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Tag: Sickle cell disease

  • Foundation to address SCD, others

    Foundation to address SCD, others

    New foundation to address Sickle Cell Disease (SCD) has been  launched.

    A statement by Founder, Festus Okechukwu Ogbu, said the foundation, named after his daughter who died from SCD, will help  patients suffering from SSC, SCD, and arthritis.

    “It is a devastating disease and that is why we are establishing a foundation to create awareness about SSC, SCD, and arthritis. Besides SCD, which many know, the state of awareness for others is low, perhaps only about 20 per cent.

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    “The foundation will create awareness and sensitise people on how to avoid being victims. Doctors will share their experiences and educate people on factors that predispose people, especially children, to these illnesses,” he said.

    Ogbu recalled that his family benefited greatly from an NGO during his child’s travails, adding he is inspired to also extend that same love to those who passing through such situation.

    “Our foundation will organise regular forums for public education and will also donate drugs to hospitals to help patients in need,” he added.

  • Flying Doctors: An ally in health care

    In need of surgery on sickle cell disease, Abiodun  Bakare, an undergraduate, was about giving up hope when he discovered a surgery would cost N18 million (about $50,000).

    His family and friends decided to take him to India. But the cost of the treatment and that of the fare  were outrageous.

    Bakare decided to look inwards. His search took him to a hospital in Sokoto where experts  agreed to perform the operation for a nominal fee.

    Bakare’s friends jumped in, launched a social media fundraiser, and pulled together the money needed for the operation.  However,  Bakare still had to overcome one huge hurdle: how to get to the hospital.

    The 18-hour journey was out of the question due to  Bakare’s  critical condition. Fortunately, a friend stepped in again and discovered a solution: Flying Doctors Nigeria, which agreed to fly Bakare to the hospital free. The offer reduced a journey that would have taken longer than a day, to just over an hour.

    “I knew we had to support  Bakare with air ambulance services because it would have been impossible for the student to pull together the funds to pay for the service,” explained Dr Ola Brown, founder of Flying Doctors Nigeria, West Africa’s first and leading indigenous air ambulance service organisation.

    The news was a surprise to Bakare. ”I didn’t even know there was an air ambulance service in Nigeria. I thought these services exist only in the Western world. My health condition opened my eyes to the fact that this kind of service is available in Nigeria,” Bakare said.

    He appreciates the  support  of Flying Doctors and understands its value. “This is a journey that the firm could charge over N1 million for. It is still like a dream to me that this kind-hearted firm would intervene in my situation and provide their air ambulance services at no cost to me,” he added.

    Brown said that there were reasons air ambulance services are essential to both the patient and the healthcare community.

    “The first hours of an emergency situation are critical and the life of individuals shouldn’t depend on how far they live from the medical facility best equipped to handle their injury or illness,” she said.

    “And we know that the sooner patients receive the proper care, the sooner and better they recover,”  she added.

    “Further, a firm like Flying Doctors helps us solve the logistical problems involved in providing good healthcare in Nigeria, where the roads are often poor and the distances between the patient and healthcare are wide,” she explained. “Ultimately, this allows us to save money by centralising healthcare services.”

    Bakare said: ”I want to say thank you to Flying Doctors for their support, and encourage other Nigerians to embrace this means of transporting critically ill patients, because if not for Flying Doctors, I could have remained in my serious and painful medical condition.”

    Brown established Flying Doctors  about 10 years ago. Since then, the firm has saved lives across the West Africa sub-region, including infants, children, and pregnant women. Corporate organisations,  such as those in  the  construction, mining, oil and gas,  have also come to depend on the services of Flying Doctors.

    Born and trained in the United Kingdom (UK), Brown graduated as one of the youngest medics in England. She is also a trainee helicopter pilot. She leads a team of 50 emergency healthcare professionals from the Flying Doctors base at  Murtala  Muhammed Airport Lagos.

  • Society challenges all on sickle cell disorder

    The American Society of Hematology (ASH), in conjuction with the Sickle Cell Disease Coalition, had a video conference, which shed light on the global state of sickle cell disorder to help improve screening and early care for children in Africa. OYEYEMI GBENGA-MUSTAPHA, who watched in Lagos, reports.

    This year, about 300,000 babies will be born with sickle cell disease (SCD) around the world. The disease is an inherited, chronic blood disorder, which can cause severe pain, stroke, organ failure and other complications, including death.

    These and many more are the facts churned out by professionals in hematology in a video conference, themed: “Global action- Improving health outcomes for Sickle Cell Disease”.

    To underscore the seriousness attached to the disease, the United Nations (UN) has designated it a global public health problem.

    According to experts, such as American Society of Hematology (ASH) President, Jelili Ojodu;  Medical Director, Ann and Robert H. Lurie Children Hospital, Chicago, Alexis A. Thompson and Medical Director of Sickle Cell Foundation of Ghana, Kwaku Ohene-Frempong, while simple public health measures, such as newborn screening, vaccinations, and early interventions have  improved childhood survival in several countries, including the United States (US), SCD has continued to be a major global public health issue.

    It has remained a major killer of infants and children in the developing world, particularly in sub-Saharan Africa, where an estimated 50–90 per cent of infants born with SCD die before their fifth birthday.

    To support World Sickle Cell Day, ASH is taking measures to raise awareness on the disease in Africa  to improve the health of those with it from infant to adulthood.

    In the video conference, the ASH made global health experts, the media, and its sickle cell disease coalition partners to address the urgent need to raise global awareness about the devastating disease.

    Experts, who participated at the conference, also discussed efforts to distribute two new videos, a public service announcement and short documentary, which addressed the need for newborn screening and counter the prevailing myths about the disease in sub-Saharan Africa.

    The videos, which were made possible by a grant from Novartis Pharmaceuticals Corporation, can be found and shared on the internet via http://scdcoalition.org/global.

    “One of the greatest hurdles we face in curbing the heartbreaking rate of mortality caused by sickle cell disease in sub-Saharan Africa is lack of awareness of the condition and the simple, relatively inexpensive interventions that can save lives. It starts with early recognition, ideally through newborn screening,”  Thompson said.

    He added: “Our hope is that by using these videos to dispel myths and tell parents that SCD is manageable, we can encourage families, communities and public officials to screen newborn children for sickle cell disease so that they can receive critical, accessible treatment that will help them survive.”

    The videos highlight efforts underway in Ghana, a country with a high incidence of SCD, to help dispel myths and eliminate the stigma associated with the disease. The videos showed families steps that can be taken to ensure that children born with SCD are diagnosed promptly so that they can get proper medical care.

    In Ghana, newborn screening and educational efforts have significantly decreased mortality rates “Unfortunately, despite the work we’ve done in Ghana and across Africa, much remains to be done to reduce infant mortality – 90 per cent of children with SCD in resource-poor countries will not survive to adulthood,” Ohene-Frempong said. He added: “In Ghana, we’ve seen that simple public health measures, especially newborn screening, helped children lead more normal lives. In the first 10 years of newborn screening, we made dramatic improvements in reducing sickle cell-related childhood mortality.”

    ASH has made conquering SCD around the world a top priority and is leading efforts to translate research into cutting-edge therapies and cures, increase access to care, educate health care providers, and encourage policymakers to make strides in universal screening and care efforts.

    In 2016, the society founded the Sickle Cell Disease Coalition to amplify the voice of SCD stakeholder community, promote awareness, and improve outcomes for individuals with SCD globally.

     

     

     

     

     

  • Lack of funds hinders govt’s policy on SCD

    Lack of funds hinders govt’s policy on SCD

    Lack of funds has stalled the Federal Government’s policy of testing every newborn against sickle cell, it was learnt.

    This is as 150,000 newborns in Nigeria are diagnosed of sickle cell, with 50 per cent of them dying before they are five.

    The World Health Organisation (WHO) also said sickle cell disease is one of the main causes of premature death among children under five in Nigeria and in some African countries.

    The estimated cost of care is more than US$ 1000 per patient yearly.

    Available record shows that sickle cell disease (SCD) affects nearly 100 million people and is responsible for over 50 per cent of deaths in those with the most severe form of the disease.

    Speaking at the presentation of Hemo TypeSc, a care test for the detection of SCD, Dr. Alayo Sopekan, National Desk Officer on Sickle cell, Ministry of Health, said: “Nigeria has the highest burden of Sickle Cell Disease (SCD) in the world ahead of Democratic Republic of Congo and India.”

    ‘’The 1990 national NCDs survey reports he also noted showed that 24  per cent of its adults  are healthy carriers of a defective S-gene.”

    “The country ranks first as the sickle cell endemic country in Africa with a yearly infant death of about 150,000 representing more than eight per cent of infant mortality in the country.

    “The WHO 2015 report estimated that two per cent of new-borns in Nigeria are affected by sickle cell anaemia, giving a total of about 150,000 affected children born every year in Nigeria alone.”

    Noting that the country has put in place a policy to address the disease, such as testing for newborn, Sopekan, however, said the lack of fund has not allowed for the implementation.

    Currently, he said the government was working on revitalising the six centres, which cut across the six get-political zones.

    He called for early diagnosis and treatment in the management of the disease.

    The National Desk officersaid the government would look into the test kits presented.

    Also, Prof. Obiagele Nnodu, director, Centre of Excellence for Sickle Cell Disease Research and Training, University of Abuja noted said there are 39 sickle cell centres in the country.

    She also spoke on the random tests carried out using the rapid testing kits,  describing it as very accurate and efficient.

    Nnodu noted that 1100 people were tested in two separate study.

  • Seeking lasting relief from sickle cell disease

    Seeking lasting relief from sickle cell disease

    The 2017 edition of the World Health Organisation (WHO) World Sickle Cell Disease Awareness Day has came and gone. The day observed on June 19 offered a platform to draw global attention to the suffering and agony brought about by sickle cell disease and further stimulate multi-dimensional interventions worldwide to mitigate the acute distress occasioned by the condition. It was to galvanise actions to reduce its occurrence as well as promoting effective ways of managing the disease through access to affordable care and support.

    Sickle cell disease is a common life-threatening haematological disorder or genetic disease that affects millions of people worldwide. The World Sickle Cell Disease Awareness Day was declared by the 63rd United Nations General Assembly in 2008 and was celebrated for the first time in 2009. The goal is to increase the awareness about the disease through effective campaigns and promote curable activities including early diagnosis and management.

    Though sickle cell disease occurs predominantly in Africa with figures indicating that more than 1000 babies are born every day having the disease in Africa, it is still a global health issue with about 90,000 to 100,000 people affected in the United States and in other countries as well.

    In Nigeria, according to Mr. Dozie Nwafor, Program Officer, Sickle Cell Aid Foundation (SCAF), Abuja, about 150,000 children are born daily with sickle cell disease while1 out of every 4 adults is an active carrier. The implication is that 1 out of every 4 couple stands a 25% chance of having an offspring with the disease.

    In general, the term sickle cell disease is used to describe a group of genetic blood disorders of red blood cells characterised by an abnormal predominance of haemoglobin S. Hemoglobin (Hb or Hgb) is a protein in red blood cells that carries oxygen throughout the body. In the person with sickle cell anaemia, red blood cells that contain the sickled haemoglobin become rigid, elongated and take the form of a sickle. Due to the rigidity and shape of the sickled red cells, there is automatically an obstruction of blood flow leading to distal tissue ischemia and inflammation. Additionally, because of the fragility of the red cells, they do not have the life span of a normal red cell (which is usually 90 days). This reduced lifespan means that the blood cell levels remain low and cannot meet the oxygen demand of the body tissues.

    Or in simpler terms, the normal red cell is flexible so that it can maneuver smaller blood vessels. Unfortunately, the sickle cell is too rigid to do this and so gets stuck while trying to pass through these really small blood vessels (called capillaries). This blockage of the blood vessels prevents blood and oxygen from getting to tissues and cells leading to serious damage to these cells.

    The main manifestations of the disease are chronic anaemia (or persistently low red blood cell levels) and organ damage caused by the blockage of blood flow and reduced oxygen supply to the cells. Though sickle cell anaemia is hereditary, it is not contagious. It is also autosomal, meaning it is not gender sensitive as it can affect both boys and girls equally.

    A “sickle cell crisis” is the trademark of sickle cell disease and it is characterised by excruciating pain when the tissues deprived of oxygen begin to suffer significant damage. This can affect any part of the body.

    According to Sylvia, a mother of one, and who  has lived with sickle cell for over 25 years ‘If I had to describe it, it would be like repeatedly being stabbed with a butcher knife in the same spot, nonstop’. It is physically disabling, socially disruptive, a cause of absenteeism in schools and work, as well as, emotional disturbance for sufferers and their family members.  Sickle cell crises often affect the bones, lungs, abdomen, and joints. Other symptoms of sickle cell disease include shortness of breath and/or dizziness, severe headaches, swollen hands and feet in children, pale skin/transient yellowish tinge of the skin or eyes due to anaemia, jaundice, or yellow eyes and skin, chest pain, leg ulcers       take a very long time to heal. Repeated sickling and ongoing haemolytic anaemia (breakdown of the hemoglobin) can lead to organ damage causing substantial morbidity and early mortality.

    The objectives of sickle cell disease  care are to prevent or relieve pain; avert or treat infections, prevent organ damage, and strokes; treat anaemia; and reduce complications.

    Mild to moderate pain, particularly during crises is often treated with over-the-counter medicine and heating pads. Severe pain must be treated in a hospital. In the hospital, the usual treatments for acute (short-term) pain crises are fluids and pain-controlling medicines. Fluids which can be administered orally or intravenously help prevent dehydration. Common medicines used to treat pain crises include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and narcotics. Treatment for mild to moderate pain usually begins with NSAIDs or acetaminophen. If pain continues, a narcotic may be needed. Moderate to severe pain is often treated with narcotics. The narcotic may be used alone or with NSAIDs or acetaminophen. Hydroxyurea, though controversial can also be used to prevent painful crises, however not to treat them when they occur.

    Bacterial infections can be a major problem of sickle cell disease. Both adults and children are at risk for a variety of infections, such as pneumonia and bone infections. However, they can be prevented or treated. As it is the case with all children, all routine vaccinations, plus vaccination(s) against Streptococcus pneumonia are to be observed. It is advised that adults who have sickle cell disease should also get vaccinated against pneumococcal infections. If a child or adult, who has sickle cell disease shows early signs of an infection, such as a fever, difficulty breathing, or localised bone pain, treatment should be given right away. They should be examined whenever they experience fevers since early diagnosis and treatment result in better outcomes. Research has shown that about 1 in 14 children with sickle cell anaemia particularly those aged 2-16 have a high risk of developing strokes (overt or silent). This debilitating complication can impede their mobility and/or impair their intellectual ability. However, stroke can be prevented, if children at risk of developing it can be identified through Transcranial Doppler (TCD) ultrasound scan.

    Blood transfusions are commonly used to treat worsening anaemia and sickle cell complications. Most patients with the sickle cell disease have at least occasional blood transfusions. Patients with severe complications–such as stroke and acute chest syndrome–may require months or years of regular transfusions every three to four weeks to prevent organ damage.  To ensure that safe blood is available in Lagos State, Lagos State Blood Transfusion Services, an agency under the Lagos State Ministry of Health in collaboration with District 9110 Rotary Club made voluntary blood donation a signature project and this was launched in November 2016 with the aim of donating 1000 units of blood in one year.

    According to the Honourable Commissioner for Health in the State, Dr. Jide Idris, a total of 104 donor drives were also carried out in various corporate organizations by LSBTS between 2016 and 2017 resulting in the recruitment of 3,694 voluntary blood donors. This state regulatory body also screened 86,419 units of blood for both private and public blood banks during the last one year out of which 82,016 were approved for use. In the course of one year, 6 new private blood banks were registered for accreditation while 4 were closed down because of the inability to maintain the State’s criteria for registration.

    Recent and ongoing researches reveal that new therapeutic options are in development, including gene therapy and gene editing. Recent advances include systematic universal screening for stroke risk with Transcranial Doppler (TCD) ultrasound scan and other point-of-care diagnostic devices.

    It is widely agreed that bone marrow transplant can bring the hope of better treatment for sickle cell disease. To this end, the Lagos state government gave a financial support of 200 million naira to Nigeria Sickle Cell Foundation for bone marrow transplant to ensure that many more Lagosians benefit from this intervention. However, though, bone marrow transplants can cure sickle cell disease, the procedure has significant risks because transplants are not appropriate for every patient. Transplants are used primarily in young patients who have severe sickle cell disease. But, the decision to give this treatment is made on individual basis.

    Bone marrow used for a transplant must come from a closely matched donor most likely 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. Scientists are also studying gene therapy as a possible treatment for sickle cell disease. Researchers want to know whether a normal gene can be put in the bone marrow of a person who has sickle cell disease which would cause the body to make normal red blood cells. Researchers are still studying several new medicines and medical intervention for sickle cell anaemia. Some of the interventions include unsickling of haemoglobin; preventing the cells from sticking to blood vessel walls, and some the possibility of raising and sustaining the levels of fetal haemoglobin (HbF) which is normally present in all individuals (including patients with the sickle cell gene) before birth and the first few years of life (which is why some patients with the sickle cell disease do not show signs or symptoms in in very early life).

    Early diagnosis of sickle cell disease is very important because many difficulties can be prevented with early diagnosis and treatment and the chance of surviving can be enhanced. Sickle cell disease and sickle cell trait can be diagnosed with a simple blood test and can also be diagnosed before the baby is born.

    In Lagos state, testing for sickle cell disease will soon become a compulsory part of the newborn screening program. The purpose is to diagnose affected babies early in life and thus introduce timely and lifesaving interventions that will manage avoidable suffering and possibly prevent death. This test will utilize blood from the blood samples used for other routine newborn screening tests. It can show whether a newborn infant has sickle cell disease or sickle cell trait.

    The prenatal (before birth) screening is done using a sample of amniotic fluid or tissue taken from the placenta. The placenta is the organ that attaches the umbilical cord to the mother’s womb. This test can be done in the first few weeks of pregnancy for people who are at high risk due to their genotype.

    The incidence of sickle cell disease can be reduced if intending parents have adequate information about genotype compatibility. According to a survey conducted in Abuja recently, 42% of the respondents do not know what genotype is. This information and genotype testing should be made accessible through religious and youth organisations.

    There are four genotypes in humans – AA, AS, SS, AC (AC being a variant of AS gene). Intending couples should know both their own genotype as well as their partner’s genotype at the early stage of their relationship before they are well rooted in love and emotions. These can easily be checked through a blood test.

     

    Possible Outcomes of Different Genetic Combinations

    AA + AA = AA, AA, AA, AA

    AA + AS = AA, AS, AA, AS

    AA + SS = AS, AS, AS, AS

    AA + AC = AA, AA, AA, AC

    AS + AS = AA, AS, AS, SS

    AS + SS = AS, SS, SS, SS

    AS + AC = AA,  AC, AS,SS

    SS + SS = SS, SS, SS, SS

    AC + SS = AS, AS, SS, SS

    AC + AC = AA, AC, AC, SS

    It is noteworthy that the life expectancy of children with sickle cell disease has improved considerably since 1960 with causes of death identified as infection-predominantly Streptococcus pneumoniae sepsis, a low level of fetal hemoglobin, a low level of total hemoglobin, and an elevated base-line white-cell count.  In adults, chronic organ damage such as renal or cardiac failure, cerebrovascular accident (stroke), and complications of pregnancy are noted as threats to survival.

    Sickle cell disease is definitely not a death sentence. Having the right attitude and outlook to life marks the difference between having an enjoyable life and an agonizing one for those with sickle cell. Being positive about life, embracing healthy habits and following a healthy diet of fruits and vegetables and food having iron, calcium and potassium can really help. Observing personal hygiene and keeping the environment clean can actually contribute to reducing some of the challenges of sickle cell disease. Taking routine drugs religiously, avoiding strenuous activities and stressful situations, as well as extreme weather conditions, are also very important.

    There are also various non-governmental associations, both in Nigeria and beyond, who offer care for people with sickle cell disease. These often include counselling patients about the importance of self-efficacy and parental support, physical and mental stability and early presentation during crises and pregnancies. With adequate care and management, people with sickle cell can get pregnant and have babies as against widely held misconceptions. The NGOs also offer help in anticipating dangerous clinical situations, and in designing targeted therapy and clinical trials. For instance, the Nigerian Sickle Cell Foundation has mobile sickle cell clinics which provide free provision of drugs and some medical equipment in a few States in Nigeria.

    They also undertake, among other things, Prenatal Diagnosis and Transcranial Doppler (TCD) ultrasound scan. The Sickle Cell Aid Foundation also pursues the double mandate of reducing incidences and making life meaningful for those affected through various programs such as Know Your Genotype Campaign. The Foundation has mobile Sickle cell clinics that service communities with the intention of identifying sickle cell patients, profiling them and enrolling those who are indigent into the Beneficiary support program which offers free medication and surgery where necessary.

    As the World Sickle Cell awareness day is being celebrated worldwide, governments, at all levels, are enjoined to regard Sickle cell disease as a major public health issue deserving meaningful and targeted government attention. There is need to provide adequate safe blood for transfusion to save and support lives. The training and recognition of a cadre of Sickle Cell Nurses, the establishment of specialist Sickle Centres are also being advised in order to improve capacity to deliver better health care to affected individuals and families. Another source of concern is that of some drugs that are freely marketed in Nigeria with unproven claims of curative or palliative properties in the treatment of sickle cell disorder.

    It is expected that with this year’s celebration, great impact in terms of reduction in the number of sickle cell diseases cases and an increase in survival rate as well as a higher quality of life for those affected will be recorded.

     

    Adeola Salako is Public Affairs Director, Lagos State Ministry of Health

     

  • Agency advises youths to undergo HIV, sickle cell tests

    Dr Shamsu Yahaya, Director of Public Health, Katsina State Primary Health Care Agency has urged  youths in the state to undergo Human Immune Virus (HIV) and Genotype tests to ascertain their health status.

    The director gave the advice at a one-day sensitisation on prevention of HIV and Sickle Cell Disease in Katsina on Wednesday.

    “It is high time youths went for the HIV test to ascertain their health status before marriage and prevent falling victim of killer diseases.

    “The test is to prevent youths from contracting the dreaded HIV or giving birth to children with sickle cell anemia.

    “Youths, both male and female, should feel free to undertake test on HIV, hepatitis and sickle cell,” he said

    Yahaya also emphasised the need for the state government to enact a law that would make it for intending couples to undergo compulsory test for marriage.

    This he said became necessary to reduce contracting HIV or bearing children with sickle cell anemia in the state.

    He urged clerics to stress in their preaching to their followers, especially the youth, the need for them to undergo HIV and sickle cell tests before marriage.

    Earlier, the state Chairman of Amalgamated youth forum, Malam Ahmed Mohammed, said the sensitisation was organised to educate youths and families on how to avoid contracting HIV and sickle cell disease.

  • 100 million people suffer from sickle cell, says haematologist

    Sickle cell disease (SCD) affects nearly 100 million people worldwide and is also responsible for over 50 per cent of deaths in those with its most severe form, a Consultant Haematologist/ Executive Secretary, Lagos State Blood Transfusion Committee (LSBTC), Dr Modupe Olaiya, has said.

    She said in Nigeria, SCD is among the top 10 non-communicable diseases (NCDs) causing significant disability, morbidity and mortality.

    Dr Olaiya spoke in Lagos during a sensitisation programme for SCD patients organised by a non-governmental organisation that caters for sickle cell disorder patients, Genotype Foundation.

    She said Nigeria has an annual infant death of 100,000 representing eight per cent of infant mortality in the continent, adding that two per cent of the population has SCD while 25 per cent has the trait.

    She said voluntary blood donation is relevant in relation to sickle cell disorder because sickle cell disorder patients require blood urgently in most cases when they are in need of it and it is crucial that blood must be available to give them.

    She said LSBTC is working to make sure that blood is readily available by putting up advocacy to motivate the public to donate blood voluntarily because, in emergency, it is only blood that is in the blood bank that can be useful;” the one that you are just collecting, you cannot give it to a patient in an emergency, because it has to go through screening. Blood that will be useful in an emergency must have already been available in a blood bank and this is why the issue of campaigning for blood donation is very important.

    “Lagos state has a centralized blood transfusion service and it is a law that every unit of blood collected in the state must be screened by LSBTC.

    “Death from shortage of blood is preventable and this is why we want to avoid it by campaigning regularly for voluntary blood donation,” she said.

    Executive Director, Genotype Foundation, Doris Gbemiloye, said the programme was borne out of the need to sensitise the masses on the need to get blood at the right place which will make a healthy for transfusion.

    She said when unsafe blood is transfused, there will be reaction and this can lead to sudden death. She noted that voluntary donation has really saved lives adding, the risk of HIV/AIDS will also be reduced.