ALL INDIA INSTITUTE OF MEDICAL SCIENCES NAGPUR

Center of Excellence for Sickle Cell Disease

From present to future

From Prevention to Cure

                                                                

 

 

Contributors

1. Dr Meenakshi Girish, Professor , Paediatrics

2. Dr Amol Dube, Associate Professor, General Medicine

3. Dr Medha Davile, Assistant Professor, Obstetrics and Gynecology,

4. Dr Nishant Banait, Associate Professor, Neonatology

5. Dr Amol Dongre, ex Additional Professor, Community Medicine

6. Dr Akash Bang, Additional Professor, Paediatrics

7. Dr Richa Juneja, Associate Professor, Hematopathology

8. Dr Somya Das, Associate professor, Transfusion Medicine

9. Dr Nitin Marathe, Associate Professor, Hospital Administration

10.Dr Vishwadeep Khushoo, Assistant professor, Medical Hemato-oncologist,

Edited by: Dr Rajshri Khot, Additional Professor, General Medicine

 

 

Contents

1. Introduction

2. Prenatal Diagnosis

3. New born screening

4. Sickle cell database

5. Community awareness and screening

6. Immunization in Sickle cell patients

7. Investigations in Sickle cell Anemia

8. Safe blood transfusion in sickle cell anemia

9. Special privileges for Sickle cell patients

10. Bone marrow transplantation- an overview

Sickle Cell Anemia – disease burden

 

India is home to over 50% of the world's patients with sickle cell disease and Maharashtra carries the second highest burden of the disease, with the affected population concentrated in the districts like Nagpur, Gadchiroli, Yavatmal, Bhandara, Chandrapur, Wardha, Amaravati, Gondia , AIIMS Nagpur serves as an Institute of National Importance for a catchment area geographically linked to all these districts where a large part of the population is constituted by the Scheduled caste, Scheduled tribe and the OBC (other backward classes), who are reported to carry the highest risk for sickle cell gene variant. 

The institute, by virtue of its eminence and location, is mandated to address the regional health needs in every possible way. AIIMS Nagpur has initiated some strategic policies towards addressing the problem by adopting coordinated multi-pronged care packages incorporating Prevention, Care, and Cure for Sickle Cell Anemia. This mission aligns well with the NHM's vision of eliminating sickle cell disease as a public health problem in India before 2047.

Sickle cell disease is inherited recessive disorder of red blood cells caused by point mutation at hemoglobin gene resulting into replacing of amino acid glutamine by valine in beta chain of hemoglobin leading to change in shape of RBC’s as C-shaped which gets easily destroyed in spleen and also causes vascular occlusion in blood vessels resulting in various complications including painful vaso-occlusive crises. SCD was mainly believed to affect the tribal population of central India, however non-tribal persons are also affected in many states such Odisha, Chhattisgarh, Gujarat, Maharashtra and Madhya Pradesh which show a burden of disease with a carrier frequency in the range of 1 to 44%.[1-4] . In Vidarbha region, Bhandara district was found to be the area of maximum SCD gene frequency (9.02%), followed by Chandrapur (8.18%), Nagpur (4.0%), Amravati (3.73%), and Yeotmal (3.17%). The SCD was diagnosed from all tribal groups and 14 caste groups. Highest frequency of

the disease was observed in Gond (14.28%) followed by Pradhan (11.49%), Bhil (11.42), Teli (10.48%), Matang (8.75%) and Korku (7.89%) [5]

Newborn screening programs for SCD have recently been initiated in Maharashtra, Gujarat, Odisha and Chhattisgarh and monitoring these birth cohorts will help to understand the natural history of SCD in India.

The new initiatives and vision under the National Health Mission provide a golden opportunity to provide a framework for prevention and management of hemoglobinopathies. This will include guidelines for adequate therapy for those affected helping them lead better lives and prevention through carrier screening, genetic counselling and prenatal diagnosis. A new born screening program will be initiated for sickle cell patients with provision for appropriate management. The World Health Organization has clearly outlined the goals for control of hemoglobinopathies - provide affordable and adequate therapy for those affected, while at the same time reduce the number of births of children with the disease through strong political, administrative and financial support.

Prevention and control will be achieved through the following strategies:

1) Carrying out awareness, education and screening programs in the community and schools.

2) Establishing laboratories for carrier screening for hemoglobinopathies and newborn screening for sickle cell disease and prenatal diagnosis

3) Screening pregnant women and their husbands.

AIIMS Nagpur is a central apex institute situated in Maharashtra where the prevalence of sickle cell genes are much higher in populations in nearby districts

Hence it is the need of the hour to develop Center of Excellence for Sickle Cell Disease at AIIMS Nagpur. The vision being elimination of Sickle cell Disease with a mission to provide comprehensive one roof management from Care to Cure.

District-wise distribution of sickle cell trait among the tribal communities in different States of India from Census of India 2011 [6]

 

Services will include comprehensive multispecialty services in OPD, IPD, investigations, vaccination, prenatal diagnostics, molecular testing laboratory, new born care, specialty  and super specialty services ( including surgery) , free drugs, UDID certification , ABHA registration. Community services in outreach RHCT and UHCT, schools and community. Care using newer drugs Crizanlizumab and research in various aspects of Sickle cell disease. In Sickle cell disease transplant indications are very selective, due to risk of morbidity associated with transplant procedure

AIIMS Nagpur has been serving patients with sickle cell disease since its services became operational in 2019. In the last one year [Jan 23-24], about 800 patients with sickle cell anemia have been managed in the OPD and IPD. All women have been screened for sickle cell anemia during pregnancy and prenatal screening in the form of amniocentesis/chorionic villi sampling had been done in 53 cases. Avascular necrosis of the head of femur is a dreaded complication in SCD , 22 sickle cell patients had undergone hip replacement surgeries at AIIMS Nagpur . More than 100 blood and blood products were issued to Sickle cell patients free of cost from blood bank AIIMS Nagpur. Facilities for curative therapy by bone marrow transplantation at the institute is under progress and will be operational soon.

Short term goals to bring down the sickle cell disease in various districts of Vidarbha to less than 10% by year 2030. After this is achieved by 2040 the target will bring it down to less than 5% by year 2040.

 

Understanding pharmacotherapy in Sickle Cell Anemia

 

SCD may be treated with the following medications:

1. Antimetabolites: Hydroxyurea (10 mg – 35 mg/kg day) is an anticancer drug now used to treat sickle cell anemia. In 2017, the USFDA approved hydroxyurea as sickle cell anemia treatment for children aged 2 years and older, as well as adults. Studies show hydroxyurea:

• • Cuts the number of VOC/acute pain crises by 50%.
  • Decreases instances of acute chest syndrome.
  • Reduces the need for blood transfusions.
  • Improves anemia symptoms.

2. Hemoglobin oxygen-affinity modulators (eg, voxelotor)
3. Crizanlizumab: This drug blocks adhesion of activated erythrocytes, neutrophils, and platelets by binding to the protein P-selectin
4. Opioid analgesics (eg, oxycodone/aspirin, methadone, morphine sulfate, oxycodone/acetaminophen, fentanyl, nalbuphine, codeine, acetaminophen/codeine)
5. Nonsteroidal analgesics (eg, ketorolac, aspirin, acetaminophen, ibuprofen) Tricyclic antidepressants (eg, amitriptyline)
6. Antibiotics (eg, cefuroxime, amoxicillin/clavulanate, penicillin VK, ceftriaxone, azithromycin, cefaclor)
7. Vitamins (eg, folic acid)
8. L-glutamine stabilizes red blood cell membrane, preventing its damage and subsequent deformity. Results have shown that it decreases number of vaso occlusive painful events.

 

Common complications in Sickle Cell Anemia

Infection: Kids with sickle cell disease are at risk for some bacterial infections. It's important to watch for fevers of 101°F (38°C) or higher, which can be signs of an infection. Adults are frequently prone for community acquired pneumonia caused by Streptococcus pneumonia or viral influenza infections.

Anemia: It occurs when the body temporarily does not make enough red blood cells and can cause severe anemia. Signs include paleness, extreme tiredness, and a fast heartbeat. It is a type of anemia where there is no iron deficiency but deformity in red blood cells leading to destruction of red blood cells under certain conditions such as infection, dehydration, and stress.

Aplastic crisis causing pancytopenia is life threatening condition caused by Parvovirus B19 infection and  needs multiple blood transfusions and supportive care.

Pain: It is painful swelling of the fingers and toes (also called dactylitis) is the first sign of sickle cell anemia in some infants. Pain crisis is the main morbidity in Sickle cell anemia patients which brings them to hospitals. Early use of opioid analgesia. e.g Morphine along with NSAIDs and Diclofenac/ Ketorolac analgesic patches for local pain will help to alleviate the pain and decrease the length of hospital stay. Treatment of underlying causes like  infection, dehydration need to be addressed simultanuously

Acute chest syndrome is caused by inflammation, infection, and blockages of small blood vessels of the lung. Symptoms include chest pain, coughing, trouble breathing, and fever. This is a life threatening complication in which patient may need mechanical ventilatory support and ICU admission. Pulmonary thrombosis is one of the important causes of mortality in acute chest syndrome.

Splenic sequestration crises: The spleen traps the abnormal red blood cells and becomes enlarged. This can lead to a serious, quick drop in the number of red blood cells in the bloodstream. Symptoms include paleness, weakness or extreme tiredness, an enlarged spleen, and belly pain.

Stroke: Sickle-shaped cells can block small blood vessels in the brain, causing a stroke. Symptoms include headache, seizures, weakness in the arms and legs, speech problems, a facial droop, or loss of consciousness. Adults with sickle cell disease are prone for Ischemic stroke and require exchange blood transfusion as a part of care

Other problems: People with sickle cell disease are also at risk for problems such as chronic non healing leg ulcers, Avascular necrosis of hip bone causing joint damage which may need hip replacement orthopedic surgery. Sickle cell patients frequently get pigment gallstones, causing cholecystitis and biliary duct obstruction. Interstitial nephritis is the cause of renal damage in SCD. Sickle cell retinopathy causes eye damage including risk of loss of vision. Cardiac complications include development of pulmonary arterial hypertension which can cause heart failure.

Recommended reading

1.Balgir RS. The burden of haemoglobinopathies in India and the challenges ahead. Curr Sci 2000; 79:1536–47

2.Research, I. C. o. M. Intervention Programme for Nutritional Anaemia and Haemoglobinopathies against some Primitive Tribal Populations of India: A National Multicentric Study of ICMR. (Indian Council of Medical Research, India 2010). 

3.Godbole, S. et al. In Proceedings of National Symposum on Tribal Health (eds N. Singh et al.) (Jabalpur 2006).

4.Patra, P. K. & al., e. Sickle Cell Screening Project - At A Glance, www.scic.cg.nic.in (2016).

5.Deore, A. U., &Zade, S. B. (2013). Epidemiology of sickle cell disorder: The urban scenario in Maharashtra, India. Int. J. Public Health Epidemiol, 2, 101-107.

6.Census of India 2011. Office of the Registrar General and Census Commissioner. Ministry of Home Affairs, Govt of India. Available from: http://www.censusindia.gov.in

 

Sickle cell disease in Pregnancy

 Q-1. How sickle cell disease is inherited by the baby?

1. If one parent is SCT and other is normal, 50% of the babies are affected and rest will be normal.

2. If both parents are sickle cell trait (SCT), 50% of the babies will have SCT, 25% will have SCD and 25% of the babies will be normal.
3. If one parent is SCT and one is SCD, 50% of the babies will have SCD and 50% of the babies will have SCT.
4. If both parents are SCD, all babies will have SCD.

Therefore, if you have SCD or SCT, your partner should be tested for the condition, before you get pregnant. It can be tested even prior to marriage, so that marriage between two such individuals and subsequent risk of transmission to the baby is reduced.

 

Q-2. What is Prenatal testing and how is it done?

If your partner is having sickle cell disease or is a carrier, testing of the baby during pregnancy (Prenatal testing) can be done by two procedures described in next section. In both procedures, a needle is inserted through your tummy to collect sample from either your placenta or the fluid within the baby sac. The sample is subjected to genetic test. If the test is positive for SCD, then you will be counselled about discontinuation of pregnancy if you wish.

 Pre-natal testing for sickle cell disease

There are two types of diagnostic tests, one is chorionic villous sampling (CVS) and the other one is Amniocentesis. During the procedure, tissue from the baby is obtained and sent for further testing.

The eligible couples are those with both the parents either carrier for sickle cell disease or if mother is sickle cell disease and father is a carrier or vice-a-versa. The test is offered only if the couple is willing for abortion in case the baby is detected to have sickle cell disease. The procedure carries a very small increased risk of abortion (1% over the risk during normal pregnancy).

Chorionic villous sampling

This procedure is performed between 11- 14 weeks of pregnancy. A local anesthesia is given and a sample of placental tissue is obtained by a small needle inserted in the placenta through mother’s tummy. The sample obtained is then sent for further testing. The report of the test is usually available within 10 days. The couple is counselled after the test report is available and decision regarding pregnancy is then taken by them

 

Amniocentesis

This procedure is performed at 16 weeks of pregnancy. Here a sample of fluid

around the baby (amniotic fluid) is obtained through a small needle inserted through mother’s tummy. The fluid contains cells of the baby. Sample is sent for further testing and the report is available within ten days. The couple is counselled after the test report is available and decision regarding pregnancy is then taken by them

 

Q-3. What extra care should be taken by mother with Sickle cell disease or trait during pregnancy

Extra Care during pregnancy

You should see an Obstetrician and a hematologist as soon as you are pregnant. If you are taking hydroxyurea, stop it as soon as you are pregnant. Your vaccinations for hepatitis B, flu and pneumonia should be updated if necessary. These vaccinations are safe in pregnancy. You should visit the antenatal clinic at least every 4 weeks until 6 months of pregnancy, and then every 1–2 weeks until your baby is born. At each visit blood pressure will be checked and your urine will be tested. Ultrasound will be done to monitor growth of the baby. Blood transfusions are not routinely given during pregnancy, but may be needed.

Which medications during pregnancy ?

If you are taking hydroxycarbamide(hydroxyurea), you should stop taking it and

continue using contraception for 3 months before you become pregnant.

 High-dose folic acid (5 mg) daily throughout your pregnancy

 Low-dose aspirin (75 mg) daily from early pregnancy to reduce the risk of pre- eclampsia.

 Keep yourself hydrated

 Visit hospital if any abnormal symptoms develop (vomiting, pain)

 

If crisis develops during pregnancy

You may need admission to the hospital. You will be given painkillers, oxygen by mask and fluids through the intravenous line. Heparin will be given to prevent formation of clots in arteries and veins and antibiotics will be started if needed.

Q-4 What complications can occur during pregnancy?

Complications during pregnancy

Pregnant women have a higher risk of developing blood clots in the legs (venous thrombosis) compared with women who are not pregnant. Episodes of painful crises

occur more often during pregnancy. Cold weather, dehydration and too much physical activity can increase the risk of painful crises. Rise in the blood pressure can occur. Growth of the baby may also be affected. Labour may start early and a caesarean delivery may be needed.

 

Q-5 What care should be taken during labour pains?

Once labour pain starts, you need to get admitted in a hospital which is able to manage the patients with sickle cell disease. You will be kept warm, fluids will be given and blood transfusion will be started if needed.

Pain relief will be given by analgesics. After delivery, you will be encouraged to mobilize early and heparin will be given at least for 7 days after normal delivery or for 6 weeks if you have undergone a caesarean delivery Breastfeeding is recommended and the newborn will be screened for sickle cell disease at birth.

 

Q-6 Which contraceptive methods should be used by Sickle cell patients?

Contraception

Progesterone-only pills, injections (Depo-Provera), implants (Nexplanon), the Mirena coil and barrier methods (condoms and caps) are safe and effective.

AIIMS, Nagpur is equipped with all the facilities needed to manage pregnant women with sickle cell disease. Pre-conceptional, prenatal, antenatal counselling and treatment are being offered. Dedicated HDU and ICU are available here.

 

Newborn Screening

As per the prevention and control of hemoglobinopathies in India - thalassemia, sickle cell disease and other variant haemoglobins, 2016, universal new born screening should be implemented in areas with high prevalence of Sickle cell haemoglobin for screening of sickle cell disease.

As per the same guidelines the testing that should be offered at Tertiary level / national referral centres.

Identification of rare Hb variants not identified at State level labs, by capillary electrophoresis, HPLC or IEF

{AIIMS Nagpur has conducted a study in which a very small amount of blood through capillary was collected from all newborn  for HPLC test to detect hemoglobinopathy and it was found to give accurate results when compared with whole blood sampling..

Now we are offering Newborn screening to all babies for a genetic test on dried blood paper spot. The test is being offered in collaboaration with the Center for Cellular and Molecular Biology, Hyderabad. In this test, baby can be identified to have either SS disease or AS. Those with AS disease, will be further subjected to HPLC to identify other variants under Sickle cell disease.

This test can be done anytime in the newborn period. Those found to have SCD will be provided anticipatory guidance and management to avoid early morbidity and mortality occurring due to the disease in infancy

 

 

Sickle cell disease database at AIIMS Nagpur

 

What is a Sickle Cell Database?

Sickle Cell Database is a structured collection of information about patients with sickle cell anemia. It will be a digital and single institution database. The information collected will be stored online under the Hospital Management Information System of the AIIMS Nagpur.

What is the purpose?

1. To describe Sickle Cell Anemia based on clinical findings and laboratory parameters and determine it’s severity.
2. For policy decisions regarding allocation of resources 
3. Identify areas for research
4. Develop guidelines for management
5. Assess utilization of resources provided by institution
6. Facilitate long term follow up
7. Prepare registry for bone marrow transplantation 

What data will be collected?

Patients’ demographic details, HPLC report, immunization status, predominant complaints requiring hospitalization or hospital visit, number and frequency of blood transfusions given, disease modifying agents used and its dosage schedule, clinical and lab monitoring parameters and family details including sibling screening. This data will be presented to administration annually as medical audit. The information will be collected at the time of patient visit to OPD or IPD, in an online structured case proforma and will be entered by a data entry operator specifically trained in the task.

  

Who will use this data?

The data will be used by hospital administrators for identifying gaps in policy implementation. It will also be used for planning research and generate treatment protocols by the doctors. Only anonymized data will be used.

How will this data be secured?

The e-Sushrut HMIS application employs HTTPS/STH protocols, ensuring that any scripts visible to users cannot be exploited to bypass firewalls or access sensitive code. Server-level access is restricted to authorized users and computers. Data exchanged between the database and application undergo encryption and authentication processes before insertion into the database. Additionally, the application implements a role-based access control system to limit users' access to relevant menus and features. AIIMS employs robust firewall protection against internal and external threats. Frequent security audits across internal networking, servers, and firewalls ensure comprehensive security measures.

 

How will it benefit patients?

Patients can avail special privileges in hospital by virtue of registering in the database. The longitudinal data collected will help better monitoring of patients and early detection of any complications due to Sickle cell anemia. The registry will help in recalling patients who have missed their appointment. Management can be customised as per patient's requirement. Stamping of visits will ensure drug compliance. Patients can avail opportunities for participation in research.

 

Community awareness and screening for sickle cell anemia

 AIIMS Nagpur has a robust community outreach programme.  in which following information is disseminated to the general public. All persons between 0-40 years are then offered blood tests for detection of SCD.

What is Sickle Cell Disease (SCD)?

Sickle cell disease is a genetic condition and someone who inherits a sickle cell gene from each parent has sickle cell disease. Hemoglobin is the protein in red blood cells that carries oxygen throughout the body. Each person inherits two hemoglobin genes, one from each parent. A normal gene will make normal hemoglobin (A). A specific change in the hemoglobin gene will make sickled hemoglobin (S).

In normal blood, red blood cells look like round discs. In sickle cell disease, they become hard, sticky and look C shaped like sickles, or crescent moons. These sickle shaped cells get stuck together and block small blood vessels. This stops blood from moving as it should, causing pain and organ damage. The most common types of sickle cell disease are hemoglobin SS, hemoglobin SC, and sickle beta thalassemia.

What is sickle cell trait?

Sickle cell trait occurs when a person carries one copy of the sickle cell gene passed down from one parent along with a normal hemoglobin gene from the other parent. If one parent has sickle cell trait, there is a 50% (1 in 2) chance with each pregnancy of having a child with sickle cell trait. In most cases, people living with sickle cell trait experience no symptoms and lead normal lives. It is important to know if you have sickle cell trait before you decide to have children.

What are the symptoms of sickle cell disease?

• pallor
• frequent jaundice
• bone & body ache
• enlarged spleen
• retarded growth
• frequent infections
• dactylitis

How is SCD managed?

Individuals with sickle cell disease should receive regular medical care for crisis prevention. Treatments may include a medication called hydroxyurea which increases the body’s level of fetal hemoglobin which prevents sickling, as well as antibiotics for infections or prevention of infections, and medicines for painful events. Everyone should eat a balanced diet and receive regular check-ups and immunizations.

How to prevent Sickel Cell Disease?

Primary prevention strategies focus on awareness generation for screening and self-care among patients and their caregivers, pre-marital and pre-conceptional counselling to prevent the conception of a child with sickle cell diseases.

Prevention thus requires screening of target population (high school and college going, eligible couples and pregnant women) using solubility test, confirmation of diagnosis by simple blood test called a hemoglobin electrophoresis and finally genetic counselling to prevent sickle cell disease in the offspring.

 

At Community Level:

1. The purpose is to set up model community services and screening programs in outreach areas of rural and urban community health centers of AIIMS Nagpur.
2. In the initial 6 months, we will create awareness among school-going children, college youths, and eligible couples for better uptake of screening tests.
3. Later, we wish to offer screening tests to target populations such as high school children, college-going, and willing eligible couples for SCD by using solubility test. Those positive in screening will be referred to AIIMS Nagpur for confirmation. Those with SCD and traits will be offered counselling. 
4. At present ANCs are screened by using a solubility test. If positive, the partner is offered a test with counseling. The quality of this service and the status of follow-up are not known. We should strengthen the quality of counseling and follow up on advice. We will monitor the indicators per the policy documents.
5. We will undertake operational research on SCD to know community awareness, perceptions, and barriers in screening uptake (if any) to address the problems at ground level.

 

INFECTION PREVENTION

Infections: A common cause of hospitalization

A person with Sickle Cell Anemia is at a higher risk of infections. There are several reasons for this. But the final outcome is that infections occur much more frequently; and they are more serious and severe. Infections can affect lung, brain, blood or internal organs. This can lead to hospitalization, school absenteeism, loss of wages and in most serious cases, even can cause death.

 

Role of Immunization

Prevention of any infection is always better, easier and cheaper than the treatment of the infection. Immunization with vaccines helps us prevent infections to a large extent. Hence, in addition to the free vaccines that are given to children through the National Immunization Schedule, it is highly recommended that every person with Sickle Cell Anemia should be given these additional vaccines even if it entails some cost.

Some Sickle Cell Anemia patients have to undergo a surgery to remove the spleen called as splenectomy or cholecystectomy if gall stones develop. Because spleen is an organ that fights the infections, in such patients, immunization with additional vaccines becomes all the more necessary. If spleen removal surgery is performed in a planned manner, it is extremely crucial to finish all immunizations 1-2 months prior to the surgery.

 

 Which vaccines are recommended?

Below is a description of all the recommended vaccines with their recommended schedule-

Vaccine Name	Recommended Schedule
H Influenza type B Conjugate Vaccine (HIB)	If not received as part of Pentavalent vaccine before 6 months of age, give dose/s as per the age at which the patient presents. 6-12 months- 2 doses 1-2 months apart ; then a booster at 15-18 months of age 12-24 months- 1 dose; then a booster after 3-6 months After 2 years of age- A single dose
Hepatitis B	If not received as part of Pentavalent vaccine, Give at 0,1,6 months
PCV-13 (Pneumococcal Conjugate)	If not received 3 doses in 1st year of life, give doses as follows- Age 2 – 6 yrs: 2 doses 2 months apart (0,2) Age 6 – 18 yrs: Single
PPSV-23 (Pneumococcal Polysaccharide)	Give single dose after 2 yrs of age AND at least 8 wks after last PCV-13 dose Booster at 5 years
Typhoid Conjugate	Single dose anytime in life after 6 mths of age
Quadrivalent Meningococcal Conjugate	9-23 mths: 2 doses 3 months apart (0,3) 2 yrs onwards: Single dose (To be given 4 wks after last PCV-13)
Hepatitis A	Can be given after 12 months of life Killed- 2 doses 6 months apart (0,6) Live- Single dose
Varicella (Chickenpox)	15-18 months onwards: 2 doses 3 months apart (0,3) >12 years: 2 doses 1 month apart (0,1)
Influenza (Flu)	Can be given after 6 months of life First time vaccination- 2 doses 1 month apart (0,1) After that- 1 dose every year

 

 What to do for vaccine related pain / fever?

After vaccine administration, the patient should be observed for 30 min in the same hospital. Routine administration of paracetamol in anticipation of pain/fever is NOT recommended. Generally, the vaccines do not cause more than mild pain/fever. If pain/fever is significant, paracetamol can be given on as and when needed basis. Cold or hot compresses, massaging etc are not recommended at the injection site. If anything unusual is observed, like excessive sleepiness, fits, inconsolable crying, noisy breathing, swelling over face, lips or skin rash etc, the patient must be taken to the nearest doctor.

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Why do patients with SCD get infections?

In young children between 0 and 6 years old with sickle cell disease, their spleen may enlarge, a condition called splenomegaly. This occurs because their blood vessels become blocked with sickle-shaped red blood cells, causing blockages and harm in the spleen. As children with sickle cell disease grow, their spleen can shrink and harden, a process known as auto-splenectomy, typically occurring by around 5 years of age. When the spleen doesn't work properly (asplenia), kids are more vulnerable to infections caused by specific bacteria like Streptococcus pneumoniae, Hemophilus influenzae type b, pneumococcus, Salmonella etc. Hence, it's crucial to understand these risks and take preventive measures, especially through vaccination, to protect against these infections.

Beyond bacterial infections, individuals with SCD face an increased risk of a spectrum of infectious diseases affecting various organ systems. Respiratory tract infections, including colds and pneumonia, are common occurrences and can lead to significant morbidity. Acute chest syndrome (ACS), characterized by chest pain and lung complications, represents a particularly serious complication of respiratory infections in SCD. Tuberculosis, with its potential for widespread dissemination, is another infection of concern in this population. Moreover, bone and joint infections, such as septic arthritis and osteomyelitis, pose significant challenges, often necessitating prompt medical intervention to prevent long-term complications.

Gastrointestinal tract infections and related complications further contribute to the complexity of managing SCD. Abdominal pain, a common symptom, may stem from various sources, including acute spleen enlargement, hepatic sequestration, infarction, or thrombosis. Cholelithiasis, the formation of gallstones, is a frequent cause of abdominal pain and can occur even in young children with SCD. Additionally, fever accompanied by diarrhoea may indicate gastrointestinal infections, requiring careful assessment and management. Leg ulcers, though less prevalent, tend to occur more frequently in males and may result from a combination of increased physical activity leading to trauma and heightened rates of Vaso occlusive crises.

Furthermore, individuals with SCD are at heightened risk of other infectious diseases, including malaria and hepatitis, which can lead to severe complications such as hepatic encephalopathy. Given the multifaceted nature of infections in SCD, comprehensive medical care, early detection, and preventive measures are essential to effectively manage infections and mitigate the associated risks in individuals living with this complex haematological disorder.

 

INVESTIGATIONS in Sickle Cell Disease

 Background: Our red blood cells carry oxygen and perform vital function of supplying oxygen to various body parts through molecule called hemoglobin. Normal adult human has 4 iron binding sites in the hemoglobin which is in the form of four strands called protein/ globin chains. In adult predominantly >95% Hemoglobin has 2 alpha and 2 beta chains and is called adult hemoglobin or Hb A. A small fraction of fetal hemoglobin (<1%) which has 2alpha and 2 gamma chains) and Hb A2 (<3.5%) which has 2alpha and  2 delta chains) is also detected normally in adults. Any abnormality in these protein/ globin chains of hemoglobin is called hemoglobinopathies. This group of diseases occur due to mutation in gene/DNA controlling production of Hb protein chains. Genes are passed on from Mother and father to child. Humans have 2 copies of every gene with one copy inherited from each parent. Hence if child has even one copy of normal gene, he produces adequate amount of adult hemoglobin to lead near normal life. These patients are called trait. Only when both parents pass the gene with defect/ mutation the child is not able to produce normal adult Hb and present with weakness, fatigue, failure to grow normally, bony pains and spleen enlargement. These group of patients have disease.

Lab diagnosis of Sickle cell Disorder

When patient has one normal gene and one gene with sickle mutation, he produces 50 to 60% normal Hb A and only 40% Hb S. These patients have sickle cell trait and are generally healthy. They can only be detected by performing special tests for sickle as mentioned below. 

When patient has mutation on both beta gene than he will produce predominantly Hb S 80 to 90 % and hardly any normal Hb is produced this condition is called sickle cell anemia (SCA). Rarely patient can inherit sickle and thalassemia mutation each of the parents and this results in Sickle-beta thalassemia.

Various lab tests are designed to detect this abnormal Hb called Hb S to diagnose Sickle cell disorder.

Screening Test- Can be done in community

These are simple and rapid test designed to screen for sickle in mass population like school, social gatherings, college students and community screening.

Types of Screening Tests

 

1. Solubility test: Patients blood is treated with set of chemical reagents in glass tube. If person has Hb S it reduces solubility of sample and sample turns turbid. We will not be able to see lines on the paper kept behind the tube due to turbidity in case of positive test.
2. Sickling Test: Suspected Patient’s blood is treated with sodium metabisuphite. In presence of Hb S the RBC will take shape of sickle. This test need microscope and expert to see sickle RBC and hence usually done in hospital

 

3. Card Test: With advance technology many cards are available which detect Sickle HB and normal Hb in a person in few minutes. These are better than Solubility and sickling tests as they differentiate between sickle trait and sickle cell anemia.

Person undergoing screening test must remember that all screening tests do not differentiate between sickle cell trait and sickle cell anemia. Normal screening test does not exclude thalassemia in person tested. Hence all positive screening tests must be confirmed by second tests called HPLC. In Punjabi, Sindhi, lohana communities’ risk of thalassemia is much higher hence they should always take up HPLC during pregnancy for screening for beta thalassemia.

Laboratory Diagnosis- only available in hospitals:

Whom to test?

All patients suspected to have sickle cell disorder, healthy people testing positive for sickle screening tests and persons at risk of thalassemia or other hemoglobinopathies should be offered Hb HPLC available in many PHC and government hospitals.

Which Test to do?

1.Hb HPLC or automated electrophoresis /CZE are tests which separate various types of Hb (Hb A, Hb F, Hb A2, Hb S, Hb E) present in human blood based on their charge and detect percentage of each type of Hb. This test can differentiate between sickle trait and sickle cell anemia by measuring normal (Hb A) and abnormal Hb (Hb S). It also detects thalassemia trait by detecting increased Hb A2 (4 to 7%) and thalassemia major by increased Hb F (>90%). Whenever available Hb HPLC or its parallel technique capillary zone electrophoresis (CZE) should be the test of choice

2. Manual HB electrophoresis: When HPLC/ CZE is not available, manual electrophoresis can be offered to the patient. However, it should be remembered that this test can only detect different types of Hb but cannot measure them. It cannot diagnose thalassemia trait. Sickle trait will show band of Hb A and S and will be reported as AS pattern. Sickle cell anemia patient will show only Hb S band or Hb S and Hb F band and will be reported as SS or SF pattern.

 

DNA testing for sickle cell Disorder

We can use various molecular tests to confirm presence or absence of sickle or thalassemia causing mutation in gene of patients. These tests are not routinely needed for diagnosis as Hb HPLC is sufficient for the same. The genetic testing is offered to the patient only in following situations.

1. Transfused Patient: Sickle and thalassemia patient need repeated transfusion. If patient has received blood transfusion in 3 months prior to testing blood-based screening and HPLC tests may give false negative results due to donor RBC. DNA based tests may confirm diagnosis in this case.
2. Prenatal testing: If both mother and father are carrying sickle mutation then baby in uterus of pregnant mother is at 25% risk of having sickle cell anemia. Baby’s sample can be collected by inserting needle in uterus and subjected to genetic testing to detect whether baby is having sickle cell anemia. Thus, couple at risk of having child with severe disease can make informed decision about continuation of pregnancy.

 

Summary: There are many methods to detect sickle cell disorder these days. We must make conscious decision to get ourselves tested and become aware of our carrier status. All Pregnant ladies must be screened during first week of pregnancy and offered prenatal testing if partner is also carrier. Early detection of sickle cell anemia gives us an opportunity to prevent complication and improve quality of life of affected Patients.

 

Test to Prevent, Test to detect and test for better quality of life for Sickle Patients!

  

 

TRANSFUSION in Sickle Cell Disease

 

What is the role of blood transfusion in managing Sickle Cell Disease ?

• Blood Transfusion is needed only in special indications. Not all patients will require blood transfusion. Doctors recommend transfusions to treat and prevent certain sickle cell disease complications. Red blood cell transfusions increase the number of red blood cells and also provide normal red blood cells that are more flexible than red blood cells with sickle hemoglobin. One may have one or more of the following kinds of transfusions:-
• Acute transfusions to treat complications that cause severe anemia.
• You may also receive transfusions for patients in case of an acute stroke, in many cases of acute chest crises, and in multi-organ failure.
• A patient who has sickle cell disease usually receives blood transfusions before surgery, to prevent complications.
• Regular or ongoing blood transfusions may help lower the chances of another stroke in people who have had an acute stroke.

Optional Indications

• People who have too many side effects from hydroxyurea.
• Children who have abnormal transcranial Doppler (TCD) ultrasound results, because transfusions can lower the chance of having a first stroke.
• Complications that do not improve with hydroxyurea

 

Possible complications to blood transfusion include alloimmunization , which occurs when the transfusion recipient develops antibodies to the blood being transfused, making it hard to find a matching unit of blood for a future transfusion. Infection and iron overload can also occur. In children receiving regular transfusions monitoring of serum ferritin and chelation therapy may be needed.

What happens during blood transfusion in managing Sickle Cell Disease ?

During a blood transfusion, your blood and the donated blood must have matching antigens, or special proteins on the surface of each red blood cell.

If the antigens in your blood and the donated blood do not match, your immune system (your body’s ability to fight germs) may attack the new blood. This transfusion reaction can cause serious health problems. Below are steps you can take for safer blood transfusions.

What you should do when you are about to receive blood transfusion in managing sickle cell disease ?

• Share Your Transfusion History with Your Healthcare Provider - Share past health information including your number of lifetime transfusions and any reactions to blood transfusions such as severe pain, fatigue, brown or red urine, and fever. If you have had past transfusion reactions, your provider may talk to you about the risks and benefits of immunosuppressants. These medicines lower the chance of your immune system rejecting the donor blood, protecting you from a life-threatening transfusion reaction.
• Know Your Blood Type - Ask your provider for an extended red cell antigen profile, a test that determines your antigens. Share the results with your healthcare providers before your blood transfusion.
• Request Blood Matching - Once you know your antigens, they need to be matched with the antigens of the donor’s blood to avoid a transfusion reaction during the blood transfusion. Ask your provider for blood that is matched for these antigens to which people with SCD most commonly have transfusion reactions: C/c, E/e, and K red cell antigens.
• Track Your Iron Levels - If you have received more than 10 transfusions in your lifetime, you may be at risk for iron overload (too much iron in the body). Ask your provider for a ferritin blood test, which measures the amount of iron in your blood. If your ferritin levels are high (greater than 1,000) and you receive transfusions on a regular schedule, your provider should run a magnetic resonance imaging (MRI) test that measures iron levels in your liver. Your provider may also run an MRI that measures iron levels in your heart.
• Talk to Your Provider About Your Transfusion Options - If you need regular transfusions, ask your provider about an automated red cell exchange, a transfusion process that removes and replaces sickled cells with healthy blood. This process may be preferred over a simple blood transfusion during which healthy blood is added to blood with sickled cells. An automated red cell exchange can lower your risk for health problems, such as iron overload.

 

What services does department of Transfusion Medicine, AIIMS Nagpur Blood Center provides in managing your Blood Transfusion in Sickle Cell Disease ?

• Department of Transfusion Medicine, AIIMS Nagpur Blood Transfusion is equipped with all the facilities needed to manage the Transfusion Support in Sickle Cell Disease.
• Option of both, simple (top up) or automated exchange transfusion, is provided and based on clinical judgement of individual cases, taking into account the indication for transfusion, the need to avoid hyperviscosity and minimise alloimmunisation, maintenance of iron balance, venous access issues and available resources.
• Packed Red Cell Transfusion Support - Transfusion of packed red blood cells (PRBCs) is offered keeping in mind the specific guidelines in mind including Leuko-depleted and Leuko-filtered are also available. 
• The unit used for transfusion in patients with SCD is ABO-compatible, and AHG-Crossmatch Compatible. If there are clinically significant red cell antibodies (current or historical) then, it is ensured the red cells selected are negative for the corresponding antigens.
• Transfusion Transmitted Infection Testing [hepatitis B, hepatitis C and human immunodeficiency virus (HIV), Malaria and Syphilis] is mandatorily performed on all the units used for transfusion. 
• Automated Exchange Transfusion is offered in managing patients with SCD.
• Provision for Extended Rh- and Kell-matched PRBC units to be made available shortly

 

SPECIAL PRIVILEGES FOR PATIENTS WITH SICKLE CELL DISEASE AT AIIMS NAGPUR

 

At AIIMS Nagpur, we prioritize the care and well-being of all our patients living with sickle cell disease, we understand the unique challenges they face and we are dedicated to providing

specialized support and services.

Some of the special privileges available to sickle cell patients at AIIMS Nagpur are mentioned below, including priority access to care, financial assistance, accommodations at our Dharamshala, and other essential points of assistance.

 

1. a) Priority Access to Care:

Sickle cell patients at AIIMS Nagpur receive priority access to Registration. A dedicated counter No.1 is for sickle cell patients. The patients can register for first time & for revisit directly at counter No.1 without any waiting time.

The medical consultations at every department required for sickle cell patients including the diagnostic tests and treatment services are also prioritized. We recognize the urgency of managing sickle cell complications and strive to minimize waiting times, ensuring prompt and comprehensive care for our patients.

 

1. b) Financial Assistance:

Managing a chronic condition like sickle cell disease can be financially burdensome.

Therefore, we offer various financial assistance programs to help alleviate the financial strain on patients and their families. The patient can approach the Medical Social work officer at Medical Superintendent office located on ground floor IPD block to get guidance on eligibility of any insurance coverage, government schemes,

BPL Category documents required and NGO to support you in covering medical expenses and related costs.

 

1. c) Accommodations at Dharamshala:

We understand that traveling for medical care can be challenging, especially for patients requiring frequent visits or extended stays. To ensure comfort and convenience, AIIMS Nagpur offers accommodations at Dharamshala facility.

Located near the Ayush Block, ‘The Dharamshala’ provides affordable stay options for patients and their caregivers. The requisition form for dharmshala should be endorsed by treating doctor and approved by the Medical Superintendent office. For further details please approach the Medical Social work officer at Medical Superintendent’s office.

 

1. d) Other Points of Assistance:

In addition to priority access to care, financial assistance, and accommodations at Dharamshala, AIIMS Nagpur offers various other points of assistance to support sickle cell patients. These include:

• Dedicated Patient Support Services: Our Sickle cell team with the Medical Social work officer is available to address your concerns, provide guidance and offer emotional support throughout your course of treatment.

• Transportation Services: We provide assistance with free internal transportation with e-rikshaw facility. The Security Department can be approached for availing the services.

• Counselling and Education &amp; Grievance/complaint handling: We offer counselling services through the Medical Social work officer &amp; the Sickle Cell team and also help you better understand your condition, manage symptoms, and make informed decisions about your health.

• Community Outreach: AIIMS Nagpur actively engages in community outreach programs to raise awareness about sickle cell disease, promote early detection and provide support to affected individuals and their families. For further details kindly contact the Dept. of Hospital Administration IPD block.

  

 

BONE MARROW TRANSPLANTATION IN SICKLE CELL DISEASE

 

Currently there is no cure for the disease, Bone marrow transplant from matched donor and gene therapy opens a possibility of permanent cure for a patient with Sickle Cell Disease (SCD).

The bone marrow transplantation has been associated with high mortality, morbidity so it is done only in selected cases and when absolutely necessary.

HbSS, SC or S/B thalassemia-are eligible for bone marrow transplantation if they have one or more of the following

1. a) Clinically significant neurological event (stroke) or any neurological deficit lasting more than 24 hrs.
2. b) Two or more episodes of acute chest syndrome (ACS) in 2 years period preceding enrolment despite supportive care measures
3. c) three or more severe vaso-occlusive crisis per year in 2- years period preceding enrolment despite supportive care measures ( pain management plan/ treatment with hydroxyurea)

The above indications are just some of the most common indications for eligibility found in the Indian population.

What is the ideal time to do BMT?

It is preferred to perform bone marrow transplantation in young children who have a HLA matched subling donor. Preferably preschool age children between 2 and 5 years. If performed in this age group, the outcome of BMT is said to be better as it prevents most of the irreversible end -organ damage which occur in patients with sickle cell disease as they grow older. It has been reported that the best outcome is seen if BMT is done before 12 yrs of age with a 100% HLA matched sibling as a donor.

BMT team requires multidisciplinary representation. AIIMS Nagpur can offer following staff and facilities required to conduct BMT:

Bone marrow transplant core team:

	Specialist/ staff
1	Clinical hematologist trained in BMT
2	Paediatric Hematologist trained in BMT
3	Hematopathologist
4	Critical care specialist/ Anesthetist
5	Infectious disease specialist
6	Dedicated fellow/ Senior resident
7	Nursing staff (trained in BMT)
9	Psychologist
11	Social worker
12	Housekeeping Staff
13	Radiation oncologist

 

Laboratory and equipments

	Laboratory item/ equipment
1	Flow Cytometer for cd 34 count-Beckman
2	HLA typing Sanger sequencer & NGS
3	Chimerism VNTRSPLIT -Sanger sequencer, FISH for CEP X/y
4	Cyclosporin/ Tacrolimus level by Mass Spectroscopy
5	Galactomannan assay
6	Air particle counter (Air sample culture)
7	DTPA and MUGA scan machine
8	QPCR
9	SPERM and OVA cryopreservation facility
10	Total body irradiator

 

Blood Bank Facility

 

	Facilities
1	Stem cell apheresis
2	Dry stem cell bathing machine
3	Cryopreservation facility for marrow / stem cell
4	Irradiator
5	Platelet agitator
6	Clinimac cell seperator
7	Rate controlled freezer and liquid nitrogen storage

Air Handling Unit (AHU)

Each room of the 4 room BMT Unit, has its own dedicated Air Handling Unit (AHU) to provide 10-15 Hepafiltered fresh air changes per hour.

The fresh air entering the patients room is first treated through special filters. Treated fresh air then passes through 0.3 Micron High Efficiency /particulate Air Filter (HEPA). Hepa removes all the bacteria, viruses and fungus.

This hepafiltered air passes through a laminar floor to reach the patient’s room at the desired humidity and temperature, which is comfortable for the patient.

Automatic and selective control system

Automatic and selective control system provides positive air pressure in the BMT room compared to ante room and the BMT corridor.

This has been done to ensure that, on opening the door of the BMT Room or the ante room, no outside air from BMT Corridor can enter the patient’s room.

Air pressure in Anteroom is 10-15 pascal higher than the BMT corridor and air pressure in BMT room is 10 - 15 pascal higher than the ante room.

Ante room is a small room between the corridor and the BMT room for maintaining positive air pressure, special hand washing (scrubbing) and wearing a sterile gown before entering the BMT room.

Stainless Steel Doors, Vinyl Flooring and Cladding of  walls are most practical to clean with disinfectants to maintain and protect patients from infections.

Other Pre transplantation requirements

Tests for detection of Cytomegalovirus,HHV6, Parvo virus B19, EPV, Galactomannan, CMV serology, Clostrodium deficile, Biofire, Varicella IgG, Anti HBs titre, Anti Hb core antibody , Anti toxoplasma antibody are available (or testing Kits will be made available) in Microbiology Lab AIIMS Nagpur.