Data concerning the prevalence, risk factors, and prognostic significance of hemoptysis in pediatric pulmonary arterial hypertension (PAH) are scarce. A Dutch national cohort of 74 children with either idiopathic or heritable PAH (IPAH/HPAH, n = 43) or PAH associated with congenital heart disease (PAH-CHD, n = 31) were followed from 1993 to 2012. During a median follow-up of 3.5 years (range 0.1 to 19.2), hemoptysis occurred in 13 children (17.6%). The hemoptysis event rate was 9.9 per 100 patient-years, equally divided between IPAH/HPAH and PAH-CHD (p = 0.824). The median age at first hemoptysis was 12.5 years, and the median time since PAH diagnosis to first hemoptysis was 6.1 years. Patients with hemoptysis had longer time since PAH diagnosis (p = 0.001) and more frequently used anticoagulant therapy (p = 0.006). Univariate Cox regression analysis indicated that older age (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.01 to 1.30, p = 0.031), World Health Organization functional class IV (HR 0.28, 95% CI 0.08 to 0.95, p = 0.042), higher mean pulmonary arterial pressure (HR 1.04, 95% CI 1.00 to 1.07, p = 0.028), and higher indexed pulmonary vascular resistance (HR 1.08, 95% CI 1.02 to 1.15, p = 0.009), all at the time of PAH diagnosis, were associated with increased risk of hemoptysis during follow-up. Ten of 13 patients with hemoptysis died or underwent (heart-) lung transplantation; in 6 patients, this was directly related to hemoptysis. In conclusion, the occurrence of hemoptysis in pediatric IPAH/HPAH and PAH-CHD increases with time since diagnosis, is a serious condition, and is, in case of life-threatening hemoptysis, associated with poor outcome.
Pulmonary arterial hypertension (PAH) is a known cause of hemoptysis, mainly reported in patients with Eisenmenger syndrome, that is, PAH due to congenital heart defects associated with intracardiac or arterial shunts (PAH-CHD), with an occurrence of 11% after a median follow-up of 6 years. Hemoptysis has also been reported in other forms of pulmonary hypertension, such as idiopathic or heritable PAH (IPAH/HPAH) and chronic thromboembolic pulmonary hypertension. Although exact numbers are unknown, prevalence numbers in these latter patient groups are assumed to be substantially fewer. Recent reports have suggested that hemoptysis in IPAH is associated with a poor prognosis and a high mortality rate, even in hemodynamically stable patients. Most available data, however, are derived from anecdotal patients instead of cohort studies, and all refer to adult patients. Therefore, we report the experience of hemoptysis in a national cohort of 74 consecutive children with PAH, followed within the Dutch National Network for Pediatric Pulmonary Hypertension. This network includes a complete national cohort and, therefore, allows for study on occurrence, risk factors, and outcome of hemoptysis in pediatric PAH.
Methods
From 1993 to 2012, 82 children with PAH, diagnosed from 3 months to 18 years of age, were followed within the Dutch National Network for Pediatric Pulmonary Hypertension. Forty-three patients with IPAH/HPAH, 31 patients with PAH-CHD, and 8 patients with PAH associated with other diseases were included. Patients with PAH associated with other diseases comprised PAH associated with connective tissue disease (n = 3), pulmonary venoocclusive disease (n = 4), and portopulmonary hypertension (n = 1). Hemoptysis occurred in 2 patients with PAH associated with other diseases. In 1 patient with cystic fibrosis and portopulmonary hypertension, the first hemoptysis occurred already before the development of portopulmonary hypertension. The other patient had PAH associated with pulmonary arterial vasculitis and pulmonary arterial aneurysms. Because both patients were regarded to be nonrepresentative for hemoptysis in pediatric PAH, all further analyses were restricted to children with IPAH/HPAH or PAH-CHD (n = 74). In 64 patients (86%), the diagnosis of PAH was confirmed with cardiac catheterization (mean pulmonary arterial pressure >25 mm Hg, pulmonary vascular resistance >3 WU.m 2 , and pulmonary capillary wedge pressure <15 mm Hg at rest). In patients without cardiac catheterization (n = 10, 14%), PAH was established echocardiographically by measurement of a maximum systolic tricuspid regurgitant velocity >2.8 m/s, according to criteria as defined by McQuillan et al or a right-to-left shunt in children with systemic-to-pulmonary shunt. Echocardiographic signs of left heart failure and/or pulmonary venous congestion needed to be absent.
Patients were treated with supportive and targeted PAH therapy according to contemporary treatment algorithms for PAH. Standardized data regarding diagnosis, hemodynamics, treatment, and follow-up, including the occurrence of hemoptysis, its recurrence rate, the use of anticoagulants, of all patients with PAH are collected in a registry database after written informed consent was obtained from parents or caregivers and with Institutional Review Board approval. Life-threatening hemoptysis was defined as the need of respiratory resuscitation and mechanical ventilation at the time of hemoptysis.
Data analysis was performed using SPSS software (version 16; SPSS 2007, Chicago, Illinois). Data are presented as number (percentage), mean ± SD, or median (interquartile range). Categorical variables were compared between subgroups using chi-square test and ordinal variables (World Health Organization functional class) using Mann-Whitney U test. Continuous variables were compared between subgroups using t test (normally distributed variables) or Mann-Whitney U test (not normally distributed variables). Risk factors for the occurrence of hemoptysis were identified using Cox regression analysis. The cumulative hemoptysis event rate (related to the total PAH population, stratified per diagnosis) was established using Kaplan-Meier curves (one minus survival).
Results
Baseline characteristics of the patients in this cohort of pediatric PAH are listed in Table 1 . During a median follow-up period of 3.5 years (range 0.1 to 19.2), hemoptysis, in ≥1 episodes, occurred in 13 of 74 patients with pediatric PAH (in 7 of 43 patients with IPAH/HPAH and in 6 of 31 patients with PAH-CHD). A total of 44 hemoptysis events occurred in these patients. The hemoptysis event rate was 9.9 per 100 patient-years (9.1 in IPAH/HPAH and 10.7 in PAH-CHD). Life-threatening hemoptysis was observed more often in IPAH/HPAH (9.3%, n = 4) than in PAH-CHD (3.2%, n = 1; p = 0.246, Fisher’s exact). Individual characteristics are listed in Table 2 . Of the 5 patients with life-threatening hemoptysis, 2 patients died during resuscitation, whereas 3 patients were initially stabilized with invasive mechanical ventilation. Eight patients presented with mild hemoptysis. The occurrence of hemoptysis in relation to time is shown in Figure 1 . Occurrence of hemoptysis increased with increasing time since diagnosis, with nearly 70% of all cases of hemoptysis (9 of 13) after at least 6-year PAH follow-up. No differences in the occurrence of hemoptysis could be demonstrated between children with IPAH/HPAH and those with PAH-CHD.
| Variables | IPAH/HPAH (n = 43) | PAH-CHD (n = 31) |
|---|---|---|
| Age at diagnosis (yrs) | 5.4 (1.2–12.4) | 2.0 (0.4–6.9) |
| Time since diagnosis of PAH (yrs) | 3.2 (0.8–7.3) | 5.3 (1.4–13.2) |
| Women | 22 (51) | 23 (74) |
| VKA anticoagulant therapy | 29 (67) | 14 (45) |
| WHO at diagnosis | ||
| I + II | 15 (35) | 10 (32) |
| III | 19 (44) | 15 (48) |
| IV | 9 (21) | 6 (19) |
| Hemoptysis | 7 (16) | 6 (19) |
| Mortality or need LTx related to hemoptysis | 4 (9) | 2 (6) |
| Age at hemoptysis (yrs) | 14 (11–15) | 13 (12–14) |
| Time interval from PAH diagnosis to hemoptysis (yrs) | 4.6 (2.2–8.1) | 7.7 (6.1–9.9) |
| Hemodynamics (RHC) at diagnosis | n = 39 | n = 25 |
| Aortic oxygen saturations (%) | 98 (91–99) | 92 (84–96) |
| Mean PAP (mm Hg) | 52 ± 17 | 53 ± 18 |
| PVR/SVR | 0.9 (0.5–1.1) | 0.9 (0.6–1.3) |
| PVRi (WU.m 2 ) | 14.1 (10.5–25.0) | 14.1 (10.0–18.8) |
| Patients | Age of Patients With Hemoptysis (Yrs)/Gender/WHO FC at Hemoptysis/Subtype | Anticoagulation | Diagnostics or Treatment, A/B/E | Targeted PAH Therapy | Life-Threatening vs Mild Hemoptysis | Outcome and Comments |
|---|---|---|---|---|---|---|
| P1 | 14/♀/III/IPAH | + | A/B | bos + epoprost | 1/1 | Death related to hemoptysis |
| P2 | 15/♀/II/IPAH | + | A | bos + sil | 0/1 | Death nonrelated to hemoptysis |
| P3 | 11/♀/III/IPAH | + | A/B | bos | 1/0 | Death related to hemoptysis |
| P4 | 2/♂/III/IPAH | − | A/B | bos + sil | 0/7 | Alive, recurrent hemoptysis |
| P5 | 18/♀/III/IPAH | + | A | bos | 0/1 | Alive, free from hemoptysis |
| P6 | 22/♀/IV/HPAH | + | A/E | bos + epoprost | 1/3 | Death related to hemoptysis |
| P7 | 15/♀/II/HPAH | + | A/E | bos + epoprost | 1/3 | LTx, related to hemoptysis |
| P8 | 12/♀/IV/PAH-CHD | + | A | — | 0/8 | HLTx, nonrelated to hemoptysis |
| P9 | 13/♀/III/PAH-CHD | + | A | — | 2/0 | Death related to hemoptysis |
| P10 | 12/♀/III/PAH-CHD | + | A | bos | 0/8 | Death related to hemoptysis |
| P11 | 10/♂/IV/PAH-CHD | + | A | bos | 0/2 | HLTx, nonrelated to hemoptysis |
| P12 | 14/♀/III/PAH-CHD | + | A | bos + sil | 0/2 | Alive, free from hemoptysis |
| P13 | 14/♀/III/PAH-CHD | + | A | bos | 0/2 | HLTx, nonrelated to hemoptysis |
Patient management in hemoptysis included systemic antibiotics and oxygen administration in all patients. Twelve of the 13 patients with hemoptysis used vitamin K antagonist (VKA) anticoagulant therapy. This therapy was stopped after the occurrence of the first hemoptysis period in all patients. At the time of hemoptysis, international normalized ratio (INR) ranged from 1.5 to 2.7. The choice of diagnostic or treatment modality was influenced by time period, available resources, and individual ability of patients to undergo such investigations. The following diagnostic modalities were used to confirm, localize, and/or treat the hemoptysis: to identify pulmonary bleeding and confirm or exclude additional pulmonary pathology a chest x-ray was performed in 12 children and a thoracic high-resolution computerized tomography and angiography in 4 children. In 3 children with recurrent mild hemoptysis, bronchoscopy was used to identify the site of pulmonary hemorrhage. Furthermore, in 2 children with HPAH with life-threatening hemoptysis, acute selective bronchial and pulmonary angiography was performed with percutaneous vascular embolization (PVE) of feeding bronchial arteries. One patient underwent initially successful PVE but died 2 months later because of massive hemoptysis, although being listed for lung transplantation. Also, the second patient experienced recurrence of hemoptysis within days after initially successful bronchial PVE, then underwent additional PVE of a bleeding pulmonary arterial branch in the right upper lobe, and finally, 6 days later, underwent a rescue bilateral lung transplantation.
Ideally, high-resolution computerized tomography and angiography were performed in all patients with mild hemoptysis and selective bronchial and pulmonary angiography with PVE in children with life-threatening hemoptysis. Characteristics of patients with PAH with and without hemoptysis are listed in Table 3 . For identification of risk factors for hemoptysis, several characteristics were analyzed in Cox proportional hazards regression analyses ( Table 4 ). Although patients with hemoptysis used significantly more often VKA anticoagulant therapy (p = 0.006), Cox regression did not identify the use of VKA anticoagulant therapy as a risk factor for the first hemoptysis event.
| Variables | Hemoptysis | p | |
|---|---|---|---|
| Yes (n = 13) | No (n = 61) | ||
| Diagnosis | |||
| IPAH/HPAH | 7 (54) | 36 (59) | 0.765 |
| PAH-CHD | 6 (46) | 25 (41) | 0.765 |
| Before tricuspid shunt | |||
| Corrected (no residual shunt) | 0 | 0 | |
| Noncorrected (residual shunt) | 0 | 1 (4) | 1.000 |
| After tricuspid shunt | |||
| Corrected (no residual shunt) | 2 (33) | 10 (40) | 1.000 |
| Noncorrected (residual shunt) | 4 (67) | 15 (60) | 1.000 |
| Age at diagnosis (yrs) | 7.0 (3.1–8.9) | 2.3 (0.6–9.3) | 0.067 |
| Time since diagnosis of PAH (yrs) | 11.4 (7.3–14.8) | 3.5 (0.7–7.2) | 0.001 |
| Women | 11 (85) | 34 (56) | 0.053 |
| Overall mortality or need for LTx | 10 (77) | 25 (41) | 0.018 |
| Mortality or need for LTx related to hemoptysis | 6 (46) | 0 | <0.001 |
| VKA anticoagulant therapy | 12 (92) | 31 (51) | 0.006 |
| WHO at diagnosis | 0.049 | ||
| I + II | 2 (15) | 23 (38) | |
| III | 6 (46) | 28 (46) | |
| IV | 5 (39%) | 10 (16%) | |
| Hemodynamics (RHC) at diagnosis | n = 11 | n = 53 | |
| Aortic oxygen saturations (%) | 93 (84–98) | 96 (90–99) | 0.302 |
| Mean PAP (mm Hg) | 66 (54–71) | 48 (37–61) | 0.005 |
| PVR/SVR | 1.0 (0.7–1.8) | 0.9 (0.5–1.1) | 0.144 |
| PVRi (WU.m 2 ) | 21.0 (14.1–32.7) | 12.7 (7.1–19.7) | 0.016 |
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