Importance of early diagnosis of Sickle Cell AnaemiaDr. J.O. Lawson FWACP, MScPH

Consultant PaediatricianZankli Medical Centre, Abuja

OutlineIntroductionAetiology /PathophysiologyPrevalence of sickle cell disorder in NigeriaClinical PresentationBenefits of early diagnosisConclusion

Sickle Cell Disease is the commonest inherited disorder in the world

It is a single-gene defect that results in sickle-shaped red blood cells that can cause multisystem morbidity and increased risk of early death

It is a relentless killer of people of African, Asian, Caribbean, Mediterranean and Middle Eastern origin

More than 13 million individuals world-wide suffer from sickle cell disease

The prevalence of the sickle-cell trait is between 10% and 30% in West Africa

Introduction

300,000 infants are born with sickle-cell anaemia in Africa every year, with Nigeria accounting for about half of these

Mortality is high, especially in the early childhood years

1-2% of the population affected and about 25-30% born with sickle cell trait (35million)

SCA contributes to 5% of underfive deaths on the African continent and up to 16% of under-five deaths in Nigeria

About 60,000 people in the USA and 10,000 in the UK have the disease

Introduction

29% of >5yrs (Fleming 1979)

25-28% (WHO, 1994)

23.7% (Omotade et al, 1998)

17.14% (AKTH, Kano, 2006)

• By the share size of Nigeria, it is one of the most affected countries in the world

• No reliable database on sickle cell disorders and trait exists in the Ministry of Health

•A clearer understanding of the proportionate contribution of SCD to mortality will greatly inform public health Mgt strategies

Estimates for sickle cell trait prevalence in Nigeria

Major sickle genotypes HbSS disease or sickle cell anemia - Homozygote for the S globin

with usually a severe or moderately severe phenotype with the shortest survival

HbSC disease - Double heterozygote for HbS and HbC characterized by moderate clinical severity

HbS/B° thalassemia - Double heterozygote for HbS and B° thalassemia and clinically indistinguishable from sickle cell anemia (SCA)

HbS/B+ thalassemia - Mild-to-moderate severity with variability in different ethnicities

HbS/hereditary persistence of fetal Hb (S/HPHP) - Very mild or asymptomatic phenotype

HbS/HbE syndrome - Very rare with a phenotype usually similar to HbS/B+ thalassemia

Rare combinations of HbS with other abnormal hemoglobins such as HbD Los Angeles, G-Philadelphia, HbO Arab, and others

Each parent has two alleles (parts of chromosomes) for hemoglobin and they pass one allele to each child

For two adults with sickle cell trait, for each pregnancy there is:

25 percent chance of having a child with sickle cell anaemia(SS)

25 percent chance of having a child with neither sickle cell trait nor SCD(AA)

50 percent risk of having a child with sickle cell trait(AS)

Aetiology of SCABlood disorder characterized by the presence of

abnormal haemoglobin.

A point mutation of the B-globin gene yielding a substitution of valine for glutamine at the 6th codon and the production of Hemoglobin S

The resulting Hb has the physical properties of forming polymers under reduced oxygen conditions

It also exhibits changes in solubility and molecular stability

These properties are responsible for the profound clinical expressions along with problems of cell volume regulation and endothelial adhesion

PathophysiologyRBCs in SCA contain mostly hemoglobin S do not live as long

as normal red blood cells (15-50 days)

In the deoxygenated state, the substituted valine on HbS binds to other adjacent β globin molecules, resulting in highly ordered molecular polymers

Cells become stiff, distorted in shape and have difficulty passing through the body’s small blood vessels, blocking small blood vessels with reduced blood supply

With repeated sickling, the rbc membrane eventually becomes permanently damaged and irreversible sickling occurs

These sickle cells become trapped in smaller blood vessels and prevent the flow of blood to various parts of the body

PathophysiologyThe clinical manifestations of SCA are mainly due to

repeated vaso-occlusion, chronic intravascular haemolysis, microvascular ischemia and organ damage

One of the most detrimental effects of sickling is vaso-occlusion within the spleen, which results in functional asplenia in 94% of SCA patients by the age of 5 years. In early life, splenomegaly has been known to be common

In later years, however, "autosplenectomy" commonly

occurs, the spleen becomes firm, smaller, nodular and finally reduced into a small remnant

With functional asplenia, the patient can no longer filter waste products such as damaged sickle cells or bacteria from the blood. Younger children with SCD are often more susceptible to infection

1960 SCD used to be a ‘disease of children’

1973, median survival was 14.3 yrs, 20% died before 2 yrs, one third before 5 yrs, half btw 5-30 yrs

30yrs ago, only one half of children with SCD were expected to reach adulthood

1994 Platt et al Median age at death 42 (M) 48(F), 50% survived beyond 50yrs in Boston

CSSCD: 85% of SS and 95% of SC survived 20yrs

Wierenga et al (Jamaica 2001) Median survival calculated was 53 years (95% CI 49.3-57.0) for men and 58.5 (55.1-67.5) for women

Telfer et al 2007 estimated survival of children with HbSS in UK study at 16 years was 99.0%

However, no firm data on the survival of patients with SCA on the African continent

History of survival

Quinn et al (2010)show that the life expectancy of children with sickle cell disease has indeed improved

In their careful study of a large cohort, identified by newborn screening and treated in a single comprehensive

sickle cell centre, the predicted overall survival of patients with Hb SS and Hb SB° at 18 years of age to be 86%

In many developed countries, most children with sickle cell anemia (93.9%) and nearly all children with milder forms of SCD (98.4%) now live to become adults

A large portion of this reduction is attributable to newborn screening programs, the early introduction of prophylactic antibiotics, and the availability of effective vaccines for the prevention of life-threatening bacterial infection

Improvement in survival

Dallas Newborn Cohort (1983-2007 Analysis)

Temporal changes in causes of death in children with sickle cell disease. 

Fleming, 1979: Nigeria, < 2% of children with SCA survived beyond 5 years in a rural community

Athale and Chintu, 1994: Zambia SCD 2.92% of pediatric admissions;but case fatality 6.61%, (55% <5yr), SCA-related mortality peaked in the 1-5 year old age group (38.71%) followed by the 6-10 year old age group (20.97%)

Thuilliez and Vierin, 1997: Gabon 8.4% of under five deaths due to SCD.

Koko, et al., 1998: 7.2% of deaths <5 yrs due to SCD

Senegal Diagne et al, 2000 Senegal 1.1 % mortality per year of follow up

Adarangani et al 2009 Kenya 1% mortality per year

Sickle Cell Disease in Africa:High childhood mortality

Survival data are not available for children with sickle cell disease (SCD)

The few previous childhood SCD studies do not reflect the benefits of modern therapy

Accurate survival data for children with SCD facilitate treatment and counseling of patients and their families, guide public health interventions, and provide the foundation for future research

The best method to measure overall survival is a cohort study of subjects identified at birth or in the first few months of life

Nigeria

Clinical presentationUsually > 4 months oldVariations in the severity and number of manifestationsThe most common signs and symptoms linked to

anemia: fatigue, paleness, easy fatigability or shortness of breath

Jaundice Frequent InfectionPainful crises: may occur in any part of the body

(Dactylitis may be the first sign of sickle cell anemia)Acute chest syndrome: Inflammation, infection, and

occlusion of small vessels may cause this syndrome. Signs include chest pain, coughing, difficulty breathing, and fever

Splenic sequestration crises: The spleen becomes enlarged by trapping (or "sequestering") the abnormal RBCs

Clinical presentation

Stroke: Impaired blood flow in the brain can occur when the sickle-shaped cells block small blood vessels, which may lead to a stroke. Signs can include headache, seizures, weakness of the arms and legs, speech problems, a facial droop, or loss of consciousness

Aplastic crisis: bone marrow temporarily slows its production of RBCs due to infection or another cause, resulting in a serious drop in RBCs and severe anemia

Severe or long-lasting anemia can damage the heart, brain, lungs, kidney, spleen, and other organs of the body

Other possible complications include leg ulcers, bone or joint damage, gallstones, kidney damage, painful prolonged erections in males (priapism) leading to erectile dysfunction, eye damage, and delayed growth.

Many patients with sickle cell disease require occasional blood transfusions

Patients with severe complications (such as stroke and acute chest syndrome) may require months or years of regular transfusions to prevent ongoing damage

Hydroxyurea may be helpful in reducing crises and the need for transfusions

Simple ultrasound of the head (TCD)can identify children at high risk for strokes

Regular checkups to detect eye damage necessary

Benefits of early diagnosisSome complications can be prevented with early diagnosis

and treatment. Sickle cell disease and sickle cell trait can be diagnosed with a simple blood test

In the United States testing for sickle cell disease is a part of their newborn screening program

It is possible to diagnose sickle cell disease before birth by amniocentesis or chorionic villus sampling

The goals of treating sickle cell disease are to prevent or relieve pain; prevent infections, organ damage, and strokes; treat anemia; and control complications

Counseling, prophylaxis, immunizations, follow up an information on new developments

WHO:• Has recognized SCD as a major public health problem

• Has recommended member nations to develop comprehensive programs to “control” SCD, including early diagnosis

• No country in Africa has implemented national newborn screening program for sickle cell disease.

• Most children with SCD in Africa are not diagnosed before clinical presentation, complications, or death.

ALL African and other nations where SCD is common should embark on newborn screening for SCD as a public health program

Newborn Screening for Sickle Cell Diseasein Africa

Newborn Screening for Sickle Cell DiseaseJustification

1. Relatively common, serious condition with clinical manifestations starting in infancy• SCD most common condition diagnosed in newborn

screening in U.S.; age 6 - 12mo had highest mortality rate.

2. Simple, accurate diagnostic tests available• Isoelectric focusing, HPLC methods highly accurate and

simple

3. Proven life-saving, inexpensive preventive treatment available• Penicillin prophylaxis is simple, inexpensive, and effective.

Good evidence that newborn screening followed by comprehensive medical care including parental health education, penicillin prophylaxis, and anti-pneumococcal vaccination have reduced early mortality in SCD

Managing SCDGo for regular checkupComprehensive ImmunizationLearn as much as possible about the diseaseGood hydrationProtect from extreme heat and coldDaily Folic acid and anti-malarialPenicillin prophylaxis in young childrenProper nutritionPsychological support

Seek medical attention when:Fever of >38°CPain that isn't relieved by oral medicationChest pain, shortness of breath or difficulty in breathingExtreme tiredness or somnolenceSevere headaches or dizzinessSevere stomach pain or swellingJaundice or extreme palenessSudden change in visionConvulsionsWeakness or inability to move any part of the bodySlurred speechLoss of consciousnessNumbness or tinglingPainful erection in males

Recent developmentsBone marrow transplants can cure sickle cell disease.

Because the procedure has significant risks, transplants are not appropriate for every patient

Bone marrow transplants are used primarily in young patients who have severe sickle cell disease. However, the decision to give this treatment is made on a case-by-case basis

Bone marrow used for a transplant must come from a closely matched donor. This is usually a close family member who doesn't have sickle cell disease

Researchers continue to look for ways to reduce the risks of this procedure and to widen its application

Gene Therapy: How a normal gene can be put in the bone marrow

of a person who has sickle cell disease. This would cause the body to make normal red blood cells.

Researchers also are studying whether they can "turn off" the sickle cell gene or "turn on" a gene that makes red blood cells behave more normally

New MedicinesSome of these new interfere with sickling of

hemoglobin, others prevent the cells from sticking to blood vessel walls, and some raise levels of fetal hemoglobin

Recent developments

Bone marrow transplant: the only known cure for sickle cell disease. Transplants are complex and risky procedures and currently are an option only for a carefully selected subset of patients with severe complications

To be eligible, a child would need bone marrow or stem cells from a "matched" donor with a low risk of rejection. Even then, the procedure has significant risks and there is the chance of rejection of the transplanted marrow

SCD continues to be a killer of Nigerians

Advances which are mainly applicable in high resource countries, have unfortunately widened the gap in terms of quality of life between patients in developed countries and those in developing countries

Need to improve the capability of laboratories to make correct diagnosis

Need for education, counseling and support

The long-term follow-up of individuals with SCD is important and Newborn Cohort studies would be a powerful tools to monitor survival into early adulthood and help identify predictors of outcome

It is expected that with early identification by newborn screening, initiation of penicillin and routine immunizations, education of those involved in the child’s care, and lifelong, specialized follow up care, many of the complications of sickle cell disease can be prevented or managed promptly so that individuals can lead healthy, productive lives

Conclusion

Tiffany McCoy “Having a good attitude affects any area of

your life. I always try my best to have a good outlook on life. I have sickle cell disease, but sickle cell doesn't have me”

THANK YOU