|Year : 2022 | Volume
| Issue : 1 | Page : 3-9
Pulmonary hypertension in people with sickle cell disease in a Nigerian tertiary hospital
Abiona Oluwadamilola Odeyemi1, Opeyemi Olalekan Oni1, Abimbola Ololade Odeyemi2, Kehinde Joyce Olufemi-Aworinde3, Oluwabukola Ayodele Ala1, Ademola Toyosi Abolarin2
1 Department of Medicine, College of Health Sciences, Bowen University, Ogbomoso, Oyo State, Nigeria
2 Department of Paediatrics, College of Health Sciences, Bowen University, Ogbomoso, Oyo State, Nigeria
3 Department of Haematology, College of Health Sciences, Bowen University, Ogbomoso, Oyo State, Nigeria
|Date of Submission||19-Dec-2021|
|Date of Acceptance||11-Feb-2022|
|Date of Web Publication||18-Apr-2022|
Abiona Oluwadamilola Odeyemi
Department of Medicine, College of Health Sciences, Bowen University, Ogbomoso, Oyo State
Source of Support: None, Conflict of Interest: None
Objectives: The aim of this article is to estimate the prevalence of pulmonary hypertension (PHTN) among patients with sickle cell disease (SCD) and to determine the associated factors. Materials and Methods: It was a hospital-based cross-sectional study involving 113 SCD participants in their steady state. Transthoracic echocardiography was done in accordance with the American Society of Echocardiography (ASE) guidelines to determine the peak tricuspid regurgitant velocity (TRVmax); complete blood count, oxygen saturation, serum creatinine, and urea were also done for all the participants. Results: The participants had a mean age of 18.1 ± 9.85 years, and 64 (56.6%) of them were males. Seven (6.2%) of the participants had PHTN as determined by a TRVmax of ≥2.5 m/s. PHTN was significantly associated with age, sex, body mass index (BMI), blood pressure, oxygen saturation, and serum creatinine. Conclusion: PHTN remains common among patients with SCD and it is associated with female gender, increasing age, a rising BMI, blood pressure and serum creatinine, and a decreasing oxygen saturation and hematocrit. We recommend regular screening of patients with SCD for PHTN and that these associated factors should be taken into consideration when screening SCD patients for PHTN.
Keywords: Pulmonary hypertension, sickle cell disease, tricuspid regurgitant jet velocity
|How to cite this article:|
Odeyemi AO, Oni OO, Odeyemi AO, Olufemi-Aworinde KJ, Ala OA, Abolarin AT. Pulmonary hypertension in people with sickle cell disease in a Nigerian tertiary hospital. Assam J Intern Med 2022;12:3-9
|How to cite this URL:|
Odeyemi AO, Oni OO, Odeyemi AO, Olufemi-Aworinde KJ, Ala OA, Abolarin AT. Pulmonary hypertension in people with sickle cell disease in a Nigerian tertiary hospital. Assam J Intern Med [serial online] 2022 [cited 2022 May 21];12:3-9. Available from: http://www.ajimedicine.com/text.asp?2022/12/1/3/343426
| Introduction|| |
Sickle cell disease (SCD) represents a group of inherited autosomal recessive conditions of the blood with significant public health interest worldwide, especially in sub-Saharan Africa.,, Globally, SCD is estimated to occur in about 300,000 births annually with an estimated 80% of the births occurring in sub-Saharan Africa where Nigeria has the greatest burden of the disease with over 90,000 births annually. It is most common in malaria-endemic regions of the world with an estimated 10–40% of the population being carriers of the hemoglobin S gene.
Although SCD affects several organs of the body, the lung is one of the main organs involved and pulmonary complications of SCD are very common among SCD patients. They are a common source of morbidity and mortality among these patients, being responsible for over 20% of mortality in them., Pulmonary hypertension (PHTN) is gradually more identified as a complication of SCD. The exact prevalence of PHTN among people with SCD is unknown. Although some authors have reported a prevalence of as low as 3.6%, others have reported prevalence in the range of 31–56%.,
Although the exact cause is unknown, the etiology of secondary PHTN among patients with SCD has been suggested to be multifactorial. It is said to be due to in-situ thrombosis, chronic hypoxemia, and vascular and parenchymal injury as a result of sequestration of sickle red blood cells, fat embolism, and infection., In addition, SCD patients suffer from chronic hemolysis with a resultant increase in cell-free hemoglobin, and this leads to an upsurge in the utilization and resistance to the effects of nitric oxide (NO), with resultant impaired vasodilation. Another important cause of PHTN is venous thromboembolism which is a common complication of SCD leading to chronic thromboembolic pulmonary hypertension in some SCD patients. In the early stage, PHTN is usually asymptomatic. However, patients with moderate-to-severe PHTN present with chest pain, hypoxemia, and dyspnea. With worsening of the disease, patients could present with features of right heart failure or sudden death from cardiac arrhythmia, systemic hypotension, and pulmonary thromboembolism. The gold standard for the diagnosis of PHTN is right heart catheterization (RHC). However, this is an invasive procedure that is not readily available in our environment. Echocardiography is a non-invasive, readily available screening test that can be used to determine the tricuspid regurgitant velocity (TRV), a surrogate for pulmonary arterial systolic pressure.
As mentioned earlier, SCD is highly prevalent in our environment and PHTN is increasingly identified as a complication. SCD patients with PHTN have been observed to have a significantly higher mortality rate compared with SCD patients without PHTN. This study, therefore, aimed to estimate the prevalence of PHTN using echocardiography and to determine the associated factors among SCD patients seen at the Hematology Clinic of a Nigerian tertiary hospital.
| Materials and Methods|| |
It was a hospital-based cross-sectional study done over 12 months at the Hematology Clinic of a tertiary hospital in Nigeria. All consenting SCD patients who were 6 years and above and in their steady state (defined as the non-occurrence of acute painful episodes, hemolytic crisis, or blood transfusion at least 3 months prior to recruitment) were involved in the study. We excluded those acutely ill, those with cardiac or chronic respiratory disease, and those who refuse to give consent. A total of 113 SCD participants were involved in the study, including 51 adults and 62 children. Hemoglobin electrophoresis result was confirmed in their medical records. Ethical approval was obtained from the Research Ethics Committee of the hospital.
A structured interviewer-administered questionnaire was used to obtain socio-demographic and clinical data of the study participants. For the purpose of this study, patients were said to be on hydroxyurea if they had used it for at least a year and recurrent blood transfusion was defined as at least three transfusions in a year. A GIMA® ASTRA weighing scale with an incorporated height meter was used to measure the weight and height after ensuring minimal dressing (additional clothing such as headgears, caps, footwears, and wristwatches was removed). The body mass index (BMI) (in kg/m2) was determined with the formula: weight (in kilograms) over height2 (in meters). Patients with respiratory symptoms were excluded using a questionnaire similar to the Medical Research Council questionnaire for respiratory symptoms. A finger probe pulse oximeter (Onyx II 9550™ by Nonin) was used to measure oxygen saturation (SpO2) using the index finger of the participant’s right hand. Blood samples were taken from the participants and sent to the laboratory for complete blood count, urea, and creatinine.
Transthoracic echocardiography was performed by a consultant cardiologist for all the participants using a Siemens Sonoline Omnia echocardiography machine in accordance with the American Society of Echocardiography (ASE) guidelines. Left ventricular stroke volume, transmitral flow, and Doppler measurements of the degree of valvular regurgitation were evaluated and graded using the ASE guidelines., Peak velocities of E and A waves, the ratio of E wave to A wave, and the deceleration time were determined using the guidelines.
Tricuspid regurgitation was assessed in the parasternal short-axis, parasternal right ventricular inflow, and apical four-chamber views, and at least five sequential complexes were documented. The average of three different peak tricuspid regurgitant jet velocity (TRVmax) measurements was documented as the TRVmax. PHTN was defined as a TRVmax of ≥2.5 m/s. Since most individuals with clinically significant PHTN have quantifiable tricuspid regurgitation, it is assumed that pulmonary artery pressures were normal in those with either trace or no tricuspid regurgitation.
The data acquired were analyzed using the Statistical Package for Social Sciences (SPSS) version 23.0 (IBM Corp., Armonk, NY, USA) and were presented in frequency tables and charts. Continuous variables were expressed as means ± standard deviation. The relationship between categorical variables was assessed for statistical significance using Pearson’s χ2. Student’s t-test was used to assess means of continuous data for statistical significance. A P-value of ≤0.05 was considered significant.
| Results|| |
Basic characteristics and PHTN among the participants
Sixty-four (56.6%) of the participants were males, whereas 51 (45.1%) of the participants were ≥18 years of age. They had a mean age of 18.1 ± 9.85 years and a mean SpO2 of 94.31 ± 4.83%. Only 13 (11.5%) were on hydroxyurea [Table 1]. Seven (6.2%) of the participants had PHTN as determined by a TRVmax of ≥2.5 m/s [Figure 1].
Laboratory parameters and SCD complications among the participants
The mean hematocrit and serum creatinine were 24.23 ± 4.41 and 91.36 ± 35.1, respectively [Table 2]. Twenty-five (22.1%) had a history of chronic osteomyelitis as a complication of SCD, whereas 14 (12.4%) had a history of stroke [Figure 2].
Relationship between participants’ basic characteristics and PHTN
There was a significant association between PHTN and age, sex, BMI, blood pressure, and SpO2 but no significant association between PHTN and the use of hydroxyurea [Table 3].
|Table 3: Relationship between participants’ basic characteristics and pulmonary hypertension|
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Relationship between a history of complications, laboratory parameters, and PHTN
There was no significant association between PHTN and a history of acute chest syndrome or stroke, but there was a significant association between PHTN and serum creatinine [Table 4].
|Table 4: Relationship among history of complications, laboratory parameters, and pulmonary hypertension|
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| Discussion|| |
Our study has shown that PHTN as determined by measurement of the peak tricuspid regurgitant jet velocity (TRVmax) on echocardiography was found in 6.2% of SCD participants, and this was significantly associated with age, sex, BMI, blood pressure, oxygen saturation, hematocrit, and serum creatinine.
The prevalence of 6.2% for PHTN as determined by echocardiography in this study is higher than the 3.6% reported by Dosunmu et al., but less than the 31.8% reported by Dahoui et al. Earlier studies have reported varying prevalence with some authors reporting prevalence as high as 58%. The reason for these varying figures appears to be multifactorial, including the age range of the study participants, selection criteria, resolution of the various echocardiography machines used, and the fact that the procedure is observer-dependent.
In this study, we observed that PHTN was significantly associated with the age of the participants as it was seen to occur more in adults when compared with children. This finding is similar to those of Ahmed et al. and Castro et al. who both observed an increase in TRVmax with increasing age. This may be due to repeated impairment in blood flow through the lungs as a result of sickling of the red blood cells within the pulmonary vessels and the resultant vasoconstriction and subsequent thickening of the intima and media of small pulmonary vessels which occur over time as the patient ages. We also observed that PHTN was significantly more in females when compared with their male counterparts. This finding is in contrast to those of earlier studies who found no significant association between gender and PHTN among SCD patients. The reason for this could not be ascertained; further studies will be needed to evaluate this finding. In this study, we also observed that BMI was significantly higher among those with suspected PHTN when compared with those without it. This finding is similar to that of Caughey et al., who also reported that PHTN was significantly associated with increasing BMI. As described in the general population, this finding may be due to pulmonary vascular remodeling associated with increasing BMI.
In the current study, we also observed that systolic and diastolic blood pressures and serum creatinine were significantly higher among those with PHTN when compared with those without. This finding is similar to earlier studies,, and it has been suggested to be due to the common pathology of recurrent hemolysis, nitric oxide scavenging, and resultant damage to the vasculature.,
Although all the patients on hydroxyurea did not have PHTN, this was not statistically significant. Similarly, there was no statistically significant relationship between PHTN and a history of recurrent blood transfusion. This is despite the fact that use of hydroxyurea and chronic blood transfusions have both been recommended as a supportive treatment for PHTN among SCD patients. Our finding of a lack of significant association between PHTN and the use of hydroxyurea and recurrent blood transfusion may be because only a few (11.5%) of our patients were on hydroxyurea and another few (15%) had a history of recurrent blood transfusion.
Our study also found no significant association between PHTN and the frequency of vaso-occlusive crisis, history of acute chest syndrome, chronic osteomyelitis, avascular necrosis, and a history of stroke. This finding is consistent with some earlier studies,, but in contrast to some other studies that observed a significant association among PHTN and avascular necrosis, history of leg ulcers, and stroke., These complications together with PHTN have earlier been ascribed to the degree of vasculopathy in patients with SCD,, but our finding and those of the earlier mentioned studies, suggest otherwise; hence there is the need for further research to evaluate this relationship.
Consistent with a possible role for hemolysis in the development of PHTN, our study revealed that hematocrit was significantly lower in SCD patients with PHTN when compared with those without PHTN. This is consistent with findings from earlier studies. Similarly, oxygen saturation was significantly lower among those with PHTN, and this has been corroborated by earlier studies.
Other laboratory findings in our study are in keeping with those of earlier studies that found no significant association between PHTN and white cell count and platelet count.,,
| Conclusions|| |
PHTN remains common among patients with SCD, and it is associated with female gender, increasing age, a rising BMI, blood pressure and serum creatinine, and a decreasing oxygen saturation and hematocrit. We recommend regular screening of patients with SCD for PHTN and that these associated factors should be taken into consideration when screening SCD patients for PHTN.
| Limitation|| |
Our limitation was our inability to perform right cauterization to confirm the diagnosis of PHTN.
We acknowledge our patients and their caregivers for consenting to be a part of this study.
Financial support and sponsorship
This work was supported by Bowen University, Iwo, Osun State, Nigeria under grant number BRE/2020/010. The University had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Conflicts of interest
There are no conflicts of interest.
All authors met the criteria for authorship by making substantial contributions to each of the following three components:
- Concept and design of study or acquisition of data or analysis and interpretation of data;
- Drafting the article or revising it critically for important intellectual content; and
- Final approval of the version to be published.
| References|| |
Modell B, Darlison M Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008;86:417-96.
Diwe K, Iwu AC, Uwakwe K, Duru C, Merenu I, Ogunniyan T, et al
. Prevalence and patterns of sickle cell disease among children attending tertiary and non-tertiary health care institutions in a South Eastern state, Nigeria: A 10 year survey. J Res Med Dent Sci 2016;4:75-81.
Olagunju OE, Faremi FA, Olaifa O Community medicine and primary health care prevalence and burden of sickle cell disease among undergraduates of Obafemi Awolowo University, Ile-Ife. J Commun Med Public Health 2017;29:74-80.
Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN Global burden of sickle cell anaemia in children under five, 2010–2050: Modelling based on demographics, excess mortality, and interventions. PLoS Med 2013;10:e1001484.
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al
. Mortality in sickle cell disease: Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639-44.
Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, et al
. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: Risks and benefits up to 9 years of treatment. JAMA 2003;289:1645-51.
Dosunmu AO, Balogun TM, Adeyeye OO, Daniel FA, Akinola RA, Josephine JA, et al
. Prevalence of pulmonary hypertension in sickle cell anaemia patients of a tertiary hospital in Nigeria. Niger Med J 2014;55:161-5.
] [Full text]
Dahoui HA, Hayek MN, Nietert PJ, Arabi MT, Muwakkit SA, Saab RH et al
. Pulmonary hypertension in children and young adults with sickle cell disease: Evidence for familial clustering. Pediatr Blood Cancer 2010;54:398-402.
Ahmed S, Siddiqui AK, Sadiq A, Shahid RK, Patel DV, Russo LA Echocardiographic abnormalities in sickle cell disease. Am J Hematol 2004;76:195-8.
Odeyemi AO, Ojo OT Pulmonary complications of sickle cell disease. In: Alebiosu CO, editor. Sickle Cell Disease: From the Laboratory to Clinical Practice. Newcastle upon Tyne: Cambridge Scholars Publishing; 2019.
Francis RB Jr, Johnson CS Vascular occlusion in sickle cell disease: Current concepts and unanswered questions. Blood 1991;77:1405-14.
Weil JV, Castro O, Malik AB, Rodgers D, Bonds DR, Jacobs TP Pathogenesis of lung disease in sickle hemoglobinopathies. Am Rev Respir Dis 1993;148:249-56.
Castro O Systemic fat embolism and pulmonary hypertension in sickle cell disease. Hematol Oncol Clin North Am 1996;10:1289-303.
Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al
. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004;350:886-95.
Medical Research Council Committee on the Aetiology of Chronic Bronchitis. Standardized questionnaire on respiratory symptoms. Br Med J 1960;2:1658.
Cheitlin M, Armstrong W, Aurigema G, Beller GA, Bierman FZ, Davis JL et al
. ACC/AHA/ASE 2003 Guideline Update for the Clinical Application of Echocardiography: Summary article. J Am Soc Echocardiogr 2003;16:1091-110.
Appleton CP, Jensen JL, Hatle LK, Oh JK Doppler evaluation of left and right ventricular diastolic function: A technical guide for obtaining optimal flow velocity recordings. J Am Soc Echocardiogr 1997;10:271-92.
Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: Clinical validation of two new methods using the apical window. Circulation 1984;70:425-31.
Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA Recommendations for quantification of Doppler echocardiography: A report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167-84.
Berger M, Haimowitz A, Van Tosh A, Berdoff RL, Goldberg E Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol 1985;6:359-65.
Castro O, Hoque M, Brown BD Pulmonary hypertension in sickle cell disease; cardiac catherization results and survival. Blood 2003;101:1257-61.
Caughey MC, Hinderliter AL, Jones SK, Shah SP, Ataga KI Hemodynamic characteristics and predictors of pulmonary hypertension in patients with sickle cell disease. Am J Cardiol 2012;109:1353-7.
Frank RC, Min J, Abdelghany M, Paniagua S, Bhattacharya R, Bhambhani V, et al
. Obesity is associated with pulmonary hypertension and modifies outcomes. J Am Heart Assoc 2020;9:e014195. https://doi.org/10.1161/JAHA.119.014195
Gordeuk VR, Sachdev V, Taylor JG, Gladwin MT, Kato G, Castro OL Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency. Am J Hematol 2008;83:15-8.
Liem RI, Young LT, Thompson AA Tricuspid regurgitant jet velocity is associated with haemolysis in children and young adults with sickle cell disease evaluated for pulmonary hypertension. Haematologica 2007;92:1549-52.
Klings ES, Machado RF, Barst RJ, Morris CR, Mubarak KK, Gordeuk VR, et al
. An official American Thoracic Society Clinical Practice Guideline: Diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med 2014;189:727-40.
Sokunbi OJ, Ekure EN, Temiye EO, Anyanwu R, Okoromah CAN Pulmonary hypertension among 5 to 18 year old children with sickle cell anaemia in Nigeria. PLoS One 2017;12:e0184287. https://doi.org/10.1371/journal.pone.0184287
Ambrusko SJ, Gunawardena S, Sakara A, Windsor B, Lanford L, Michelson P, et al
. Elevation of tricuspid regurgitant jet velocity, a marker for pulmonary hypertension in children with sickle cell disease. Paediatr Blood Cancer 2006;47:907-13.
Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, et al
. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med 2011;365:44-53.
Kato GJ, Hsieh M, Machado R, Taylor J VI, Little J, Butman JA, et al
. Cerebrovascular disease associated with sickle cell pulmonary hypertension. Am J Hematol 2006;81:503-10.
Nouraie M, Lee JS, Zhang Y, Kanias T, Zhao X, Xiong Z, et al
. The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe. Haematologica 2013;98:464-72.
Minniti CP, Sable C, Campbell A, Rana S, Ensing G, Dham N, et al
. Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: Association with hemolysis and hemoglobin oxygen desaturation. Haematologica 2009;94:340-7.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]