patients without CF compared to a placebo group at the dosage of 500mg/5ml 3-4 times a day. Study has passed its completion date and status has not been verified in more than two years.

There is still no consensus on the agents which should be used for preventing recurrence of hemoptysis in people with CF.

Clinical studies are needed to determine whether TX should be routinely used as an adjunctive therapy of hemoptysis in CF, or whether it should be reserved for patients who have failed conventional therapies. No conclusive data are available concerning the benefits or the disadvantages of both medical and surgical treatments.

No trials have been detected in order to define the role of BAE in Cystic Fibrosis.

 

 

 

Keywords: Hemoptysis;