Long-term Prognostic Outcomes in Patients With Hemoptysis

Background: Hemoptysis is a challenging symptom which can be associated with potentially life-threatening medical conditions. Follow-up is key in these patients to early detect new or misdiagnosed pathologic ndings. Few prospective studies evaluated long-term prognostic outcomes. Furthermore, the role played by antiplatelet and anticoagulant drugs on mortality and recurrence rates is unclear. The aim of the study was to assess the mortality after 18 months of follow-up; furthermore, it was evaluated the incidence of recurrences and the factors associated with both recurrence and death (including the role played by anticoagulant and antiplatelet drugs). Methods: Observational, prospective, multicentre, Italian study. Results: 451/606 (74.4%) recruited patients with hemoptysis completed the 18 months follow-up. 22/604 (3.6%) diagnoses changed from baseline to the end of the follow-up. 83/604 (13.7%) patients died. In 52/83 (62.7%) patients, death was the outcome of the disease which caused hemoptysis at baseline. Only the diagnosis of lung neoplasm was associated with death (OR (95%CI): 38.2 (4.2-347.5); p-value: 0.0001). 166 recurrences were recorded in 103/604 (17%) patients. The diagnosis of bronchiectasis was signicantly associated with the occurrence of a recurrence (OR (95% CI): 2.6 (1.5-4.3)); p-value <0.0001). Anticoagulant, antiaggregant, and anticoagulant plus antiaggregant drugs were not associated with an increased risk of death and recurrence. Conclusions: Our study showed a low mortality rate in patients with hemoptysis followed-up for 18 months. Pulmonary malignancy is the main etiology and the main predictor of death, whereas bronchiectasis is the most frequent diagnosis associated with recurrence. Antiplatelet and/or anticoagulant therapy do not change the risk of death

Anticoagulant, antiaggregant, and anticoagulant plus antiaggregant drugs were not associated with an increased risk of death and recurrence.
Conclusions: Our study showed a low mortality rate in patients with hemoptysis followed-up for 18 months. Pulmonary malignancy is the main etiology and the main predictor of death, whereas bronchiectasis is the most frequent diagnosis associated with recurrence. Antiplatelet and/or anticoagulant therapy do not change the risk of death or recurrence. Follow-up is recommended in patients initially diagnosed with lower airways infections and idiopathic bleedings.

Background
Hemoptysis is a challenging symptom which can be associated with potentially life-threatening medical conditions 1,2 . Recent studies showed that lung cancer, bronchiectasis, and lower respiratory tract infections are the most frequent etiologies [2][3][4][5][6][7][8] . However, despite an accurate initial work-up, a subgroup of patients with hemoptysis does not have an etiological diagnosis (i.e., idiopathic or cryptogenic hemoptysis) [2][3][4][5][6][7][8][9] ; furthermore, diagnostic changes from the baseline assessment to recurrences were recently described 2,9 . In particular, lung cancer was found in patients with idiopathic hemoptysis or lower respiratory infections and a diagnosis of bronchiectasis was performed in a non-negligible proportion of patients initially diagnosed with cryptogenic bleeding 2,10 .
Several factors might in uence the long-term prognostic outcomes of patients with hemoptysis. Few prospective studies evaluated their survival rate, the mortality-related risk factors, as well as the incidence of recurrence and its associated variables 7,8 . Furthermore, the role played by antiplatelet and anticoagulant drugs is still unclear.
The primary aim of this study was to assess the mortality after 18 months of follow-up; furthermore, the incidence of recurrences and the clinical factors associated with recurrence and mortality were evaluated.
The role of anticoagulant and antiplatelet drugs on these outcomes was also studied.

Study design
This is a secondary analysis of an observational, prospective, multicentre, Italian study aimed at evaluating the epidemiology of hemoptysis in Italy and the diagnostic yield of the most frequently prescribed diagnostic techniques 5 . It was approved by the ethical committees of ve Italian participating hospitals and registered at ClinicalTrials.gov (identi er: NCT02045394). Written informed consent was signed by all recruited patients 5 , who were followed-up for 18 months.
One month after the recruitment and the rst initial assessment, a hospital clinical re-evaluation was scheduled. After three, six, nine, twelve, and eighteen months a phone call was planned for every patient. At each follow-up visit information on occurrence, timing, and severity of recurrences was collected.
In case of recurrence a new clinical assessment was performed; data on clinical, radiological, endoscopic examinations, as well as on symptom management were recorded.

Patients and interventions
From July 2013 to September 2015, adult (i.e., ≥ 18 years old) patients with haemoptysis requiring an etiological diagnosis were considered eligible for recruitment 5 and consecutively enrolled. Exclusion criteria were the following: 1) etiology of haemoptysis already known; 2) refusal to sign the informed consent.
The follow-up period lasted from December 2015 to February 2018.

Outcome measures
The primary outcome was the survival rate of patients with hemoptysis. Furthermore, it was calculated the incidence of recurrence and the main factors associated with recurrence and the mortality. The effectiveness of antiplatelet and anticoagulant drugs on these outcomes was speci cally investigated.
Changes in the diagnosis of hemoptysis from baseline to the end of follow-up were recorded.

Statistical analysis
Qualitative and quantitative variables were collected with an ad hoc electronic form. Qualitative variables were described with absoluter and relative (percentage) frequencies, whereas quantitative variables were summarized with medians (interquartile ranges, IQR) for their non-parametric distribution. Univariate and multivariate logistic regression analysis was performed to assess the relationship between clinical, demographic, and epidemiological variables and the outcomes death and recurrence. A two-tailed p-value less than 0.05 was considered statistically signi cant. All the statistical computations were performed with the statistical software STATA version 16 (StatsCorp, Texas, USA).
Results 451 out of 606 (74.4%) patients who were recruited 5 completed the 18 months' follow-up.
The initial etiological diagnoses were previously described 5 .
In 52/83 (62.7%) patients, death was the outcome of the disease which caused hemoptysis at baseline: 42 died for lung cancer (eight during a recurrence), seven patients for metastatic pulmonary malignancy, two patients for pneumonia, and one for a bronchiectasis exacerbation. One patient, initially diagnosed with idiopathic hemoptysis, died during a recurrence without an identi able cause of bleeding.
In the univariate analysis, age > 70 years (odds ratio, OR, (95%CI): 9. pack/years: 1.9 (1.1-3.4)); p-values: 0.02), and pulmonary malignancy (OR (95%CI): 15.6 (9.2-26.5); pvalue: <0.0001) were associated with an increased risk of mortality. In the multivariate analysis only the diagnosis of lung neoplasm resulted signi cantly associated with the above-mentioned outcome (OR (95%CI): 38.2 (4.2-347.5); p-value: 0.0001) ( Table 1).  (Table 2). In particular, pulmonary malignancy was described in four cases initially diagnosed with idiopathic bleedings, in two patients with an exacerbation of chronic obstructive pulmonary disease (COPD) (both with a smoking history > 20 pack/years), and in four patients with pneumonia/lung abscess (two of them active smokers). In 7/22 (32%) patients the new diagnosis was performed during a recurrence: lung cancer was described in two patients with an initial diagnosis of pneumonia/lung abscess and in one with an idiopathic bleeding. In two patients an upper airways lesion was found after an initial diagnosis of acute bronchitis and idiopathic bleedings. An upper digestive hemorrhage and a pulmonary embolism were diagnosed in two patients initially diagnosed with cryptogenic hemoptysis and pneumonia, respectively. and 13 (100%) patients, respectively), whereas in case of lung cancer mild to moderate bleedings were found in 10 (45.5%) patients. 2 (7.1%) severe recurrences were recorded in patients with both bronchiectasis and lung cancer.  The univariate analysis showed that bronchiectasis was signi cantly associated with the occurrence of a recurrence (OR (95% CI): 2.6 (1.5-4.3)); p-value < 0.0001) ( Table 4).

Discussion
To the best of our knowledge this is the largest prospective study describing the long-term prognostic outcomes (18 months) of patients with hemoptysis.
An overall mortality rate of 13.7% was found; the number of deaths increased from 18.1-31% after one year of follow-up and, then, decreased to 8.4% at the end of the study period. Most of the deaths occurring during the follow-up were related to the etiology which caused the hemoptysis, with pulmonary neoplasms being the leading cause.
Malignancy, which was reported as the most frequent etiology in patients with hemoptysis in several studies 3-6, 8,11 , represents the only signi cant predictor of mortality in our study.
Hemoptysis related to bronchiectasis, lower respiratory tract infections, and other less frequent etiologies showed a positive prognosis.
Two previous prospective studies based on poor sample size and on a follow-up of 1.8-2.7 years, described a slightly higher mortality rate (19.5-22%) 7 In our study, four patients initially diagnosed with acute bronchitis and COPD exacerbation based on clinical and chest X-ray ndings were then diagnosed with bronchiectasis.
The present scienti c evidence suggests the importance of a clinical and radiological follow-up in patients with bleedings of unknown origin and related to an acute lower respiratory tract infection, as well as a more accurate radiological assessment (i.e., chest CT) in patients with hemoptysis and risk factors for bronchiectasis 19 . Very few data can be retrieved on the impact of antiplatelet or anticoagulant therapies on long-term prognostic outcomes. In a large retrospective cohort study, Lee et al. failed to demonstrate a potential role of aspirin on recurrence 15 . Similar ndings were showed by Ryuge et al. who studied the mechanism of hemoptysis relapse in patients who underwent BAE: they demonstrated that antiplatelet and anticoagulant therapy did not increase recanalization, i.e. the most frequent mechanism underlying re-hemoptysis 13 .
We prospectively proved that these drugs, individually or in combination, did not change the risk of death and of recurrences.
Some study limitations can be found. The observational nature cannot help discriminate the role played by some medical conditions for the background noise of confounders. However, for ethical reasons it is currently the best methodological approach. Differences in some standard operating procedures in the recruited centers could affect some results in terms of diagnostic accuracy. However, the recruited hospitals were reference national centers and, then, the operating variability should be not relevant. Subgroup analyses by etiology could have affected the statistical power of some ndings; future studies focused on speci c etiologies could con rm our novel results.

Conclusions
In conclusion, our study shows a low mortality rate in patients with hemoptysis followed-up for a long period. Pulmonary malignancy is the main etiology and the main predictor of death in these patients, whereas bronchiectasis is the most frequent diagnosis associated with recurrence. Antiplatelet and/or anticoagulant therapy do not change the risk of death or recurrence. Follow-up is recommended in patients initially diagnosed with lower airways infections and those with idiopathic bleedings, to detect new or misdiagnosed lung malignancies. Guarantor: MM is the guarantor of the content of the manuscript, including the data and analysis. Author contribution: MM: contributions to the conception and design of the work, acquisition, and interpretation of data for the work; drafting the work; nal approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. PC: contributions to the conception and design of the work, acquisition, and interpretation of data for the work; revising the manuscript critically for important intellectual content; nal approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. LS: contributions to the analysis and interpretation of data for the work; revising the manuscript critically for important intellectual content; nal approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. GS: contributions to the conception or design of the work, analysis and interpretation of data for the work; drafting the work; nal approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved-GC, MP, FT, PP, AF, AA, SC, SG, MB, ACC, SM, FA, SDP, SC: acquisition of data for the work; revising the manuscript critically for important intellectual content; nal approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.