The phenotypes of sickle cell disease: strategies to aid the identification of undiagnosed patients in the Italian landscape

Abstract

Sickle cell disease (SCD) is an inherited autosomal recessive monogenic blood disorder characterized by red blood cell sickling responsible for recurrent vaso-occlusive crises and chronic hemolysis. Clinical manifestations vary and SCD patients experience increased morbidity and mortality. In Italy, SCD patients cluster into two distinct subpopulations: those of sub-Saharan African descent and those of Caucasian descent. Most sub-Saharan African SCD patients are children or young adults and carry the homozygous genotype hemoglobin (Hb) S, or SC, whereas Caucasian SCD patients tend to be older and have predominantly HbS/β-thalassemia. Patients of African descent typically present with acute SCD-related events, including vaso-occlusive crises, acute chest syndrome, anemia, fever, and pneumonia. Caucasian patients, according to the different distribution of SCD genotypes, may exhibit either acute episodes or chronic long-term complications. Regardless of age, genotype, or ethnic background, most SCD patients in Italy are undiagnosed, and pain, fatigue and anemia should be regarded as presenting signs and symptoms of this disease. The tests needed to diagnose SCD are simple, and a complete blood count together with erythrocyte morphology, wherever available, hemolysis markers, should be performed whenever SCD is suspected. If a patient presents with two risk factors –family history, ethnicity, or a significant clinical feature – a first-level screening test (e.g. assessment of Hb fractions with HPLC), where available, should be performed immediately, or a referral should be provided. Here, we present an overview of the clinical features of SCD that may be encountered in real-world clinical practice in Italy from a practical perspective. This narrative review may aid non-specialist physicians in identifying disparate clinical conditions that may be symptoms or signs of SCD.

Introduction

Sickle cell disease (SCD) is an inherited monogenic disorder caused by mutations in the hemoglobin (Hb) β-globin subunit. A point mutation in the β-globin gene results in the production of an abnormal hemoglobin variant, known as HbS [1, 2]. In specific clinical situations, such as infection and dehydration, or even exposure to low temperature, HbS molecules can polymerize forming rigid, rod-like structures inside red blood cells, that become deformed into a “sickle” shape [1]. SCD is a genetically heterogenous group of rare hemolytic anemias characterized by multifaceted clinical features, and phenotype depends on the co-inheritance of HbS with mutations in β-globin genes, such as β^C or β-thalassemic alleles, that contribute to increase the diversity of phenotypes [3] (Table 1). Severe forms are caused by the homozygous presence of the HbS (HbS/HbS), coded as a rare disease in Orphanet [4], or the co-inheritance of HbS with the β⁰-thalassemia mutation (HbS/β⁰), while milder forms include the co-inheritance of HbS with the β⁺-thalassemia mutation (HbS/β⁺) [5]. Compound heterozygous of βS allele and βC allele, HbS/HbC disease, although historically considered less severe than HbS/HbS is associated with substantial clinical complications, that tend to become more pronounced with advancing age [6].

Table 1 Summary of hemoglobin isoforms, genetic mutations, and genotypes associated with SCD

Sickling and hemolysis of red blood cells with consequent endothelial dysfunction and aseptic inflammation lead to vaso-occlusion and associated ischemia, with clinical manifestations ranging from acute severe pain to end-organ damage, increasing morbidity and premature mortality [1, 5, 7,8,9,10]. In patients with SCD, acute complications present as vaso-occlusive crises (VOC), acute chest syndrome (ACS), stroke, acute splenic sequestration crisis, acute kidney injury, acute anemia, acute aplastic crisis, acute infections, and priapism, while chronic SCD complications involve chronic pain, leg ulcers, cerebrovascular disease, cognitive decline, avascular necrosis of bones, and heart, hepatic and renal failure [1] (Table 2). However, the boundary between acute and chronic complications is often blurred, as acute events may progress into chronic conditions, and chronic complications can be punctuated by acute exacerbations [1, 11, 12].

Table 2 Acute and chronic symptoms in children with SCD

In Italy, a total SCD all age prevalence of 4.4 (3.8–5.0) per 100,000 population is reported in 2021, but the data are believed to be underestimated due to the lack of an organized national screening [13, 14]. SCD clinical presentation and evolution is complex and varies according to its genotype, severity at diagnosis, and the simultaneous presence of vaso-occlusive and hemolytic features. The progression of the disease may also be influenced by geographic origin and socioeconomic factors, as many low-income countries lack widespread newborn screening programs with difficulties in the access to healthcare service [7]. As a result, SCD often goes undetected and untreated in its early stages, leading to more severe clinical manifestations later in life [11]. Although hematologists specialized in hemoglobinopathies are well-aware of the key signs, symptoms, and phenotypes of SCD as part of their specialized training, hematologists mainly dealing with adult patients, general practitioners, pediatricians, internists, and emergency room physicians may lack the same level of familiarity due to limited daily clinical exposure. Given that SCD is a rare disease with a significant increase in registered cases in Italy over the last decade, the risk of misdiagnosis, inappropriate management, delays in diagnosis and referral by healthcare providers who encounter the disease infrequently remains high [11, 15,16,17,18]. These gaps in knowledge and clinical handling significantly impact SCD patients, underscoring the need for enhanced training and awareness among non-specialist healthcare professionals to improve patient outcomes [19]. Reported delays in diagnosis suggest that the SCD awareness among non-specialists has not been relevantly impacted by the recent attention for the SCD and the presence of international and national guidelines and recommendations [17, 20].

As the timely and accurate diagnosis of SCD is paramount to providing safe and effective medical care, we present here an overview of the clinical features of SCD that may be encountered in real-world clinical practice in Italy from a practical perspective. This narrative review may aid non-specialist physicians in interpreting disparate clinical conditions as possible symptoms or signs of SCD.

Methods

This narrative review used PubMed to identify examples of Italian patients with SCD in observational studies or real-world clinical practice. Search terms included “Italy” AND “sickle cell disease” OR “thalassemia” AND “phenotype” OR “phenotyping.” The publication date was limited to the previous five years. Relevant articles were selected to assess the clinical features and factors implied in SCD.

Clinical phenotypes in Italian SCD patients and first-line approach

Ethnic migration from SCD-endemic sub-Saharan African regions has changed the Italian SCD landscape [21]. Nowadays, the SCD population can be seen as an endemic subpopulation located mainly in Southern Italian regions and a multi-ethnic subpopulation in Central and Northern regions [13, 22]. In detail, 76.5% of Italian SCD patients report a Black ethnic background, while 21% are of Caucasian descent [23]. There is also a disparity between the patient’s country of birth and the mother’s country of birth; only 14.8% of the mothers of Italian SCD patients were born in Italy, while most were born in Western Africa, primarily Nigeria (38.3%) and Ghana (12.3%) [23]. Consequently, SCD patients in Italy cluster into two distinct subpopulations: those of sub-Saharan African descent and those of Caucasian descent [18].

Regardless of age, genotype, or ethnic background, most SCD patients presenting at emergency departments in Italy are undiagnosed. Physicians should keep in mind two key symptoms, namely fatigue and pain of unknown origin in both patient subpopulations, as these are commonly reported complications of SCD [24, 25] and easily assessed clinical conditions also at the emergency room (ER) [16, 26], in conscious patients. The third key pillar for diagnostic suspect is the presence of anemia, that is also easily assessed in all clinical settings, including the ER [26, 27]. In any case, erythrocyte morphology and Hb HPLC should be undertaken, where available, as this is a simple test that can identify abnormal erythrocyte shape, Hb levels and abnormal Hb variants, together with an assessment of the presence of anemia in other family members (Fig. 1).

Fig. 1

Identifying suspected SCD cases based on patient profiles in the Italian population, according to Graziadei et al. [18]

Patient type at presentation: young adults (mostly Caucasians)

In the Italian landscape, young adult SCD patients are typically Caucasian, with a respective median age of 38 years (IQR 25–49 years) [18].

Physicians should pay attention to Caucasian patients presenting with acute symptoms of VOC, ACS, sepsis, and bone necrosis (Table 2). In Caucasian SCD patients (n = 400, median age: 24 years), of whom 46.6% had a HbS/β⁺-thalassemia genotype (Table 1) attending Italian Hematology Centers, the incidence of complications was highest for VOC (95.4%), followed by hospitalization (77.9%), ACS (40.9%), bone necrosis (25.3%), silent cerebral infarction (17.7%), leg ulcers (7.8%), chronic kidney disease (4.9%), pulmonary hypertension (4.2%), and stroke (3.8%) [28]. Children with HbS/β⁺-thalassemia (median age 10.9 years) also develop severe and disabling complications, with VOC registered in more than half of the patients, sepsis, ACS, and (AVN) in approximately 10% of cases, aplastic crisis in 5%, and stroke in 2.4% of cases. This demonstrates that the HbS/β⁺ form is not as mild and complication-free as traditionally considered [29]. Moreover, an Italian study reported that in a cohort of SCD patients and a pre-existing diagnosis of AVN, 75% had the HbS/β form, with about half of the patients presenting the HbS/β° subtype. All patients showed impaired joint function as measured by the Patient-Reported Outcome Measures (PROMs) used in the study, with a tendency toward greater dysfunction in patients with the HbS/β° subtype. This suggests that chronic joint pain in the hips and shoulders in young adults could be a marker of the disease [30].

It has been reported that HbS/β individuals experience splenic complications, such as splenomegaly and hypersplenism, and require increased splenectomy [31, 32]. Therefore, splenomegaly, alongside hemolytic anemia or in a patient with typical symptoms, should raise the suspicion of SCD and prompt the initiation of the diagnostic process.

Patients of Caucasian descent may also present with chronic and disabling complications (Table 2). In an Italian real-world analysis of 1,816 SCD patients, SCD was mainly identified through secondary diagnosis in patients without crisis (78.9% ≥18 years; 70.9% HbS/β genotype; 12.4, 6.9, and 4.3 cases per 100,000 health-assisted individuals, respectively, in Southern, Northern, and Central regions) [24]. However, more recent data (2022), reported on the website of the Italian Society for Thalassemia and Hemoglobinopathy (SITE), indicate a number of approximately 2600 prevalent cases [33]. Primary diagnoses were heterogeneous and included obstructive chronic bronchitis with (acute) exacerbation, iron deficiency anemias secondary to blood loss (chronic), atrial fibrillation, congestive heart failure, or unspecified chest pain [24].

Hemoglobin HPLC and/or erythrocyte morphology should be performed for all patients who present with acute symptoms of common complications of SCD (Tables 2 and 3) and in acute cases where the cause of the presenting symptom/s is uncertain (Fig. 1).

Table 3 Key diagnostic tests in the management of sickle cell disease

As mentioned above, the difference in the clinical manifestations of SCD relies on the different distribution of genotypes among different ethnic groups. Caucasian SCD patients display the typical spectrum of clinical symptoms, although the frequency and severity of symptoms may vary depending on the β-thalassemia mutation (β⁺, β⁺⁺, or β⁰) (Table 1). In HbS/β⁺⁺ genotype the presence of a residual expression of normal adult Hb (HbA), which can interfere with the sickling process of red blood cells, is likely responsible for the milder symptoms, as even small amounts of HbA can modulate disease severity [3]. In addition, the co-inheritance of deletions or mutations in alpha-thalassemia genes can mitigate the clinical expression of the disease [34]. Most (75%) Caucasian SCD patients are HbS/β⁺ or HbS/β⁰, and only 21% are HbS/HbS [18] (Fig. 2). All clinicians should be aware of the extreme variable presentation of SCD, either acute or chronic and pay particular attention to familiar anamnesis. If asked, patients often report the presence of SCD or other forms of not better specified anemia in parents or other relatives but may not refer this information spontaneously as they may not be aware of their underlying genetic disease and, importantly, also relatives could have not received a specific diagnosis yet.

Fig. 2

Genotype (%) in the ethnic groups in the Italian-diagnosed population [18]

Patient type at presentation: children or adolescents (mostly Sub-Saharan Africans)

In contrast to Caucasian patients, in the Italian scenario, Sub-Saharan African SCD patients are younger with a reported median age of 12 years (IQR 7–22 years) [18]. These patients are usually children presenting to the ER with pain, swelling of both hands and feet, or splenic sequestration, a life-threatening complication arising when a large amount of sickled red blood cells become trapped in the spleen, causing spleen enlargement, a sudden drop in hemoglobin levels, and severe anemia [14, 35,36,37].

Sub-Saharan African refugees visiting ER in Italy, either children or adults, commonly report acute sickle-cell-related events, including VOCs, anemia, fever, ACS, and pneumonia [38]. Similarly, hospitalization (82.5%), VOC (82.2%), ACS (40.7%), bone necrosis (22.2%), and silent cerebral infarction (14.3%) were common complications in untreated SCD patients of African descent from Italian hematology treatment centers [28]. Young adults more frequently present to hematology centers after blood testing have identified acute, not better specified anemia [38]. The socio-economic status of sub-Saharan African patients is also important as these patients are less likely to be seen by specialist hematologists [18]. Therefore, the presence of hemolytic anemia and its sequelae [15] in patients of African descent should always be a red flag to test for the presence of SCD.

An increased risk of ACS [39, 40], echocardiographic cardiac abnormalities, including left atrial dilation and left ventricular hypertrophy, which were significantly correlated with markers of hemolytic anemia [41] are also reported in sub-Saharan African pediatric SCD patients. In addition, the risk of stroke can be evaluated by transcranial Doppler imaging (TCDi)-assessed flow velocities. This non-invasive test measures the speed of blood flow through the brain’s blood vessels as an indication of their blockage and damage due to the sickling of red blood cell [42]. Higher blood flow velocities (> 200 cm/s) are significantly associated with higher risk of stroke (Table 3) [43]. However, TCDi fails to predict the risk of cerebral hemorrhage, which typically increases during adolescence and in young adults with SCD accompanied by high mortality rates [44, 45]. In addition, TCDi blood flow velocity is not standardized in adults and peak of systolic velocity could be a valid index to identify abnormal cerebral blood flow [46].

As reported in Sub-Saharan Africans, non-acute events, including abdominal discomfort, pregnancy complications, cardiopathy, seizures, and the inconsolable crying of a baby, have also led to the identification of SCD [38]. In terms of chronic complications, the annual rate of VOCs was strongly associated with the presence of AVN detected by magnetic resonance imaging (MRI) in 11 asymptomatic pediatric SCD patients, mostly of African descent, and significantly correlated with the number of sites involved (humerus, 17 lesions; femur, 11 lesions; vertebrae, 4 lesions) [9]. The evaluation using joint-specific PROMs, although lacking statistical significance, showed that patients with HbS/HbS tended to have Oxford hip score and Oxford shoulder score values more than 10 points higher than those with HbS/β, suggesting a lower long-term impact of this complication in individuals with HbS/HbS compared to those with HbS/β [30]. Therefore, non-specialist clinicians should pay attention to this subpopulation and suggest a blood/genetic test to screen for the presence of SCD even in the absence of clear symptoms. From a genetic background, most (71%) sub-Saharan African SCD patients are HbS/HbS, followed by HbS/HbC (21%) (Fig. 1) (17).

Discussion

Recent data suggest an increasing presence of SCD in Italy, with a prevalence of around 2600 SCD cases in 2022, affecting 0.3% children with different family background (Europe, Asia, America, Africa), and up to 0.56% subjects with African family background assessed by the primary care pediatricians [33, 47], and a high disease burden with multiple hospitalizations is reported for these patients [24, 38]. Two subpopulations of SCD patients are described, grouped with respect to the ethnic background, genotype and age, which may present different signs and symptoms in clinical practice [18].

Sub-Saharan African SCD patients in Italy are significantly younger than Caucasian SCD patients and have a higher prevalence of the HbS/HbS genotype [18]. Sub-Saharan African SCD patients commonly present to ERs with acute SCD-related events, including VOCs, ACS, anemia, fever, and pneumonia, splenomegaly and acute splenic sequestration, and have a higher risk of echocardiographic cardiac abnormalities and abnormal TCDi results. Conversely, Caucasian SCD patients are older and are predominantly HbS/β-thalassemia, either HbS/β⁺, or HbS/β⁰. The higher prevalence of these genotypes compared to the HbS/HbS reflects the substantial number of thalassemia patients in Italy [48]. While HbS/β⁰ show a phenotype similar to homozygous HbS, HbS/β⁺ patients tend to have a more indolent clinical phenotype, with SCD often identified secondary to a primary diagnosis, although they are clinically heterogeneous and not always with a mild disease [3].

Improving outcomes in SCD is paramount [49]. While work is underway to implement best practices in SCD in the European Union [19], the approach needed to diagnose SCD is simple and based on first level assessments: screen at first suspicion. A complete blood count, as a quick first-level test, and erythrocyte morphology, if available, should be performed whenever SCD is suspected. Besides, monitoring the levels of hemolysis scavenger proteins as biomarkers of hemolytic activity a hallmark of SCD [50]. Specifically, if a patient presents with two risk factors—family history/ geographic origin/ethnicity, or a significant clinical feature—a first-level screening test should be performed immediately, or a referral should be provided.

The SCD genotype correlates to the diverse manifestations of the two subpopulations in Italy, which also depend on geographic origin. The genetic and ethnic background interplay with non-biological factors. Very often migrant individuals arriving in Italy from economically disadvantaged areas have been suffering from a reduced access to care, even in the early stages of the disease. As most children and adolescents with SCD in Italy are first- or second-generation immigrants from English or French-speaking African countries, these socially vulnerable groups may experience linguistic, social, and economic barriers to the healthcare system despite it being freely available [22]. Indeed, language barriers experienced by immigrant patients with SCD may prevent them from accessing medical care or encourage hospitalization rather than outpatient care, as seen in pediatric and adult HbS/HbS and HbS/β⁰-thalassemia patients in Italy, where the management of pain crises is almost exclusively in hospitals rather than the ER/Day Hospital [51].

For acute presentations, it is important to recognize the clinical features of SCD for timely and appropriate diagnosis and treatment. Patients not given the appropriate attention at first presentation/hospitalization may experience delays in being introduced into the appropriate healthcare pathway and lead to repeated hospitalizations for severe conditions as well as the development of potentially disabling long-term complications [13].

Finally, the chronic condition is characterized by recurrent clinically significant SCD manifestations. For this reason, timely diagnosis and referral are crucial for the appropriate management of the disease and to limit its high clinical burden [49].

Conclusions

General awareness of the extremely variable clinical presentation of SCD is crucial to achieve an appropriate and timely diagnosis and offer the specific therapeutic strategies. If not early recognized, SCD can cause multi-organ damage and failure. Therefore, an appropriate knowledge of the evidence-based clinical segmentation of the population and expected features in the different subpopulations in the Italian scenario may facilitate a diagnostic suspicion of SCD, and an appropriate and timely referral.

Ultimately, a complete blood count with erythrocyte morphology, HPLC and hemolysis markers, as a quick and everywhere available first-level test, should be performed whenever SCD is suspected. Physicians should also be aware that affected patients may not present with acute pain crises, and that there are other types of presentation, perhaps less frequent or less classically associated with SCD, which are still relevant and significant.