Role of Sociodemographic and Economic Variables in Predisposition to Vaso-Occlusive Crisis and Mortality in Patients with SCD: Case Study of Sub-Saharan Africa

Abstract

Sickle cell disease (SCD) is a major public health challenge. It is a common cause of acute and chronic illness and death, which results from a single amino acid substitution (glutamic acid to valine) at position 6 of the beta (β) chain of the hemoglobin molecule. The pathophysiology is based on the polymerization of deoxygenated hemoglobin S (HbS) and production of irreversibly sickled red cells and vaso-occlusive crisis (VOC). The disease is associated with recurrent episodes of acute pain and organ damage. This chapter highlights the role of SES on the predisposition to VOC and mortality among SCD patients. Findings from this review will enable the development and implementation of policies that can facilitate the effective management of SCD in the region. More awareness and education of parents of children and adults living with SCD are needed to identify factors that predispose patients to VOC and common-sense measures to prevent these triggers. SCD patients should be protected against malaria. The need for nutritional intervention, proper hydration, avoidance of dietary intake of sodium, strenuous physical activity, and extreme weather to reduce the incidence of VOC cannot be overemphasized. Protective immunization and access to effective prophylactic and therapeutic agents should be implemented.

1. Introduction

Sickle cell disease (SCD) is of major public health challenge globally, with majority of affected patients residing in sub-Saharan Africa [1]. It is a genetic disorder resulting from the inheritance of abnormal gene (HbS) from both parents [2]. The difference between the abnormal hemoglobin S (HbS) and the normal adult hemoglobin A is a single amino acid substitution of valine for glutamic acid in the sixth position in the β-globin chain. In sub-Saharan Africa, about 300,000 infants are born with major hemoglobin disorders and about 2% of all children have SCD [3]. The frequency of the trait is between 15 and 30% in West Africa [4]. SCD disproportionately affects people in the African continent compared to other parts of the globe. The United Nations estimates that 12–15 million of the world’s 25 million SCD patients live in the African continent [5], while an insignificant 10% live in high-income countries (HICs) [6]. The mortality rate from the disease in children under 5 years of age is estimated to exceed 50% in the African continent where healthcare infrastructure is suboptimal and the population are significantly impoverished [7]. Recurrent and random episodes of vaso-occlusive crisis (VOC) are the hallmark of sickle cell disease. The pathophysiology of vaso-occlusive crisis lies in the fact that upon deoxygenation, the mutant HbS molecule polymerizes and attains a characteristic sickle shape. The sickle-shaped red cells adhere to leukocytes immobilized to the endothelium, causing microvascular occlusion and vaso-occlusive crisis (VOC), tissue ischemia, and resultant pain. The actual causes of VOC are unknown. However, factors including exposure to cold (hypothermal), dehydration, infection, malaria infection, and stress may play a role [8]. Painful vaso-occlusive crisis (VOC) is the commonest cause of hospital admission in patients with SCD. Socioeconomic status (SES) and demographic variables seem to play a key role in the prevalence, development of complications, and mortality in several diseases including sickle cell disease (SCD) and particularly in low-income developing countries. The aim of this chapter is to review the several sociodemographic and socioeconomic variables that can predispose to vaso-occlusive crisis among sickle cell disease patients.

2. Effects of sociodemographic and economic factors in VOC in SCD

Sociodemographic variables play a role in hospitalization of SCA children. The level of educational attainment of parents has a significant role in the incidence and presentation to hospital with VOC. A previous report in Sokoto, North Western Nigeria, indicated that majority of the parents of children presenting to the children emergency unit with vaso-occlusive crisis were either educated up to secondary school or had no formal education. Also, a SCD child’s position in a family had a role in presentation in emergency unit with VOC. Majority of the subject presenting to hospital in VOC were ≥ 6th position [9]. Higher levels of education and income mitigate the deleterious effects of the psychosocial consequences (anxiety and depression) associated with SCD. Parents of SCD children with higher education or income are more likely to make better informed decision about nutritional requirements and use of insecticide-treated mosquito nets to protect their children from malaria. They are also able to afford the medication and the various treatment options required for the effective management of their SCD children [10]. There are several factors that play a role in an individual’s socioeconomic status (education, profession, and income). SES of an individual can play a role in the development, complications, negative outcome, and increased mortality of patients with SCD [11]. The effects of these factors often begin in the prenatal stages before a child is born and tend to continue through life [12]. A study that investigated the influence of SES factors on hematological and clinical parameters in children with SCD in Saudi Arabia [13] indicated that a significant number of children affected with the SCD were from the low socioeconomic class on <5000 SAR. The prevalence of VOC, adverse events, and more deranged hematological indices was more prevalent among patients in the lowest SES.

2.1 Role of poverty on incidence of VOD in SCD patients

Inability to pay for healthcare can have a significant effect on accessibility and promptness of assessing care for many indigent patients. Many SCD patients do not access care on time until complications have developed. This can potentially result in longer lengths of stay for the treatment of complications of their underlying disease [14]. A previous report in Sokoto, North Western Nigeria, indicated that majority of the parents of children in vaso-occlusive crisis had income of < N36,000 naira (equivalent of <$75) monthly [9]. The management of SCD patients is not cheap. In the United States, the estimated total healthcare cost per year for children and adults with SCD stand at USD1.1 billion [15]. Children from low socioeconomic status (SES) with and without chronic disease have been reported to have worse health outcomes and higher utilization of health resources compared to those who are more advantaged [16]. They are more likely to be admitted to the hospital, have longer lengths of hospital stay, and generate more healthcare-associated costs particularly in the first 10 years of life compared to children from higher SES [17]. However, a previous report that examined the association between socioeconomic status and length of hospital stay for children with sickle cell disease observed that SES has no clinically important effect on the length of hospital stay [18]. Efforts are being made to better understand the pathophysiology, prevent and ameliorate the consequences, and ensure the effective management of VOC in sickle cell disease using novel targeted therapies [19]. The major challenge that may limit the access to these therapies in developing countries where this disease is more prevalent is cost [20]. Managing patients with SCD comes with a huge cost [21]. In 2004 alone, more than 80,000 hospitalizations were attributable to adult SCD patients in the United States, costing nearly $500 million, with majority of the cost arising from inpatient hospitalization associated with VOC [8, 22]. Managing chronic illness like SCD in low- and middle-income countries (LMICs) can incur very high out-of-pocket (OOP) payments for healthcare. Many households do not have the necessary money. Some are left with no other option than to adopt one or more “coping strategies,” such as borrowing money often times at outrageous interest rates, or selling assets like land, farm produce, and jewelleries [23]. Out-of-pocket expenditure can prevent a number of SCDs from accessing care promptly due to unaffordability, and this can affect the delivery of a prompt and efficient management of patients with sickle cell disease [24]. There is need for government across sub-Saharan Africa to provide universal access to quality care for patients with SCD as well as to improve the awareness among patients on the need to promptly access care to prevent complications. These implementations can potentially help improve health outcomes.

2.2 Effect of malnutrition on the incidence of VOC in SCD

There seems an interconnection between nutritional state, host defense, susceptibility, and disease outcomes. Previous report indicates that micronutrient deficiencies are associated with signs of poor growth, increased susceptibility to infection, and recurrent occurrences of VOC in patients with SCD and outcomes [25]. The important role nutrition plays in the health-related quality of life of patients cannot be overemphasized. A previous report indicated that the health-related quality of life of a cohort of SCD patients improved significantly after tailored micronutrient program was initiated among the patients [26, 27]. Qualitative malnutrition seen among SCD tends to be multifactorial and often results from suboptimal intake or uptake of macro- or micronutrients. SCD-related increased nutritional demands, presence of attendant chronic gastrointestinal diseases and infections, socioeconomic status, and lifestyle factors tend to predispose SCD patients to frequent hospitalizations primarily due to vaso-occlusive crises and other SCD-related complications [28]. Zinc and omega-3 fatty acid supplementation have been associated with limited reduction in vaso-occlusive crises [29]. The disparity in SES, migrations, food insecurity, fast-food habits, and social and cultural patterns seem to be the main causes of altered nutrition in individuals throughout the globe [30]. Suboptimal intake of macro- and micronutrients has been shown to be associated with predisposition and negative outcomes in SCD patients. Micronutrient deficiencies, including zinc, copper, folic acid, pyridoxine, vitamin E, B₆, and B₁₂, omega-3 fatty acids, vitamin D, and arginine have been shown to play a role [31, 32, 33, 34]. Similarly, the use L-glutamine has been shown to be beneficial in decreasing the incidents of SCD-related vaso-occlusive (VOC) pain events without significant safety concerns [35]. Zinc supplementation has been associated with decreased incidence of infections, number of hospitalizations, and vaso-occlusive pain crisis among SCD patients [36]. The serum copper, selenium, RBC, HCT, HGB, MCV, MCH, and MCHC were significantly lower among sickle cell disease patients compared to controls. It is recommended that trace elements (copper and selenium) and hematological parameters are monitored routinely among sickle cell disease children to optimize the care offered to these individuals [9]. Vaso-occlusion is understood to be the root cause of sickle cell pain. Nitric oxide (NO) is a potent vasodilator [37] that plays a role in the vaso-occlusive complications of SCD [38]. Recent findings indicate that one of the pathophysiological pathways of sickle cell disease (SCD) lies on the role of red cell hemolysis and nitric oxide (NO) depletion on the occurrence of acute and chronic complications including VOC. Nitric oxide is produced in the endothelium from its obligate substrate L-arginine, which is converted to citrulline by a family of enzymes, the NO synthases (NOS). P. falciparum malaria is a common trigger of VOC in SCD patients. P. falciparum malaria is associated with hypoarginaemia among preschool children of African descent [39]. Arginine is a safe and inexpensive intervention with narcotic-sparing effects that may be a beneficial adjunct to standard therapy for sickle-cell-related pain in children [40, 41, 42]. SCD children have lower values of antioxidant enzymes compared to controls. Superoxide dismutase (SOD) and glutathione peroxidase (GPX) levels in sickle cell disease patient in vaso-occlusive crisis are significantly lower compared to that of non-sickle cell controls [43]. There seems a justification to urgently develop dietary reference intakes (DRIs) and recommended dietary allowances (RDAs) for patients with SCD and integrate nutritional intervention as a vital adjunct in the prevention of VOC and the treatment of patients [44].

2.3 Socioeconomic disparity in access to health

SES is defined as a complex combination of several factors including occupation, income, knowledge, education, and power in a society that affect an individual’s well-being [45]. The quality of healthcare delivery is on a decline in many developing economies and limits access to health products particularly for those with low SES [46]. Abnormal growth, stunting, and a low BMI are commoner in children with SCD of lower socioeconomic class [47]. Data from the United Kingdom shows that SCD children from low SES constitutes the majority of those hospitalized. The hospital admissions were majorly due to episodes of VOC [18]. The need for government particularly in low-income settings to address the issue of inequalities in access to health products cannot be overemphasized. There is disparity in access to care in SCD in urban setting compared to those in rural settings. Reports from the island of Jamaica and the United States indicate that SCD patients with more severe genotypes tend to live in higher poverty-stricken rural settings and tend to travel longer distance to access healthcare services and advocate that government particularly in developing countries ensure that better access to healthcare services is provided for SCD patients residing in rural settings [48, 49, 50].

2.4 Lack of education and awareness on the management of patients at home to prevent the risk of VOC

Painful crises are the causes of 50–60% of emergency visits and 60–80% of hospitalizations in children with SCD [51]. Triggers for VOC vary and can include inflammation, stress, increased viscosity, decreased flow, hemolysis, infection, exposure to cold, hypoxia, acidosis, dehydration, physically demanding activity, emotional stress, and malaria, or a combination of factors [19, 52]. A previous report from Nigeria indicates that malaria (76.7%) and bacterial infection (60%) were common trigger of VOC among SCD subjects [9]. A significant association has been observed between the parents’ awareness of VOCs and a better disease outcome in their children, as they had fewer attacks and hospital admissions [53]. The need to provide information required to enable parents of children and adults with SCD effectively manage themselves at home to reduce the incidence VOC and need for hospitalization cannot be overemphasized. There are a number of commonsense measures that can be implemented to reduce the risk of VOC-related admissions. Parents of children and adult patients with SCD must take the issue of optimal hydration seriously. Poorly hydrated erythrocytes lead to increased viscosity and may contribute to the vaso-occlusive crisis in SCD [54]. It is crucial for SCD patients to promote proper hydration by frequent intake of water, avoidance of dietary intake of sodium, and avoidance of strenuous physical activity and extreme weather that result in excessive sweating [55, 56]. Majority of SCD patients live in Plasmodium falciparum endemic African countries [57]. SCD patients are highly vulnerable to malaria infection as a result of impaired splenic function which is a common feature in SCD patients [58]. Infection with Plasmodium falciparum in SCD patients can trigger painful vaso-occlusive crisis, increase the severity of anemia, and contribute to early childhood mortality [59]. Efforts must be made to keep SCD patients safe from malaria infection by providing them with antimalarial chemoprophylaxis and insecticides-treated mosquito nets, and the implementation of vector control measures [60, 61]. Evidence from the UK indicates that environmental factors including increased wind speed and low humidity have a significant effect on acute pain in SCD. Others indicates that low levels of carbon monoxide and nitric oxide were associated with increased numbers of VOC-related hospital admissions [62, 63]. Parents of children with SCD and adult patients have a duty of care to ensure that these preventive measures are implemented. Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive crisis (VOC). Patients with SCD tend to have impaired immunity due to splenic infarction which predisposes them to recurrent infections [64]. Other infection predisposing factors in SCD include abnormalities of opsonization, suboptimal antibody production, impaired leukocyte functions, and cell-mediated immunity [65]. The clinical course of the disease is characterized by periodically painful vaso-occlusive crisis, which can be triggered by psychological, physical, and infective factors [66]. Hyposplenism predisposes SCD patients to severe infections with malaria and encapsulated organisms, including Haemophilus influenza, Mycoplasma pneumoniae, Salmonella typhimurium, Staphylococcus aureus, Escherichia coli, and Streptococcus pneumoniae [64, 67]. Respiratory tract infections are common in SCD and vary and range from mild upper tract infection to moderately severe uncomplicated pneumonia that can be managed with appropriate antibiotics. Respiratory tract infection if poorly managed can predispose patients to acute chest syndrome (ACS) which is a serious and potentially fatal complication. There is the need to reduce the burden of infection on SCD patients by ensuring that patients are administered the relevant protective immunization, have access to effective prophylactic and therapeutic use of antimicrobial, keep their environment, clean and are provided with barrier protection [68]. There is need for governments across the sub-Saharan Africa to take realistic steps to eradicate poverty and illiteracy as enshrined in the United Nations’ millennium development goals for underdeveloped countries. This will go a long way in reducing the high incidence of infection among SCD patients in particular and improving the quality of life of patients.

2.5 Psychosocial realities of vaso-occlusive crisis in SCD

A previous report indicated that sociodemographic characteristics and quality of life play a major role in SCD, and these have serious psychosocial consequences, especially anxiety and depression, on SCD patients [69]. Vaso-occlusive pain crises (VOC) is the most common cause of emergency department visits and hospitalizations in patients with sickle cell disease [70]. Sickle cell disease (SCD) patients with VOC may experience a broad range of mental health disorders. Pediatric patients with SCD and a history of a mental health diagnosis have longer length of stay (LOS) and higher admission rates for the management of VOC. Ultimately, these findings suggest that mental health pose a challenge to the management of VOC-related pain in patients with SCD [71]. Pediatric patients diagnosed with a psychiatric disorder, specifically mood or anxiety disorders, have longer LOS for VOC. These findings suggest that future interventions aimed at managing VOC may need to consider adjunctive psychiatric assessment and intervention [72]. Comorbid depression is significantly associated with longer LOS, more severity of illness, and higher hospital charges [73]. Healthcare providers caring for adults with SCD should consider screening and managing the mental health of SCD patients to improve the health-related quality of life. SCD patients with depression had a higher prevalence of acute vaso-occlusive pain and acute chest syndrome visits per year, developed more complications related to organ damage, and incurred significantly higher outpatient and inpatient total healthcare costs compared to controls [74]. VOC-related acute pain and fatigues resulting from anemia are major hallmarks of SCD. These factors predispose patients to psychological disorders, depression, anxiety, and a negative impact on their quality of life (QoL) [75]. Previous report indicates that the rates of depression in SCD patients (18–46%) are similar to those seen in other chronic diseases [76]. Depression seems prevalent in patients with SCD and may be correlated with demographic and social factors. A previous study investigated the prevalence of depression and anxiety among SCD patients from different sociodemographic groups in Jeddah, Saudi Arabia. Finding indicated that there was a significant association between depression rate and the two variables of patient employment status (49.3%; p = 0.047) and a family history of SCD (51%) [77]. A depression rate of 48.2% was reported among the SCD patients in Qitaf, Eastern Province of Saudi Arabia [78]. Depression among SCD patients in sub-Saharan African may even be higher for a number of reasons; apart from the fatigue and VOC-associated pain, many SCD patients have to grapple with paying for their healthcare cost which tends to be funded out of pocket, and patients also worry about the availability of safe blood transfusion (lack of effective screening for TTIs, risk of possible hemolytic transfusion reaction, and alloimmunization to foreign donor red cells antigens). Many blood transfusion laboratories in sub-Saharan African countries lack facilities for routine alloantibody screening and extended red cell phenotyping. There is also the risk of iron overload and the cost implication of iron chelation therapy [79]. There are a number of factors that may be responsible for the increased incidence of depression among patients with SCD particularly in low-income settings in sub-Saharan Africa; the higher the rate of healthcare utilization, there are higher costs of out-of-pocket medical care and the challenge associated with the effect of the VOC crisis-related pain [80, 81]. There is need to routinely examine the health-related quality of life and mental health status of SCD in relation to VOC-related pain during hospital admissions and target appropriate psychological interventions for the effective management of pain in these patients [82].

3. Conclusion

This review indicates that socioeconomic and demographic factors play a key role in the prevalence of VOC, development of complications, and mortality in sickle cell disease (SCD) particularly in low-income developing countries.

4. Recommendations

1. Governments across sub-Saharan Africa need to take realistic steps to eradicate poverty and illiteracy as enshrined in the United Nations’ millennium development goals for underdeveloped countries. This will go a long way in reducing the high incidence of VOC among SCD and improving the quality of life of patients.

2. There in need for more awareness and education of parents of children and adult living with SCD on the factors that predispose patients to VOC and commonsense measures that can be taken to prevent these triggers.

3. There is need to invest significantly on tackling Goal 10 of the Sustainable Development Goals (SDGs) with the hope of reducing the growing inequalities and closing the widening inequality in access to SCD-related care as well as relative income inequality within and among countries.

4. Efforts must be made by government of sub-Saharan African countries to keep SCD patient safe from malaria infection by providing them with antimalarial chemoprophylaxis, insecticides-treated mosquito nets, and implementation of vector control measures.

5. SCD patients should be encouraged to ensure proper hydration by frequent intake of water, avoidance of dietary intake of sodium, and avoidance of strenuous physical activity and extreme weather that result in excessive sweating to reduce the incidence of VOC.

6. There seems a justification to urgently develop dietary reference intakes (DRIs) and recommended dietary allowances (RDAs) for patients with SCD and integrate nutritional intervention as a vital adjunct in the prevention of VOC and the treatment of patients.

7. There is the need to reduce the burden of infection on SCD patients by ensuring that patients are administered the relevant protective immunization, have access to effective prophylactic and therapeutic use of antimicrobial, keep their environment clean, and are provided with barrier protection.

8. Government of sub-Saharan African countries should ensure that there is improved access to healthcare services for SCD patients particularly those residing in rural settings.

9. There is need to routinely examine the health-related quality of life, mental health status of SCD in relation to VOC-related pain during hospital admissions and target appropriate psychological interventions for the effective management of pain in these patients.