2.1 Global and Regional Trends in PAH From 1990 to 2021

Globally, the numbers of DALYs in 1990 and 2021 were 687,419.3 (95% uncertainty interval [UI]: 535,240.8–813,086.3) and 642,104.3 (95% UI: 552,272.7–728,993.2) with a decrease of 6.6% during the past 30 years, while a 13.9% increase was exhibited in high SDI countries. The middle SDI regions recorded the highest cases of DALYs in both 1990 and 2021, as well as the greatest number of PAH cases. The ASRs for DALYs globally were 13.2 out of 100,000 in 1990 and 8.2 out of 100,000 in 2021, indicating a 37.9% reduction. A decrease in DALY ASR was observed across all five SDI regions over the past few decades, with the high-middle SDI showing the largest significant decrease of 50.4% and 2.20 in the estimated annual percent change (EAPC) (Table 1).

Global PAH deaths consistently increased from 14,842.5 in 1990 to 22,020.5 in 2021. During the past 30 years, almost all SDI countries were on an upward trend, especially in the high SDI regions with a 76.6% increase. ASR of deaths decreased globally from 3.5 cases/million in 1990 to 2.7 cases/million in 2021 (a 22.9% and a 0.57 EAPC decrease), with significant declines in high-middle SDI countries (a 31.4% and a 1.07 EAPC decrease) (Table 2).

The prevalence of total PAH cases nearly doubled between 1990 and 2021, rising from an estimated 105,703.3 cases (95% UI: 86,381.4–130,334.3) to 191,808.2 cases (95% UI: 155,356.9–235,787.1). This increase was observed across all five SDI regions, with middle SDI countries accounting for the largest number of patients in both 1990 and 2021. Notably, the low SDI regions experienced the greatest percentage increase, with a 1.18-fold rise. The global ASR of PAH prevalence has remained relatively stable at 22.8 cases/million, and the increase in ASR of prevalence was more pronounced in middle and low-middle SDI quantiles, with percentage changes of 7.0% and EAPCs of 0.21 and 0.27, respectively (Table 3).

2.2 National Trend of PAH Burden From 1990 to 2021

Tables S3–S5 provide the DALYs, deaths, and prevalence data for each country and region. In 2021, China mainland, India, and the United States remained the top three countries in terms of DALY numbers, with 150,940.7 (99,583.3–186,503.4), 94,736.7 (69,016.9–131,902.1), and 36,197.6 (33,003.8–38,647.8) cases, respectively. From 1990 to 2021, the number of DALYs in five countries or regions, including Taiwan (Province of China), Qatar, Mauritius, Afghanistan, and Kuwait, more than doubled. Taiwan (Province of China) and Qatar ranked first and second, with percentage changes of 273.9% and 268.7%, respectively. Puerto Rico, Greenland, and Egypt were the top three regions with the largest reductions in DALYs, showing decreases of 81.0, 76.4, and 69.8% over the past three decades. Regarding ASR, Egypt (74.2 out of 100,000 in 1990 vs. 16.7 out of 100,000 in 2021) and Mongolia (50.7 out of 100,000 in 1990 vs. 43.9 out of 100,000 in 2021) were the highest-ranking countries in 1990 and 2021. Puerto Rico, Egypt, and Greenland exhibited a significant decrease in DALY ASR, with reductions of 83.2, 77.8, and 77.6%. While the ASR of DALYs decreased in most countries, six nations and territories showed the opposite trend: Mauritius, Latvia, Georgia, Guyana, Taiwan (Province of China), and Kuwait (in descending order of growth change). Notably, the SDI in these countries was greater than or equal to the medium SDI level (Table S3).

In terms of the number of deaths, similarly, China mainland, India, and the United States of America were the top three countries in both 1990 and 2021, with 7318.0 (4835.7–9075.8), 2611.6 (1738.6–4059.8), and 1785.1 (1535.4–1944.9) deaths, respectively, in 2021. From 1990 to 2021, Puerto Rico experienced the most significant decrease in the number of deaths. Notably, of the top 10 countries with the largest increases in deaths, 80% were high- or high-middle-SDI countries. Taiwan (Province of China) and Latvia, both with high SDI levels, recorded the largest increases in the number of deaths, with increases of 510.0 and 486.4%, respectively. After age standardization, Cyprus ranked first in 1990 with 20.9 cases per million, while Mongolia ranked first in 2021 with 15.9 cases per million. Similar to the DALY ASR, Puerto Rico, Egypt, and Greenland also saw a significant decrease in death ASR, with reductions of 70.9, 63.7, and 61.2%, respectively. While age-standardized mortality declined in most countries, ASR increased in nine countries or regions, including Latvia, the Republic of Moldova, Georgia, Mauritius, Guyana, Lithuania, Taiwan (Province of China), Kuwait, and Estonia (in descending order of positive percentage change), most of which were high-SDI areas (Table S4).

The number of prevalent cases increased in nearly all countries over the past three decades. In 1990 and 2021, China mainland led with 22,027.9 (17,840.2–27,321.5) and 41,135.2 (32,838.9–51,357.3) cases, respectively, followed by India with 10,592.0 (8,714.5–13,169.4) and 23,741.7 (19,176.4–29,559.1) cases, respectively. Among the top 10 countries in 1990, the United States of America, Japan, Brazil, and Indonesia saw increased rankings in 2021, whereas Russia, Germany, Italy, and France declined. From 1990 to 2021, Qatar experienced the greatest percentage increase in cases of 7.17, followed by the United Arab Emirates of 6.16 and Jordan of 3.54. Countries with low or low-middle SDI levels comprised more than half of the top 30 countries with increased prevalence. Bulgaria had the most significant reduction, with a 29.1% decrease in prevalence number. ASR data showed that Switzerland consistently ranked first, with 67.6 cases/million in 1990 and 70.9 cases/million in 2021, followed by Sweden, with 60.5–63.0 cases/million. In 1990, the top 20 countries by ASR were predominantly high or high-middle SDI, with exceptions such as Ghana, a low-middle SDI country. In 2021, high-SDI countries dominated the top 20. Nigeria had the most notable increase in ASR of 52.9%, followed by El Salvador of 46.7% and Bangladesh of 42.1%. Among the top 10 countries with the highest ASR increases, seven were from low-middle SDI regions, two were high SDI countries, including Denmark and Germany, and one had middle SDI level (Türkiye) (Table S5).

2.3 Age and Sex Differences in PAH from 1990 to 2021

Based on the established age division of GBD, individuals with PAH were divided into four age groups: younger than 14 years, 14–49 years, 50–69 years, and older than 70 years.

Regarding the global DALYs number, younger age groups (0–14 and 15–49 years) predominated in earlier years. Notably, the number of DALYs in younger populations steadily declined over time, while the burden in older age groups, particularly those over 70 years, continued to rise. Similar trends were observed across different SDI countries, with higher proportions of DALYs attributed to older populations in countries with higher SDI. This trend was most pronounced in middle-high and high SDI nations. In contrast, low and lower-middle SDI countries still saw a high proportion of DALYs in younger populations, indicating a significant difference in the age distribution of DALYs between higher and lower SDI regions. A similar trend was observed in both males and females. Compared with females, the proportion of DALYs number among males was higher in younger individuals across different SDI countries, especially in children aged 0–14 years (Figures 1A and S3A and Tables S6 and S7).

Over the past 30 years, the number of deaths among children aged 0–14 years has gradually declined, while the number of elderly individuals aged over 70 years has continued to rise. This trend is more pronounced in countries with middle, high-middle, and high SDI. In terms of gender differences, the proportion of child deaths in the male population remains higher than in females, especially in those low and low-middle SDI regions (Figures 1B and S3B and Tables S6 and S7).

Globally, the highest prevalence was observed in the 15–49 and 50–69 years age groups. In countries with higher SDI, particularly in high-SDI countries, individuals aged 70+ years constituted a greater proportion, whereas younger age groups (0–14 and 15–49 years) were more prevalent in lower-SDI countries. Females accounted for 62.71% of the global prevalence and there was a pronounced increase in older male populations (aged 50–69 and 70+ years) in high-middle- and high-SDI countries during the past decades (Figures S2 and S3C and Tables S6 and S7).

2.4 The Trends in Pediatric PAH from 1990 to 2021

The presentation of epidemiological data on pediatric PAH is crucial for enhancing disease management and control. The data across age and sex groups from 1990 to 2021 in the population aged 0–19 years were analyzed. We categorized individuals under 19 years of age into six age groups—less than 12 months, 12–23 months, 2–4 years, 5–9 years, 10–14 years, and 15–19 years—based on GBD age divisions.

Globally, the highest numbers of DALYs and deaths occurred in children under 12 months of age, followed by a significant decline after the first year. Over the past three decades, the numbers of DALYs and deaths in children under 12 months of age have decreased by 62.6% globally, with the most notable reductions seen specifically in low-middle and middle SDI countries. The number of DALYs for children aged 10–19 years has remained nearly unchanged from 1990 to 2021. The ASR of DALYs and deaths followed a similar pattern, peaking in children under 1 year of age. From 1990 to 2021, the ASR of DALYs and deaths in children under 1 year significantly declined across all five SDI country groups. Nonetheless, low and low-middle SDI regions continue to exhibit higher ASRs of DALYs and deaths compared with higher SDI regions, which requires further attention (Figure 2A,B and Tables S8 and S9). Among PAH patients under 10 years of age, males demonstrated higher ASRs of DALYs and deaths, especially in low-SDI countries, with this trend reversing as age increased. In the 10–19 years age group, females accounted for a higher proportion of DALYs and deaths, showing a significant upward trend over the past three decades. Globally, compared with 1990, the proportion of DALYs and deaths among female children aged 1–4 years declined in 2021 (Figure S4A,B).

In 2021, the prevalence of PAH globally increased with age. For the 10–14 and 15–19 years age groups, prevalence rose by 22.1 and 17.8%, respectively, compared with 1990. Trends in prevalence across different age groups in 1990 and 2021 were generally consistent with the trends in absolute numbers. The ASR of prevalence in children under 5 years old was similar across all five SDI groups. However, in older age groups, higher ASRs were observed in high-middle and high-SDI countries (Figure 2A,B and Tables S8 and S9). PAH was more prevalent among females under 19 years of age, accounting for over 50% of cases, particularly in low-SDI regions. The sex distribution of PAH prevalence did not change significantly from 1990 to 2021 (Figure S4C).

2.5 Associations Between PAH Burden with SDI and Universal Health Coverage Index Levels

Figure 3 presents the associations of SDI and universal health coverage index (UHCI) in 2021 with the ASRs of DALYs, deaths, and prevalence. In summary, all ASRs were significantly correlated with both SDI and UHCI levels. As SDI levels improved, the ASR of DALYs (r = −0.20 [−0.27, −0.12], p < 0.001) and deaths (r = −0.11 [−0.19, −0.03], p = 0.010) decreased. In contrast, SDI was positively correlated with the prevalence ASR (r = 0.41 [95% CI: 0.34–0.47], p < 0.001), indicating higher PAH prevalence in countries with higher SDI levels. Similarly, a higher UHCI was associated with a lower ASR of DALYs (r = −0.19 [−0.27, −0.11], p < 0.001) and deaths (r = −0.09 [−0.17, −0.01], p = 0.030), but a higher ASR of prevalence (r = 0.43 [0.36–0.49], p < 0.001).

2.6 Age, Period, and Cohort Effects on PAH Burden in Different SDI Regions

The APC model was employed to reveal the actual burden of PAH, independent of the specific impacts of age, period, and birth cohort. Figure 4A–C presents APC model-derived estimates of PAH DALYs by SDI quantiles. Globally and across all SDI quantiles, DALYs in the 0–5 years age group showed a significant decline. As age increased, DALYs gradually rose, particularly among individuals over 50 years old, with middle SDI countries experiencing the most pronounced increase. In high SDI countries, a gender disparity in DALYs was evident, with female DALYs levels exceeding those of males. However, as age progressed, the DALYs for male patients rose sharply, approaching those of female patients and, in some cases, surpassing those of female patients, particularly in middle SDI countries. Period effects revealed a decreasing trend in DALYs rates among both males and females globally and across all five SDI quintiles. Notably, the decline in DALYs was more pronounced in high-middle SDI countries, and across all regions, the reduction in DALYs over the past 30 years was greater for male PAH patients than for females. Cohort effects indicated that patients born between 1912 and 1932 experienced an increase in DALYs, which was more pronounced in males than in females. In contrast, DALYs rates improved significantly for those born after 1932, particularly in high SDI countries. Moreover, the APC results for death show a similar trend to those observed for DALYs (Figure S5).

PAH prevalence rates increased with age, except in the 80–84 years age group. Females consistently showed higher prevalence rates than males across all age groups. Period effects showed an increasing prevalence rate globally in males but not in females. Moreover, period effects varied among the SDI quintiles, with a continuously increasing prevalence rate in the past 30 years in low-middle and middle SDI quintiles. Cohort effects were less pronounced globally, with trends varying across SDI regions as indicated by improvements in low-SDI regions and deterioration in low-middle, middle, and high-middle-SDI regions (Figure S6).

2.7 Age, Period, and Cohort Effects on PAH Burden in Exemplary Countries

We illustrated the unfavorable trends of the disease in exemplary countries across the SDI quintiles to further reveal the changes of PAH during the past three decades, which provided more reliable support for policy formulation and implementation in regions and countries.

Despite a global downward trend in DALYs and deaths, some countries have yet to witness notable improvements, and in some cases, the situation has actually worsened. Ten countries or regions including two high-SDI regions [Taiwan (Province of China) and the United States of America], two high-middle-SDI countries (Greece and Libya), two middle-SDI countries (Algeria and Tunisia), two low-middle-SDI countries (Pakistan and Sudan), and two low-SDI countries (Yemen and Zimbabwe) were selected, which presented the unsatisfactory APC effects in DALYs (Figure 5A–E). Similarly, across these representative nations, there was a marked reduction in DALYs among children under 10 years of age, which then rose significantly with advancing age. In addition, gender disparities have been noted in certain countries. Period effects have shown an increasing trend in DALYs rates over time in Taiwan (Province of China), Greece, Libya, Algeria, Tunisia, Sudan, Yemen, and Zimbabwe. On the other hand, despite a slight downward trend in the United States and Pakistan, it was not significant, and even exhibited a contrasting pattern in some instances. Cohort effects suggested that, in most of the exemplary countries including Taiwan (Province of China), Libya, Algeria, Tunisia, Sudan, Yemen, and Zimbabwe, patients born after 1997 even exhibited a trend of increasing DALYs. Although a few selected countries exhibited a declining trend in DALYs for later birth cohorts, the decrease was not very significant.

We also selected ten countries including two high-SDI regions (Germany and the United States of America), two high-middle-SDI countries (Italy and Spain), two middle-SDI countries (Algeria and Sri Lanka), two low-middle-SDI countries (Morocco and Sudan), and two low-SDI countries (Afghanistan and Yemen) to exhibit the unsatisfactory APC effects in deaths (Figure S7A–E). Similar to DALYs, deaths showed a notable decline among children under 10 years old, followed by a significant increase with age. Moreover, gender differences were observed in some countries. Both period and cohort effects suggested that, in most representative countries, there had been no significant improvement in mortality over time or across cohorts, particularly in countries with SDI lower than high-middle.

The APC effects of prevalence in exemplary countries are illustrated in Figure S8A–E. We analyzed ten countries representing various SDI levels: two high-SDI countries (France and Germany), two high-middle-SDI countries (Italy and the Russian Federation), two middle-SDI countries (China mainland and Türkiye), two low-middle-SDI countries (Nigeria and Bangladesh), and two low-SDI countries (Chad and Afghanistan). In all cases, prevalence rose sharply with age. Period and cohort effects generally showed an upward trend across most countries. Moreover, notable sex differences were observed, especially emphasized by age effects.

2.8 PAH Burden Projections Through 2050 Across Different Sex Populations

Global projections were needed to properly evaluate the burdens of PAH and its long-term outcomes. After demonstrating the historical trends of the PAH burden globally, we conducted a regression model to further forecast the cases and ASRs of DALYs, deaths, and prevalence through 2050 (Table S10).

A declining trend in DALYs was observed globally, primarily among the male population. The global DALY cases were projected to reach 519,398.8 (412,506.0–626,291.6), reflecting a 19.11% decrease compared with 2021. In contrast, the number of deaths was expected to gradually increase, with a significant rise among females. By 2050, global PAH-related deaths were projected to reach 36,594.8 (32,487.7–40,701.9), marking an increase of nearly 70% from 2021. The prevalence cases were projected to grow rapidly over the next 30 years for both males and females, with females consistently representing the majority across all time points. By 2050, the number of cases was expected to reach 300,484.7 (240,568.8–360,400.6), nearly doubling the count from 2021 (Figure S9A).

The ASR of DALYs and deaths were projected to decline over the next 30 years, particularly among male patients. In contrast, the ASR of prevalence is expected to remain stable throughout the projected period, with a slight upward trend observed in the male population (Figure S9B).

4.1 Overview

An available dataset, the GBD, provides data compiled by the WHO and collaborating countries, accessible via the Global Health Data Exchange query tool (http://ghdx.healthdata.org/gbd-results-tool) for data extraction. Data collection is iterative and continuous to demonstrate dynamic disease changes. The GBD contains epidemiological data on 371 diseases and injuries across 204 countries and territories [41]. Compared with GBD 2019, the updated GBD 2021 includes statistics up to 2021 and introduces estimates for PAH. The GBD study adhered to ethical principles in data collection and study design, as detailed in previous publications [42, 43]. In this study, the DALYs, prevalence, and mortality of PAH were comprehensively analyzed based on the GBD 2021 dataset.

Briefly, our work is designed as an observational study to reveal the burden of PAH at global, regional, and national levels, thereby raising awareness of this fatal disease.

4.2 Data Source

DisMod-MR 2.1 was employed to estimate the prevalence of PAH utilizing covariates such as the healthcare access and quality index, the natural log of age-standardized schistosomiasis prevalence, and an age-standardized summary exposure value scalar for HIV prevalence.

Disability weights were applied to each patient with PAH to calculate unadjusted years lived with disability (YLDs). Through the comorbidity correction model, initial estimates were adjusted for comorbid conditions, resulting in comorbidity-adjusted YLDs. The sum of the adjusted YLDs with the years of life lost (YLLs) due to premature mortality yielded estimates of DALYs.

4.3 DALYs, Deaths, and Prevalence

DALYs represent a comprehensive measure for assessing the total disease burden. They are calculated as the sum of YLDs, which quantify the loss of one full healthy year due to disability or illness, and YLLs, which measure the impact of premature mortality.

Prevalence signifies the total number of existing cases by the end of a year, reflecting the ubiquity of a disease. The definitions used to estimate the prevalence of PAH in GBD studies were based on the World Health Organization classification of the group 1 PH.

The DALYs, deaths, and prevalence attributable to PAH were estimated across different levels of geographical stratification, disaggregated by sex and spanning 25 years age groups (from 0 to 95 years and older) for each year from 1990 to 2021.

All reported measurements included numbers, age-standardized rates (ASRs) per 100,000 people, and 95% UIs for all estimates. The 95% UIs were derived from the 2.5th and 97.5th ordinals of 500 draws from the posterior distribution [45].

4.4 Global Regions

Our analysis included 204 countries and territories [46]. This geographical division aids in understanding and researching the global distribution of the disease burden, facilitating detailed analyses and comparisons across various countries to inform targeted public health interventions and policies.

4.5 SDI and UHCI

The SDI is a composite metric derived from three key factors: per capita income, average education level among individuals aged 15 years and older, and total fertility rate among females under 25 years of age. This index reflects social and economic conditions and serves as a comprehensive indicator of the developmental status of a country or region. In the 2021 GBD study, all countries and territories were categorized into five SDI levels: low (<0.46), low-middle (0.46–0.62), middle (0.62–0.71), high-middle (0.71–0.81), and high (>0.81); detailed information is provided in Table S1 [47]. This study also included an analysis of the disease burden across these SDI categories.

The UHCI is a composite measure used to evaluate individuals’ access to essential health services without suffering financial hardship. It typically includes indicators that assess service coverage and financial protection. The index aims to reflect the availability, accessibility, and quality of health services, as well as the equity and financial risk protection provided by a healthcare system. The goal of the UHCI is to ensure that everyone can obtain the health services they need without being pushed into poverty by healthcare costs [48] (https://www.who.int/data/gho/indicator-metadata-registry/imr-details/4834).

The associations of SDI and UHCI with DALYs, deaths, and prevalence were explored.

4.6 Statistical Analysis

Our analysis included diverse age groups and both sexes to comprehensively illustrate the global burden of PAH from 1990 to 2021, as measured by DALYs, deaths, and prevalence. The EAPC, calculated based on linear regression models and natural logarithm fitting data, was used to quantify the changes over a specific time interval. EAPC was calculated using the formula 100 × (eβ − 1), and more specific information was provided in a previous study [49]. In this study, we used the EAPC to estimate the trends in ASR from 1990 to 2021.

To explore the correlations of PAH DALYs, deaths, and prevalence with the SDI and UHCI, we performed a Pearson correlation analysis and fitted the linear trend model globally. The UHCI data were obtained from the World Health Organization website (https://www.who.int/data/gho/data/indicators/indicator-details/GHO/uhc-index-of-service-coverage).

The APC model examined the effects of age, period, and birth cohort on trends in PAH burden, addressing collinearity among age, period, and cohort, offering a distinct advantage over conventional epidemiological analyses [10]. The detailed methodology has been reported in previous studies [50, 51]. Specifically, the prevalence and population numbers of each country or region were set as the input data. Because of the scarce number of PAH cases above 85 years (Figure S1), this analysis mainly included populations aged 0–84 years. The study period, from 1992–1996 to 2017–2021, was segmented into six 5-year periods. Age was categorized into 17 groups, ranging from 0–4 years and up to 80–84 years at 5-year intervals. The birth cohorts were divided into 22 groups from 1908–1916 to 2013–2021 at 5-year intervals (Table S2). The APC output included net and local drifts, age, period, and cohort effects, as defined in our previous studies [52, 10, 53, 54].

We generated forecasts for global PAH burden using the number and ASRs of DALYs, deaths, and prevalence. Detailed information about the forecast methods was mentioned in the previous study [55]. Briefly, for prevalence and mortality projections, we used data from 1990, 1995, 2000, 2005, 2010, 2015, and 2019 as input for our regression models. For DALYs, considering the distinct temporal pattern (initial decline followed by an increase before 2012, and a continuous decrease thereafter), we utilized data points from 2012, 2014, 2016, 2018, 2020, and 2021 to better capture the current declining trend to improve forecasting accuracy. Our regression models included year and age as predictors, with a cubic spline term for age to account for nonlinear age effects. Sex-specific models were run 1000 times, and the resulting coefficients were used to predict rates for 2030, 2040, and 2050. The predicted rates were then multiplied by forecasted global population estimates to obtain the absolute numbers of cases, deaths, and DALYs. Additionally, we calculated ASRs using the WHO World Standard Population.

All analyses were performed using R software (version 4.3.2). Significance was determined using two-tailed p values, with statistical significance set at p < 0.05.