Prevalence of pulmonary hypertension in non-transfusion-dependent thalassemia patients at tertiary level hospital in Bangladesh

Ethical clearance

Before commencing the study, ethical approval was obtained from the Ethical Review Committee of Dhaka Medical College (ERC-DMC/ECC/2023/286). The confidentiality of the study participants and their information was maintained strictly, and only the authorized persons had access to the patient identification data. Both verbal and written informed consent was obtained from each participant with a confirmed diagnosis of NTDT to ensure their clear understanding of being included in the research work voluntarily. Before obtaining their consent, study participants were informed about the nature, purpose, and procedures of the study, and they had right to refuse, accept, or withdraw their participation anytime from the study. The participants did not receive any financial compensation for their participation in this research work.

Study population

The cross-sectional study applied purposive sampling and therefore recruited the diagnosed 50 beta NTDT patients visiting the indoor and outdoor facilities of the Department of Hematology and Bone Marrow Transplant Unit, Dhaka Medical College Hospital, Dhaka. The characteristics of NTDT patients include (a) no need for blood transfusion before 2 years of age and (b) can maintain Hb levels within the range of 7–10 g/dL without blood transfusion, though occasional or frequent transfusions are required under specific clinical circumstances. The inclusion criteria of the study subjects were age >18 years and patients diagnosed with the beta NTDT. The patients with clinical TM, severely ill patients, and patients with known cardiac or pulmonary conditions were excluded from the study.

Sample size

According to a study from Iran, the prevalence of PH among NTDT patients was 24%.^[16] Thus, for this study, the prevalence of PH was considered 24%, as no study on Bangladesh was conducted on the prevalence of PH among NTDT patients. Sample size was calculated with 95% confidence interval and 10% allowable error. The following formula is used for calculating sample size:

Here, for 24% prevalence p = 0.24 and q = 0.76 and for 95% confidence level Z = 1.96 and for 10% error (d) = 0.1, q = (1−p) = (1−0.24) = 0.76n = 1.96² × 0.24 × 0.76/(0.1)², n = 70.01 ≈ 70

Calculating with 95% confidence interval and 10% allowable error, the estimated sample size was about 78. Initially, we have started with 78 subjects but with the time being, some cases worn out, some others were less responsive, and hence, ultimately, 50 subjects were enrolled by fulfilling all the inclusion and exclusion criteria.

Data collection

The data of the sociodemographic, clinical, and hematological parameters including the current and last 1-year Hb and mean serum ferritin levels were collected from the patients’ questionnaire and medical reports. The chest X-ray radiographs (CXRs), electrocardiograms (ECGs), and color Doppler echocardiography tests of the participants were performed, together with their pulmonary arterial pressure measurement. The ECG indexes and their prevalence in NTDT patients with and without PH were analyzed. The chest X-ray of the participants was performed at the posterior-anterior view; moreover, cardiac chamber enlargement and cardiothoracic ratio were documented. The color Doppler echocardiography was performed to assess tricuspid regurgitant jet velocity (TRV (v), in m/s unit), and tricuspid regurgitant gradient (TRG, in mmHg unit), presence or absence of restrictive cardiomyopathy, and diastolic ventricular dysfunction in all of the patients. The TRG was measured from the TRV’s value (v) using the formula of TRG=4×v². The pulmonary arterial systolic pressure (PASP) was measured from TRG and Right Atrial Pressure (RAP), using the Bernoulli formula, PASP = TRG +RAP (in the case of the patients without pulmonary stenosis). The RAP was estimated by Inferior Vena Cava (IVC) collapsibility at end expiration by observing IVC diameter variation with sniff and quite respiration. In patients without severe pulmonary stenosis, the RAP value was considered to be 5 mmHg, and in pulmonary stenosis cases, the value was considered to be about 10-15 mmHg by assessing IVC collapsibility at end expiration. For the measurement of mean pulmonary artery pressure (mPAP), the following formula was applied mPAP = (0.61× PASP) +2 in which the aforementioned PASP value was used.^[17] Based on a recent echocardiographic guideline, TRV ≥2.5 m/s, TRG ≥25 mmHg, and mPAP > 20 mmHg were set as cutoff values for diagnosing PH in NTDT patients.^[17] All parameters were compared between the patients with PH and without PH.

Statistical analysis

Data analysis was performed in the Statistical Package for the Social Sciences version 25 (IBM Corp., Armonk, NY). For describing and presenting the observations of the categorical variables, frequency tables and figures were generated. As for the continuous variables, these were analyzed and expressed as mean, median, interquartile range (IQR), and standard deviation (SD). Independent sample t-test (normal distribution) or Mann–Whitney test (skewed data distribution) was performed for comparing continuous variables. A p-value of <0.05 was considered to be statistically significant at 95% CI.

Sociodemographic background of the NTDT patients

In this study, the age of the NTDT patients ranges between 18 and 40 years [Table 1]. Most of the participants were within the age range of 18–20 years (36%) and 26–30 years (32%). Regarding gender, 25 (50%) were male and 25 (50%) were female. In terms of residency, 35 (70%) of the study subjects were from rural areas and 15 (30%) were from urban areas. Furthermore, most of the NTDT patients were students, comprising 21 (42%) of the total participants.

Age of diagnosis of NTDT

As shown in the pie-chart [Figure 1] of the patients’ age at diagnosis of NTDT, it is obvious that most of the patients (34, 68%) were diagnosed early, within the age range of 11–20 years, followed by 14 (28%) being diagnosed at 21–30 years of age.

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Figure 1: Pie chart of the age of first diagnosis of non-transfusion-dependent thalassemia in the study participants (n = 50).

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Evaluation of the hematological parameters

As Table 2 shows, the mean of mean Hb concentration in the past 1 year was 8.09 ± 0.093 g/dL and mean of current Hb level was 8.37 ± 0.058 g/dL which is higher than the previous one but they did not differ significantly. Moreover, the median of serum ferritin level in the past 1 year was 345 ng/mL (IQR = 146.25 ng/mL) while the median of current serum ferritin level was 320 ng/mL (IQR = 120 ng/mL [Table 2]). Serum ferritin levels showed skewed distribution, while Hb levels showed normal distribution.

Findings of ECG, chest X-ray, and echocardiogram

Figure 2 depicts that out of 50 patients, 3 (6%) and 1 (2%) patients had abnormal findings from ECG and chest X-ray analysis, respectively. Among the 3 patients with abnormal ECG reports, one patient was diagnosed with PH. Moreover, reports from echocardiography showed tricuspid regurgitation in 5 (10%) of the 50-NTDT patients [Figure 2]. However, diastolic ventricular dysfunction and restrictive cardiomyopathy were absent in the study participants. Abnormal chest X-ray findings showed increased cardiothoracic diameter, i.e., cardiomegaly, but the other positive CXR findings such as prominent pulmonary conus and pruning of pulmonary vessels were not found, while abnormal ECG findings exposed right atrial hypertrophy.

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Figure 2: Distribution of the non-transfusion-dependent thalassemia patients by chest X-ray, ECG, and echocardiography, tricuspid regurgitation (echocardiographic parameters for tricuspid regurgitation included morphology of tricuspid valve and annulus, right atrial and ventricular enlargement with their functions, inferior venacaval diameter, effective regurgitant surface area along with tricuspid regurgitant jet velocity) findings (n = 50).

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Diagnosis of patients with PH

Five (10%) of the 50 thalassemia patients were diagnosed with the PH as they had TRV, TRG, and mPAP levels that exceeded their cut-off values, i.e., ≥2.5 m/s for TRV, ≥25 mmHg for TRG, and >20 mmHg for mPAP. The TRV, TRG, RAP, PASP, and mPAP values of the 5 pulmonary hypertensive NTDT patients, along with their age, are presented in Figure 3, which shows that the lowest values of these parameters were 2.5 m/s, 25 mmHg, 10 mmHg, 35 mmHg, and 23.35 mmHg, respectively. Furthermore, it was observed that the mean±SD age of the pulmonary hypertensive patients was 26.20 ± 5.01 years. In addition, the figure also presents that the TRG, PASP, and mPAP values increase with the increase of age, except for the patient P1 who is of age 28.

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Figure 3: The figure depicts the tricuspid regurgitant jet velocity (TRV, in m/s), and tricuspid regurgitant gradient (TRG, in mmHg), right atrial pressure (RAP, in mmHg), pulmonary arterial systolic pressure (PASP, in mmHg), and mean pulmonary arterial pressure (mPAP, in mmHg) of the nontransfusion-dependent thalassemia patients diagnosed with pulmonary hypertension.

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Association of clinical, hematological, and echocardiographic parameters with the development of PH

The study showed that the current mean Hb level and TRV were significantly associated with the development of PH in NTDT patients (unadjusted P < 0.05 [Table 3]). However, as presented in Table 3, the mean Hb level in the past 1-year, current serum ferritin level, serum ferritin level in the past 1 year, and the age at the time of the first diagnosis of NTDT patients with and without PH did not differ significantly.

Recommendations and limitations

In the present study, there are some limitations although PH is prevalent in adults (≥18 years) age; however, it is not unlikely to affect under 18 years of age. Besides, the diagnosis of PH was based on echocardiographic criteria, whereas right heart catheterization remains the gold standard for PH diagnosis, and the assessment of body iron quantification was only done with serum ferritin which needs liver iron concentration assessments. The study has limitations regarding sample number; therefore, further study on a representative number of NTDT patients is necessary for confirmation of the prevalence at population level and for addressing this disease at the policy level. The study emphasizes early screening for the diagnosis of PH in NTDT patients, facilitating early intervention strategies and minimizing the risk of subsequent complications, i.e., cardiac failure. Long-term follow-up studies need to be performed to monitor patients and assess their prognoses. Further research should be carried out on cardiac index, and right heart catheterization methods should be explored to minimize the complications.