Dornase alfa

Background: Massive hemoptysis is a complication commonly reported in patients with cystic fibrosis (CF). An understanding of the pathophysiology of this complication and its consequences is important for the management of patients with CF.

Objectives: To identify risk factors associated with massive hemoptysis, and to determine the prognosis of patients following an episode of massive hemoptysis.

Design: A retrospective, observational cohort study of the National CF Patient Registry between the years 1990 to 1999.

Patients: The Registry contained data on 28,858 patients with CF observed over 10 years at CF centers across the United States.

Results: Massive hemoptysis occurred with an average annual incidence of 0.87% and in 4.1% of patients overall. There was no increased occurrence by sex, but it was more prevalent in older patients (mean age, 24.2 [+ or -] 8.7 years [[+ or -] SD]) with more severe pulmonary impairment (nearly 60% of patients who had an episode of massive hemoptysis had FE[V.sub.1] < 40% predicted). The principal risks associated with an increased occurrence of massive hemoptysis included the presence of Staphylococcus aureus in sputum cultures (odds ratio [OR], 1.3) and diabetes (OR, 1.1). There was an increased morbidity (eg, increased hospitalizations and hospital days) and an increased 2-year mortality following massive hemoptysis.

Conclusion: Massive hemoptysis is a serious complication in CF patients, occurring more commonly in older patients with more advanced lung disease. Nearly 1 in 100 patients will have this complication each year. There is an attributable mortality to the complication and considerable morbidity, resulting in increased health-care utilization and a measurable decline in lung function.

Key words: cystic fibrosis; hemoptysis; lung disease

Abbreviations: ABPA = allergic bronchopulmonary aspergillosis; CF = cystic fibrosis; CFF = Cystic Fibrosis Foundation; NS = not significant; OR = odds ratio

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Hemoptysis is a complication commonly reported in patients with cystic fibrosis (CF). (1) Although often the hemoptysis is minor, with only scant blood streaking of the sputum, many patients will experience massive hemoptysis, defined as acute bleeding > 240 mL in a 24-h period or recurrent bleeding > 100 mL/d over several days. (2) Such bleeding may be life threatening by causing either obstruction of the airway (asphyxiation) or hypotension.

The pathogenesis of hemoptysis in CF patients has not been determined. It has been attributed to the persistent airway inflammation and vascular growth that results in markedly enlarged and tortuous bronchial arteries. (8) These arteries contain systemic pressure and are closely adjacent to the bronchi. Chronic and acute inflammation weakens the vessel walls and can lead to episodic or persistent bleeding into the bronchial lumen, with subsequent hemoptysis. According to this hypothesis, it would be expected that massive hemoptysis would occur in patients with more severe disease, yet the complication has been known to occur in patients with seemingly milder disease. (4)

Most of the literature on hemoptysis in CF is dedicated to its treatment and not to its pathogenesis or prognosis. The massive hemoptysis section of the Cystic Fibrosis Foundation (CFF)-sponsored consensus statement (2) on pulmonary complications of CF conceded that recommended therapies are based on clinical observations, experience, and case reports. These therapies include discontinuation of specific medications including aspirin, penicillin-like antibiotics, nonsteroidal anti-inflammatory drugs, N-acetyl-cysteine, and aerosolized antibiotics, implying that these may be related to the hemoptysis, either causally or by exacerbating the severity.

Using data from CF patients in the national CFF Patient Registry, multiple clinical features were analyzed to identify risk factors associated with massive hemoptysis and to determine the prognosis of patients following an episode of massive hemoptysis. The CFF Patient Registry defines massive hemoptysis as either > 240 mL/d or requiring blood transfusion.

MATERIALS AND METHODS

The CFF supports and accredits CF care centers nationwide. These centers provide specialized care for persons with CF and offer comprehensive diagnosis and treatment, as well as participation in clinical trials of experimental therapies. The CFF Patient Registry contains data on patients with CF seen at one of the accredited CF care centers in the United States. This represents approximately 90% of all CF patients in the United States. The CFF has sponsored the patient registry since 1966 and requires all CFF-accredited care centers to complete standardized questionnaires for all patients seen in their centers. (5) The questionnaires are completed by each center using local resources available to them. The CFF serves as the coordinating center for data collection and quality, contacting the CF centers to retrieve or correct all missing and out-of-range values.

The CFF Patient Registry database was analyzed for the years from 1990 to 1999. For this period, the database contained 28,858 unique patients with a total of 197,156 separate entries (an average of 6.8 entries per patient). There were missing dates for 16,614 entries. This left a working database of 28,191 unique patients with 180,542 entries (an average of 6.4 entries per patient). The CFF Patient Registry records only one entry per patient per year and so is a collection of year-end summary data. Complications are reported only if present during a specific year and may not reflect repeat occurrences. Therefore, the data are presented assuming no more than one episode of massive hemoptysis for each patient in a given year, although there could have been more. Patients who experience a complication away from the CF center may not have this included in the Registry.

Clinical variables that may influence massive hemoptysis were retrieved and analyzed: (1) demographic data (eg, date of birth, sex, race, and insurance status); (2) complications related to CF (eg, pancreatic insufficiency, cirrhosis, diabetes, allergic bronchopulmonary aspergillosis [ABPA], lung transplantation); (3) severity of disease (eg, FE[V.sub.1] as a percentage of predicted, FVC as a percentage of predicted, percentage of ideal body weight, body mass index, supplemental [tube] feeding, supplemental oxygen); (4) organisms present in cultures of the airways (eg, Pseudonumas aeruginosa, Burkholderia cepacia, Staphylococcus aureus, methicillin-resistant S aureus, Stenotrophomonas maltophilia, Aspergillus, atypical mycobacteria); (5) CF-related therapies (eg, dornase alfa, inhaled tobramycin, high-dose ibuprofen, corticosteroids); and (6) outcomes (eg, mortality, clinic visits, hospitalizations, hospital days, IV antibiotic days).

Statistical analysis consisted of [chi square] for categorical comparisons, Student t test for comparison of normally distributed means, and logistic regression for simultaneous control of multiple potential confounders. Logistic regression was used to obtain the independent effect of multiple risk factors for massive hemoptysis. The database did not collect all variables for all 10 years. For example, inhaled tobramycin, dornase alfa, and use of ibuprofen were included in the database only since 1997. Thus, multiple models were constructed to include variables collected for specific time periods.

Change in lung function over time (eg, FE[V.sub.1]) was also assessed using mixed-model analysis of repeated measures, which utilizes restricted maximum likelihood methods for estimation. (6) Corey et al (7) demonstrated several advantages of mixed-model analysis in assessing pulmonary function decline in CF patients, including the ability to account for both between- and within-subject variability within the same model. Selection of a satisfactory covariance structure is important to make appropriate inferences from repeated-measures data. (6) Two models were fit with different covariance structures: an unstructured model, and a first-order autoregressive model. The first-order autoregressive covariance model describes correlation between observations where adjacent observations are more highly correlated than observations that are further apart in time, and was selected as the most appropriate for the data on the basis of information criteria assessing the fit of the model. Statistical software was used for these analyses (SAS Proc Mixed, SAS System for Windows 9.0; SAS Institute; Cary, NC). Values reported are mean [+ or -] SD unless stated otherwise; p < 0.05 was considered significant.

RESULTS

There were 1,153 patients (4.1% of the total population) who had at least one episode of massive hemoptysis. Sixteen of these patients did not have a date recorded for their single episode of massive hemoptysis and are not included in all analyses. There were a total of 1,606 entries with massive hemoptysis as a complication; 15 of these entries did not have dates and are not included in some analyses. Most patients had only one recorded event (n = 858), although many had more than one reported event, and one patient had seven entries (Table 1).

The average annual incidence rate of massive hemoptysis was 0.87%, with no yearly increase over time (range, 0.67 to 1.21%; p = not significant [NS]). The average age at the first hemoptysis episode was 24.2 [+ or -] 8.7 years (median, 23 years; range, 0 to 58 years). The occurrence of massive hemoptysis is more prevalent in adult patients (Fig 1). Only 25% of patients with this complication had massive hemoptysis prior to the age of 18 years, and half of the patients with this complication had their first episode between the ages of 18 years and 30 years. The mean age at the time of initial massive hemoptysis for each year did not change during the 10 years analyzed.

[FIGURE 1 OMITTED]

There were 632 male (54.8%) and 521 female (45.2%) patients who ever had massive hemoptysis, which is similar to the proportion of the sexes in the entire database (male, 53.2%; female, 46.8%; p = NS). The occurrence by race was 93.4% white, 3.0% African-American, and 3.0% Hispanic. This generally followed the racial distribution of all patients within the database (90.3%, 3.6%, and 5.5%, respectively), although there was a slight decrease in massive hemoptysis occurrence in the Hispanic population (p < 0.0001).

The average lung function of the patients with massive hemoptysis (first episode) was of moderate-to-severe impairment (Table 2); 61.2% of the patients with massive hemoptysis had an FE[V.sub.1] < 40% of predicted (Fig 2). However, this complication also occurred in patients with only mild pulmonary impairment (11.0% of patients) as well as those with normal measures of lung function (11.4% of patients).

[FIGURE 2 OMITTED]

Risk Factors

Specific variables that might be associated with massive hemoptysis were evaluated, including infectious organisms, features of severity of disease, additional complications of CF, and specific therapies. All variables that met statistical significance in a univariate analysis are listed in Table 3. Logistic regression was used to examine the independent effects of risk factors simultaneously, and their adjusted odds ratios (ORs) are shown in Table 3. Patients with S aureus (OR, 1.3) and diabetes (OR, 1.1) had increased risk of massive hemoptysis. There was a lower risk of massive hemoptysis in patients with P aeruginosa (OR, 0.4) and B cepacia (OR, 0.5), who received supplemental enteral feeding (OR, 0.8), and who also had cirrhosis (OR, 0.4), nasal polyps (OR, 0.8), and pneumothorax (OR, 0.7). There was a trend toward an increased risk for patients with Medicaid insurance (OR, 1.1; p = 0.08) to have massive hemoptysis. It is impossible to determine whether massive hemoptysis occurs during a pulmonary exacerbation, as the database does not contain the dates to establish such a correlation. There was a reduced risk among patients using dornase alfa (OR, 0.7) and inhaled tobramycin (OR, 0.6), although these medications were included in the database for only the last 3 years.

Mortality

There were 508 deaths (44.1%) in the group of patients who had one or more episodes of massive hemoptysis. Patients with massive hemoptysis had a higher occurrence of death during the period of database entries than those who did not have massive hemoptysis (p < 0.001). The average age at death in patients with massive hemoptysis was 26.4 [+ or -] 9.0 years (median, 26.0 years; range, 2 to 62 years). This compares to an average age at death of 22.6 [+ or -] 10.9 years (median, 22.0 years; range, 0 to 72 years) in those patients who never had a reported episode of massive hemoptysis. Many patients (n = 179; 35.2% of deaths) died the same year as the massive hemoptysis. A Kaplan-Meier survival curve from the first massive hemoptysis episode is shown in Figure 3.

[FIGURE 3 OMITTED]

Since massive hemoptysis occurred in patients with more severe respiratory impairment, it was necessary to see whether the mortality was due solely to pulmonary impairment or could be attributed to the massive hemoptysis. The 2-year mortality rate was calculated for patients with massive hemoptysis grouping them according to the severity of pulmonary impairment (ie, FE[V.sub.1] as a percentage of predicted) at the time of the first episode of massive hemoptysis. These were compared to 2-year mortality rates of patients who never had an episode of massive hemoptysis, also grouping them according to pulmonary impairment (Fig 4). The 2-year mortality was always greater for the patients with massive hemoptysis, with an attributable risk for mortality due to massive hemoptysis between 5.8% and 16.1%. The relative risk of dying for patients with massive hemoptysis and FE[V.sub.1] > 50% of predicted was 7.4 compared to those with similar pulmonary impairment but without massive hemoptysis.

[FIGURE 4 OMITTED]

Change in Lung Function

To evaluate the effects of massive hemoptysis on changes of lung function, data were analyzed from patients who had pulmonary function tests reported for all three time periods (year before, year of, and year following hemoptysis; n = 409). There was a statistically significant drop (p < 0.0001) in both FVC and FE[V.sub.1] (as percentages of predicted) from the year before massive hemoptysis to the year following (Table 2). Results of mixed-model analysis also showed a statistically significant change in lung function over time as measured by change in FE[V.sub.1] (p < 0.001).

Utilization of Resources

Utilization of services of patients with massive hemoptysis was analyzed including outpatient visits, hospitalizations, and IV antibiotics, comparing the year before, during, and following massive hemoptysis (Table 4). There was an increase in the median number of hospitalizations and hospital days in the year following massive hemoptysis. Although the average number of office visits and hospitalizations per patient did not change in the year of massive hemoptysis, there were greater overall numbers of each compared to the year previous. This is due to the fact that the patients with massive hemoptysis were less likely to present to the clinic or the hospital in the year previous. Thus, there was greater overall utilization of services in the year of massive hemoptysis, resulting in 663 more office visits, 492 more hospitalizations, and 7,712 more hospital days compared to the year prior.

DISCUSSION

Hemoptysis is common for patients with CF, although typically the bleeding is scant or mild. Massive hemoptysis occurs frequently in patients with CF as well. In this analysis of 10 years of data, collected from a large population of patients with CF, we found that 4.1% of patients overall had at least one episode of massive hemoptysis. In addition, there is a high risk of subsequent episodes of massive hemoptysis. Nearly 26% of patients had more than one occurrence. The database only takes into account one episode of massive hemoptysis per year. Since it is likely that some patients will experience more than one episode in a given year, this value of 26% may be an underestimate of the actual recurrence rate. Prior reports (4,8) of massive hemoptysis in CF have been single-center, retrospective experiences. The largest and most recent of these reported on 20 years' (from 1980 to 1999) experience of "major hemoptysis" in CF children in Australia, (4) and reported an incidence of 6%, slightly more than we found in our analysis, but they included chronic recurrent hemoptysis in their definition, accounting for half of their patients. They, too, reported frequent recurrence with 102 total episodes in 51 patients, 1 of whom had 7 episodes.

There is a clear association of this complication with age, with most events occurring in adults (Fig 1), and it is more common in patients with severe lung disease (Fig 2). The association with older age is likely because of the greater time for the inflammation to be present and for the vascular system to be altered. Two reports of massive hemoptysis in single CF centers found the mean age of first episode to be 16.5 years (8) and 15 years. (4) The differences from our finding of a mean age of first episode (24.2 years) are easily explained. The landmark report by Stern et al (8) was published in 1978. Survival has improved considerably over the last 2 decades, and it is likely that CF therapies have had an effect on this complication as well as on survival. The second report, (4) although more recent, was limited to an evaluation of massive hemoptysis in children, only four of whom (8%) were < 10 years old.

The presence of P aeruginosa (9) and B cepacia (10) is associated with increased inflammation and a decline in lung function, yet there is a reduced association of these organisms with massive hemoptysis. These findings may be related to phenotypic features of these bacteria (eg, mucoid phenotype, exotoxins) or to the immune response that they generate. This analysis found an increased prevalence of massive hemoptysis when S aureus is present in sputum cultures. Hemoptysis has been reported in non-CF patients who have S aureus necrotizing pneumonia. (11,12) S aureus virulence factors (eg, leukocidin (11)) may induce inflammatory changes in the epithelium and vasculature that would lead to massive hemoptysis. Studies (13,14) evaluating chronic anti-Staphylococcal antibiotics (eg, cephalexin) in patients with CF did not address any effect on reducing the risk for massive hemoptysis in these patients.

The presence of Aspergillus in sputum cultures was not associated with a risk of massive hemoptysis in CF patients. Aspergillus fumigatus has been associated with massive hemoptysis in non-CF patients, especially in those with mycetomas. (15-17) Aspergillus is commonly cultured from CF sputum and is often thought to be a colonizer and not necessarily a pathogen. (18) It is impossible to determine if any of the patients in the database had an aspergilloma, but this is an uncommonly reported finding in patients with CF. (19,20) The presence of Aspergillus in sputum cultures may indicate ABPA, an asthma-like complication that occurs commonly in patients with CF, (21) but this analysis did not find an increased association of ABPA with massive hemoptysis. However, the database does not capture key markers of ABPA (eg, serum IgE level, aspergillus precipitins), and the diagnosis is dependent on clinician reporting. The lack of an association of Aspergillus with massive hemoptysis does not exclude the possibility that the organism is a pathogen inducing airways inflammation. Antibodies specific to A fumigatus have been demonstrated in patients with CF, even in the absence of ABPA, and the authors suggested that Aspergillus may promote subclinical airways inflammation. (22)

There was a reduced association between massive hemoptysis and cirrhosis. One might expect an increased risk with cirrhosis, perhaps due to an impaired clotting system, allowing what could be minor hemoptysis to be more severe. There are other conditions in which liver disease is associated with a change in the pulmonary vascular system, such as hepatopulmonary syndrome, in which intrapulmonary shunts are formed, but massive hemoptysis is not a common feature of this illness. (23) It is possible the vascular changes are limited to the pulmonary arteries rather than the bronchial arteries, which is ultimately protective.

Recent years have seen increased use of inhaled medications, especially dornase alfa and tobramycin. The former is used to enhance clearance of airway secretions, while the latter is used for its antibacterial properties. These medications may reduce the inflammation by allowing greater clearance of secretions containing bacteria and inflammatory mediators (24) or by reducing bacterial density. (25) One might predict that such chronic therapies, if they reduce inflammation over time, might reduce the risk for massive hemoptysis. Alternatively, inhaled medications may irritate the airways potentially causing hemoptysis. Instillation of sputum from CF patients into the airways of mice caused bleeding if pretreated with bovine dornase alfa, an effect not seen with dornase alfa alone. (26) It was thought that release of neutrophil elastase activity was the cause of lung injury. This analysis found a reduced association of massive hemoptysis with inhaled tobramycin or dornase alfa favoring the explanation of reduced inflammation. This is a cautious interpretation, as these data have been captured in the database for only 3 years.

It is possible that patients treated with steroids to reduce the inflammation within the lungs might reduce the risk of hemoptysis. We cannot assess the use of long-term steroids by patients within this database, but no similar effect was seen in patients receiving high doses of ibuprofen, which is used for its anti-inflammatory properties. It may be that we could not detect an effect because data regarding ibuprofen use have been collected for too short a period (3 years) to measure an effect. There is a potential for increased bleeding with nonsteroidal anti-inflammatory medications like ibuprofen because of their transient effects on platelets, (27) which may negate any beneficial effects of its anti-inflammatory properties with respect to massive hemoptysis.

There must be additional factors that are associated with risks of massive hemoptysis that are not captured in this database. There are patients who have this complication who are very young or who have seemingly good, perhaps normal, lung function. There are likely genetic factors, such as vascular growth factors, that increase the predisposition of some patients to have massive hemoptysis by allowing development of enlarged and tortuous vessels under the influence of inflammation. Angiogenesis and microvascular remodeling are features of chronic inflammation, with changes occurring soon after initial infection. (28) The relative proportion of angiogenesis and microvascular remodeling appears to be genetically controlled, at least in mice. (28) One of the factors known to promote angiogenesis, vascular endothelial growth factor, has been shown to be elevated in the serum of patients with CF, and these levels decrease following treatment with IV antibiotics (29) Although vascular endothelial growth factor has not been associated with enlarged bronchial arteries or hemoptysis, the concept is intriguing.

Massive hemoptysis is associated with a high rate of mortality in patients with CF. Although most of the deaths can be attributed to the severity of lung disease, there is an attributable risk of death due to the massive hemoptysis at all degrees of pulmonary impairment (Fig 4). Death due to massive hemoptysis can be because of asphyxiation or hypovolemia. (30) It is impossible to determine the actual cause of death in patients in this database, but the report by Stern et al (8) had no deaths during the acute episode of massive hemoptysis. Barben et al (4) reported four deaths as a result of severe hemoptysis, three of them occurred during anesthesia induction for bronchial arterial embolization. Survival of non-CF patients with massive hemoptysis is often evaluated with respect to the treatment, with survival rates better in patients who underwent surgical resection. (31) Patients with CF are generally not considered to be candidates for surgical resection of the lung, especially in those with severe pulmonary impairment.

Massive hemoptysis is also a cause of considerable morbidity. Most patients will be hospitalized and treated with IV antibiotics. Some patients may undergo bronchoscopy for localization of the bleeding followed by more definitive therapy, such as bronchial arterial embolization. (3) This analysis has demonstrated a considerable increase in hospitalization days in the index year. The increase in outpatient visits, hospitalizations, and hospital days may be the direct result of the massive hemoptysis or indirectly because of worsening impairment of the pulmonary function and infection. In addition, there is a negative effect on lung function with a measurable decrease in both FVC and FE[V.sub.1].

There are some important limitations to this analysis. The incidence of massive hemoptysis is likely to be underestimated. Stern et al (8) reported a 45% recurrence rate in their center. Although the database does not allow detection of recurrent massive hemoptysis occurring in the same year, it might be expected that a higher rate of subsequent massive hemoptysis than is reported here (approximately 26%). Also, patients could have had massive hemoptysis that was not included in this database. This could occur because patients could have had massive hemoptysis prior to 1990 or entry into database, and so the analysis is not of their first true episode, the data were inadvertently omitted from the database, or because patients were unavailable for follow-up from a CF center and no data could be entered for those years. The database does not include treatment, unless the increased use of IV antibiotics is considered treatment, but there is no information regarding the use of bronchial arterial embolization. This study has several implications for therapy. First, CF patients should have periodic sputum cultures performed in accordance with the CFF guidelines, given the association of massive hemoptysis with S aureus. Second, antibiotics are recommended as standard therapy for patients with massive hemoptysis, (2) and it may be prudent on admission to choose antibiotics that are effective against S aureus until the culture results are available. Third, inhaled tobramycin for the suppression of P aeruginosa may be beneficial for the prevention of massive hemoptysis. Arguably, long-term antibiotics to suppress S aureus may also be beneficial. However, a previous study (14) did not show benefit of cephalexin, based on changes in lung function, and may have led to increased infection with P aeruginosa; the potential benefit of reducing S aureus may be outweighed by the risk of P aeruginosa. This suggestion is offered with caution, as the data on inhaled tobramycin use is in the database for only 3 years, and there are no studies that have looked at long-term antibiotic therapy and its effects on reduction in risk of hemoptysis. Fourth, consideration should be given to the use of inhaled dornase alfa, as it also was associated with a reduced rate of massive hemoptysis. The same caution for this interpretation is suggested. Finally, there is debate about using a specific FE[V.sub.1] value as a criterion for lung transplant. (32) However, one should give serious consideration for lung transplantation for those patients with an FEV < 30% predicted and massive hemoptysis given the increased risk of 2-year mortality.

In conclusion, massive hemoptysis is a serious complication that occurs more commonly in older CF patients. Nearly 1 in 100 patients will have massive hemoptysis each year, and we have shown that approximately 4% overall will have this complication during the 10-year period of observation. The principle risk factor appears to be time in the setting of chronic inflammation of the airways. The presence of S aureus in the airways appears to increase the risk somewhat. There is an attributable mortality to the complication and considerable morbidity, resulting in increased health-care utilization and a measurable decline in lung function.

ACKNOWLEDGMENT: The authors are grateful to Dr. Preston Campbell and Dr. Bruce Marshall for editorial assistance.

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* From the Departments of Medicine (Dr. Flume), Pediatrics (Ms. Ebeling and Dr. Hulsey), and Biometry and Epidemiology (Ms. Clark), Medical University of South Carolina, Charleston, SC; and Department of Medicine (Dr. Yankaskas), University of North Carolina at Chapel Hill, Chapel Hill, NC.

This work was supported in part by a grant from the Cystic Fibrosis Foundation.

Manuscript received July 28, 2004; revision accepted January 25, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Patrick A. Flume, MD, FCCP, Medical University of South Carolina, 96 Jonathan Lucas St, 812-CSB, Charleston, SC 29425; e-mail: flumepa@musc.edu

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