Hereditary Hemorrhagic Telangiectasia (HHT) is a rare autosomal dominant vascular disorder characterized by the presence of large and small arteriovenous malformations in a number of vascular beds. HHT has an estimated prevalence of 1 in 5,000 to 1 in 10,000 individuals and is diagnosed using the Curacao criteria [
We obtained a representative sample of hospitalized HHT patients in the United States by using the Nationwide Inpatient Sample (NIS) database. The Nationwide Inpatient Sample (NIS) is a large administrative database that contains a yearly record of
We recorded the following baseline patient characteristics: age, gender, and race. Age was categorized into four groups: <18, 18–50, 51–65, and >65 and race was categorized as White, Black, Hispanic, and Asian exactly as recorded in the NIS database. Baseline comorbidities studies included smoking status, presence of hypertension, presence of diabetes mellitus, and Charlson comorbidities index (CCI). The Charlson comorbidity index is a validated prognostic index for administrative use that has been shown to be predictive of 10-year mortality [
Complications were divided into hemorrhagic, cardiopulmonary, neurologic, and hepatobiliary related. Hemorrhagic complications included anemia, gastrointestinal bleeding, epistaxis, hemoptysis, and hematemesis. Cardiopulmonary complications included congestive heart failure (CHF), acute myocardial infarction (MI), coronary artery disease, atrial fibrillation, ventricular fibrillation/cardiopulmonary arrest, deep venous thrombosis (DVT), pulmonary embolism, pulmonary hypertension, and pulmonary arteriovenous malformation (PAVM). Neurologic complications studied included acute ischemic stroke, transient ischemic attack (TIA), intracranial hemorrhage (ICH), subarachnoid hemorrhage (SAH), seizure, headache, cerebral abscess, brain arteriovenous malformation (BAVM), and spinal vascular malformation. Hepatobiliary complications included cirrhosis, portal hypertension, acute and chronic liver failure, jaundice, and biliary complications. In addition to diagnoses, we studied procedural utilization including cardiac catheterization, cardiopulmonary resuscitation, hemodialysis, blood transfusion, upper and lower gastrointestinal endoscopy, liver transplantation, inferior vena cava (IVC) filter placement, and epistaxis management including nasal packing, endovascular therapy, and surgical ligation.
Outcomes studied included in-hospital mortality, discharge location (home, short term care facility versus a long term care facility) hospital length of stay (LOS), rates of iatrogenic complications, and hospital billing data. All complications and outcomes were compared according to the 4 different age groups as noted above.
All statistical analysis was performed using the SAS-based statistical software package JMP13.0 (https://www.jmp.com, Cary, NC). All categorical variables were compared using the chi-squared test. All continuous variables were studied using the Student’s
Baseline patient characteristics are shown in Table
Baseline characteristics in different age groups.
Age | <18 | 18–50 | 51–65 | ≥65 |
|
|
458 | 1938 | 3097 | 4800 | |
Elective admission | 70 (16.9) | 353 (20.5) | 483 (17.6) | 629 (15.8) | <.0001 |
|
254 (55.7) | 1247 (64.3) | 1732 (55.9) | 2969 (61.9) | <.0001 |
Race | |||||
White | 251 (65.0) | 1121 (70.5) | 1811 (71.0) | 3223 (83.3) | <.0001 |
Black | 39 (10.1) | 249 (15.7) | 381 (14.9) | 288 (7.4) | |
Hispanic | 63 (16.3) | 163 (10.3) | 286 (11.2) | 256 (6.6) | |
Asian | 5 (1.3) | 16 (1.0) | 33 (1.3) | 23 (0.6) | |
Income quartile |
|||||
1 | 63 (13.8) | 444 (23.5) | 780 (25.9) | 913 (19.3) | <.0001 |
2 | 107 (23.5) | 434 (23.0) | 735 (24.4) | 1190 (25.2) | |
3 | 144 (31.6) | 487 (25.8) | 716 (23.8) | 1243 (26.3) | |
4 | 142 (31.1) | 524 (27.7) | 778 (25.9) | 1379 (29.2) | |
CCI | 0.0 (0.2) | 0.5 (0.9) | 0.9 (1.2) | 1.2 (1.2) | <.0001 |
CCI = Charlson comorbidity index.
Complications and procedures in hospitalized HHT patients are shown in Table
Complication rates and procedures in different age groups.
Age groups | |||||
---|---|---|---|---|---|
Complication | <18 | 18–50 | 51–65 | >65 |
|
|
458 | 1938 | 3097 | 4800 | |
|
70 (15.3) | 1032 (53.3) | 2085 (67.3) | 3268 (68.1) | <.0001 |
Anemia | 53 (11.6) | 867 (44.7) | 1789 (57.8) | 2775 (57.8) | <.0001 |
Epistaxis | 11 (2.4) | 265 (13.7) | 592 (19.1) | 801 (16.7) | <.0001 |
GI bleed | 19 (4.2) | 192 (9.9) | 328 (10.6) | 572 (11.9) | <.0001 |
Hematemesis | 3 (0.7) | 26 (1.3) | 36 (1.2) | 43 (0.9) | .29 |
Hemoptysis | 3 (0.7) | 4 (0.2) | 12 (0.4) | 31 (0.7) | .09 |
|
51 (11.1) | 329 (17.0) | 1075 (24.7) | 2761 (57.5) | <.0001 |
CHF | 3 (0.7) | 94 (4.9) | 467 (15.1) | 1488 (31.0) | <.0001 |
Coronary artery disease | 0 (0.0) | 81 (4.2) | 371 (12.0) | 1266 (26.4) | <.0001 |
Atrial fibrillation | 0 (0.0) | 31 (1.6) | 298 (9.6) | 1094 (22.8) | <.0001 |
Pulmonary hypertension | 44 (9.6) | 161 (8.3) | 295 (9.5) | 450 (9.4) | .48 |
MI | 0 (0.0) | 11 (0.6) | 52 (1.7) | 108 (2.3) | <.0001 |
Pulmonary embolism | 0 (0.0) | 25 (1.3) | 43 (1.4) | 49 (1.0) | .046 |
DVT | 0 (0.0) | 16 (0.8) | 42 (1.4) | 50 (1.0) | .04 |
Pulmonary AVM | 8 (1.8) | 20 (1.0) | 33 (1.1) | 21 (0.4) | .0006 |
Vfib/cardiac arrest | 0 (0.0) | 3 (0.2) | 12 (0.4) | 17 (0.4) | .28 |
|
77 (16.8) | 453 (23.4) | 385 (12.4) | 361 (7.5) | <.0001 |
Seizure | 38 (8.3) | 211 (10.9) | 207 (6.7) | 172 (3.5) | <.0001 |
Headache | 25 (5.5) | 186 (9.6) | 99 (3.2) | 53 (1.1) | <.0001 |
Stroke | 2 (0.4) | 39 (2.0) | 56 (1.8) | 138 (2.9) | .0004 |
BAVM | 20 (4.4) | 37 (1.9) | 22 (0.7) | 9 (0.2) | <.0001 |
TIA | 0 (0.0) | 9 (0.5) | 20 (0.7) | 40 (0.8) | .09 |
Cerebral abscess | 0 (0.0) | 23 (1.2) | 24 (0.8) | 8 (0.2) | <.0001 |
ICH | 1 (0.2) | 16 (0.8) | 8 (0.3) | 6 (0.1) | <.0001 |
SAH | 2 (0.4) | 12 (0.6) | 7 (0.2) | 0 (0.0) | <.0001 |
Cerebral aneurysm | 1 (0.2) | 10 (0.5) | 9 (0.3) | 11 (0.2) | .27 |
Spinal vascular malformation | 1 (0.2) | 4 (0.2) | 0 (0.0) | 0 (0.0) | .0009 |
|
5 (1.1) | 113 (5.8) | 265 (8.6) | 277 (5.8) | <.0001 |
Cirrhosis | 2 (0.4) | 67 (3.5) | 201 (6.5) | 178 (3.7) | <.0001 |
Biliary complications | 2 (0.4) | 32 (1.7) | 54 (1.7) | 81 (1.7) | .22 |
Portal hypertension | 1 (0.2) | 20 (1.0) | 61 (2.0) | 51 (1.1) | .0004 |
Chronic liver failure | 1 (0.2) | 10 (0.5) | 16 (0.5) | 19 (0.4) | .71 |
Jaundice | 0 (0.0) | 4 (0.2) | 9 (0.3) | 7 (0.2) | .39 |
Acute liver failure | 0 (0.0) | 5 (0.3) | 1 (0.0) | 6 (0.1) | .12 |
|
97 (21.2) | 875 (45.2) | 1768 (57.1) | 2617 (54.5) | <.0001 |
Transfusion | 59 (12.9) | 586 (30.2) | 1343 (43.4) | 1920 (40.0) | <.0001 |
Upper endoscopy | 15 (3.3) | 184 (9.5) | 286 (9.2) | 496 (10.3) | <.0001 |
Lower endoscopy | 8 (1.8) | 80 (4.1) | 124 (4.0) | 244 (5.1) | .002 |
Surgical ligation for epistaxis | 5 (1.1) | 62 (3.2) | 141 (4.6) | 196 (4.1) | .001 |
Nasal packing | 2 (0.4) | 31 (1.6) | 102 (3.3) | 240 (5.0) | <.0001 |
Endovascular treatment of epistaxis | 16 (3.5) | 48 (2.5) | 51 (1.7) | 36 (0.8) | <.0001 |
Cardiac catheterization | 2 (0.4) | 40 (2.1) | 95 (3.1) | 138 (2.9) | .003 |
Hemodialysis | 0 (0.0) | 35 (1.8) | 30 (1.0) | 67 (1.4) | .005 |
IVC filter | 0 (0.0) | 19 (1.0) | 34 (1.1) | 39 (0.8) | .11 |
CPR | 1 (0.2) | 7 (0.4) | 5 (0.2) | 7 (0.2) | .31 |
GI = gastrointestinal; CHF = congestive heart failure; MI = myocardial infarction; DVT = deep vein thrombosis; AVM = arteriovenous malformation; Vfib = ventricular fibrillation; BAVM = brain arteriovenous malformation; TIA = transient ischemic attack; ICH = intracranial hemorrhage; SAH = subarachnoid hemorrhage; IVC = inferior vena cava; CPR = cardiopulmonary resuscitation.
Age and frequency of specific complications. GI = gastrointestinal; CHF = congestive heart failure; AVM = arteriovenous malformation; BAVM = brain arteriovenous malformation; SAH = subarachnoid hemorrhage; ICH = intracranial hemorrhage; TIA = transient ischemic event.
Proportion of patients with a specific complication in each age group.
Prevalence of complications by age group.
Cardiopulmonary complications were the second most common group of complications noted in the HHT population affecting 41.0%
Neurological events were the third most common category of complications seen in 12.4%
Hepatic complications occurred in 6.4%
Procedures were noted in a total of 5357 admissions (52.1%). Blood transfusions were the most frequent accounting for 73.0%
In hospital outcomes are summarized in Table
Outcomes in different age groups.
Age | <18 | 18–50 | 51–65 | ≥65 |
|
|
458 | 1938 | 3097 | 4800 | |
Long term | 5 (1.1) | 64 (3.3) | 220 (7.1) | 919 (19.2) | <.0001 |
Home | 417 (91.1) | 1663 (85.9) | 2431 (78.5) | 3011 (62.8) | <.0001 |
Short | 10 (2.2) | 65 (3.4) | 80 (2.6) | 105 (2.2) | .048 |
Death | 3 (0.7) | 21 (1.1) | 44 (1.4) | 132 (2.8) | <.0001 |
LOS | 4.1 (6.0) | 4.3 (5.6) | 4.4 (5.5) | 4.8 (5.8) | .0006 |
Charge | 29908 (71669) | 32793 (60523) | 30616 (48943) | 28149 (46686) | .008 |
Iatrogenic complication | 33 (7.2) | 119 (6.1) | 214 (6.9) | 280 (5.8) | .22 |
Long-term = discharged to a long term care facility; home = discharged to home; short = discharged to a short term rehabilitation facility; LOS = hospital length of stay; charge = total hospital charges.
Our data provide the first comprehensive assessment of the impact of age on various complications in a very large nationwide sample of hospitalized HHT patients. We show for the first time that the vast majority (>75%) of hospitalizations occur in HHT patients older than 50 years of age. In addition, more than 80% of bleeding and cardiopulmonary and hepatobiliary complications occurred in this same age group. Although the primary reason for hospitalization could not be ascertained from this database, the progressive increase in the rates of bleeding and cardiovascular and hepatobiliary complications suggest that these were the likely drivers for hospitalization in the older age groups.
Several previous studies have investigated the effect of age on the prevalence and complication rates amongst HHT patients [
We have previously shown a high rate of bleeding related complications amongst hospitalized HHT patients [
A very similar age trend is also noted in cardiovascular and hepatobiliary complications with more than 90% of cardiopulmonary and 82% of hepatobiliary complications occurring in those older than 50. Congestive heart failure alone accounted for 30% of all cardiopulmonary complications and pulmonary hypertension was noted in 14% of cases. Although the exact etiology of these complications (HHT- versus non-HHT-related) can be debated, the age-related increases in anemia, CHF, atrial fibrillation, pulmonary hypertension, and hepatobiliary complications all appear to point towards worsening AVM related disease burden in older HHT patients. This is the first study to show these surprisingly high rates of cardiopulmonary and hepatobiliary complications amongst hospitalized HHT patients. Current HHT treatment guidelines do not advocate screening for liver involvement in asymptomatic HHT patients [
Neurological complications were somewhat unique in that the highest incidence of seizures, headaches, brain abscess, ICH, SAH, cerebral aneurysm, and spinal vascular malformations occurred in the 18–50 age group. This is a very interesting and somewhat counterintuitive observation, given that de novo CNS vascular malformations rarely (if at all) occur in adult HHT patients. There are several potential explanations for this significant time-delay in the occurrence of neurological complications: (1) poor knowledge and understanding of HHT amongst patients and healthcare providers resulting in prolonged diagnostic delays into adulthood [
Limitations of our study include potential coding and documentation errors which remain a concern for any data obtained from large administrative databases. Additionally, the lack of individual patient level clinical and genetic data prevents the assessment of individual HHT characteristics and the number of Curacao criteria met. These factors have been previously shown to influence rates of complications and outcomes [
In a large nationwide sample of hospitalized HHT patients in the USA, the vast majority of serious complications occurred in those older than 50 years of age. There was also a significant, age-related increase in the rates of hepatobiliary, cardiovascular, and bleeding related complications amongst these patients. These findings provide convincing evidence that older patients bear a vast majority of the HHT-related disease burden especially in relation to bleeding and cardiovascular complications.
The authors declare that there are no conflicts of interest.
Vivek N. Iyer and Waleed Brinjikji (primary) were responsible for study design and concept with contribution from all authors. Vivek N. Iyer, Waleed Brinjikji, Dinesh Apala, Aditya Kotecha, and Bibek S. Pannu were responsible for data collection and analysis. Vivek N. Iyer prepared and revised the first draft of the manuscript and all authors revised the paper. Vivek N. Iyer and Waleed Brinjikji were the guarantors.