What’s in a name?

Cite this article as:
Alex Gibbs. What’s in a name?, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32037

Rightly or wrongly, stereotyping is engrained in physicians from when they start medical school. Consider the classic medical exam questions regarding a South Asian gentleman with a cough. Students are almost conditioned to start recalling their knowledge of tuberculosis before they have even finished reading the question. Stereotyping saves lives. Following Occam’s razor of common things being common means that a patient attending A&E with fever and hypotension is likely to receive potentially life-saving antibiotics even before rarer diagnoses have been excluded. However, one of the toughest skills of being a doctor is recognising when our conditioned stereotypes are hindering our ability to provide good care. 

Race and health are often linked. This might be to illustrate the varying prevalences of different diseases within different ethnic groups. Occasionally, treatment for a certain disease will vary by the patient’s ethnicity (such as choice of anti-hypertensive in the under 55s). Nevertheless, Covid-19 has demonstrated that not all generalisations based on race and disease are valid. In the first few weeks of the pandemic, when it was first realised that ethnic minorities in the UK and USA seemed to be much more likely to die from the disease, speculation regarding genetic susceptibility to the novel virus was rife. Yet ultimately, as is often the case, it appears that socio-economic factors, rather than genetics, explain these tragic differences. 

Yet sickle cell disease is one condition where there is undoubtedly a correlation between ethnicity and the likelihood of having the disease. Sickle cell disease (SCD) is caused by a mutation on the eleventh chromosome, affecting the gene that codes for one of the protein molecules in haemoglobin. The results of this mutation are abnormally ‘sickle-shaped’ red blood cells which cause an array of complications: from episodes of vaso-occlusive crisis (severe pain due to restricted blood flow to different parts of the body); strokes; anaemia and splenic infarction leading to infection susceptibility. The life expectancy of a baby born in the UK with sickle cell disease is less than 60 years. In order to have sickle cell disease, a child must inherit a mutated copy of the gene from each of their parents. Inheriting just one copy of the mutated gene has been shown to be protective against malarial infection. This selective advantage has meant that the sickle cell trait gene remains prevalent in areas of the world where malaria is endemic, most notably in Sub-Saharan Africa. Consequently, the vast majority of people with SCD are of African origin.

Until I began working as a doctor, I had only a biochemical view of sickle cell disease. I had learned about the genetics behind the disease and how these manifest as symptoms. However, as my medical school was in a predominantly white area of the UK, I encountered very few patients with SCD during my clinical placements. I did not regularly care for patients with sickle cell until I started to work in London, a couple of years after I had graduated from medical school. What struck me then was the negative attitude that some of my medical colleagues exhibited towards patients that we encountered with the disease. Patients with SCD most commonly presented to hospital complaining of severe pain due to vaso-occlusive crisis. Despite the clearly established pathology that explained their presentation, I found that many of my colleagues would question whether the patients were really in as much pain as they claimed. Strong analgesia would be prescribed reluctantly and often only after delay and discussion about ‘opioid seeking behaviour’. This is where I was first introduced to the term ‘sickler’.

A ‘sickler’ is a patient with sickle cell disease. It is often used in discussion between medical professionals as a faster way of saying ‘a patient with sickle cell disease’. Patients with SCD, like any other patient group with a chronic, incurable condition, can be difficult to manage. Seeing a patient return multiple times to A&E with the same complaint is frustrating for any clinician who takes satisfaction in curing their patient’s ailments. Sadly, SCD is something that cannot be ‘cured’. Patients have to live their lives knowing that the next painful vaso-occlusive crisis could occur at any moment. As is often the case with people who unfortunately have had to grow up in and out of hospital, a significant number of patients with SCD have behavioural or mental health issues that add to the challenges of managing their condition. Yet I did not see doctors show the same level of frustration towards patients suffering from other chronic conditions that often led to similar mental health problems; such as patients with type 1 diabetes, childhood cancers or inflammatory bowel disease.

In a 2013 study by Glassberg et al1, 655 Emergency Medicine physicians were surveyed on their use of the term ‘sickler’, their attitudes towards patients with SCD and the frequency with which the physicians adhered to evidence-based guidelines when providing analgesia to patients presenting in vaso-occlusive crisis. It was found that doctors using the term ‘sickler’ were more likely to harbour negative attitudes towards patients with SCD. 50% of the physicians surveyed admitted to using the term ‘sickler’ either “frequently” or “always”. Within the group of physicians who “frequently” used the term ‘sickler’, there was a statistically significant reduction in adherence to evidence-based guidelines when managing vaso-occlusive crisis pain, compared to those physicians who either “rarely” or “never” used the term ‘sickler’. A further study found a similar association; medical practitioners with negative attitudes towards individuals with SCD displayed lower adherence to treatment guidelines for managing vaso-occlusive crisis2. A 2010 study carried out in Chicago3 found that patients attending the emergency department in vaso-occlusive crisis were having to wait for an average of 80 minutes for analgesia, 30 minutes longer than the average wait time for patients presenting to the same department complaining of renal colic; despite the fact that patients in vaso-occlusive crisis reported higher average pain scores on arrival to the department than those with renal colic. In a 2020 survey of patients with SCD, two-thirds of respondents reported that they had delayed attending an emergency department for care during a vaso-occlusive crisis because of previous negative healthcare experiences and stigma around their disease4. However, it is not just on the ‘shop floor’ that these negative attitudes manifest. In 2007 Solomon5 reviewed a range of medical textbooks providing educational information about analgesic treatment regimes for patients in vaso-occlusive crisis. He found that less than 40% of the books sampled noted that opioid addiction was infrequent in this population of patients. However, over 90% of the textbooks reviewed offered such assurance when discussing treatment for cancer-related pain.

I associate the term ‘sickler’ with the frustration that healthcare professionals have towards managing patients with SCD. I do not use the term ‘sickler’ and am uncomfortable when I hear my colleagues use it. Tellingly, I have never heard a medical professional use the term ‘sickler’ in front of a patient with SCD.  When I consider the reasons behind why SCD patients are stereotyped in the way that they are by healthcare professionals, I can’t help but focus on the fact that most ‘sicklers’ are black. It is much easier for someone to empathise with a condition that they can relate to. I suggest that for predominantly white physicians with predominantly white middle class family and friendship groups, it is much more difficult to empathise with a condition that affects mainly black people than a disease that could occur to either themselves or a loved one.

After the Lockdown Summer of 2020, with the re-emergence of the ‘Black Lives Matter’ movement and the introduction of the term ‘unconscious bias’ into the mainstream, it is an apt time to discuss the dangers of using the term ‘sickler’. The term trivialises what is a severe and life-limiting genetic condition. It promotes the idea that patients presenting to A&E with severe pain in vaso-occlusive crisis are opioid seeking. This has led to patients receiving delayed or inadequate care. I know that most doctors I have worked with do not consider themselves as racist. Yet when we as medical professionals, consciously or subconsciously, act upon stereotypes that we have developed in our careers, to impact negatively upon patient care; then that is a form of racism. Whilst the term ‘sickler’ continues to be used amongst healthcare professionals, the stereotypes attached to the term will propagate through to future generations of doctors and medical students. It is not racist to feel frustration at a patient with sickle cell disease that is demanding treatment. However, it is racist to allow that frustration to impact upon the treatment that that patient, or the next one, receives. 

References

1. Glassberg, J., Tanabe, P., Richardson, L. & Debaun, M. Among emergency physicians, use of the term "Sickler" is associated with negative attitudes toward people with sickle cell disease. Am. J. Hematol. 88, 532–3 (2013).

2. Glassberg, J. A. et al. Emergency provider analgesic practices and attitudes toward patients with sickle cell disease. Ann. Emerg. Med. 62, 293-302.e10 (2013).

3. Lazio, M. P. et al. A comparison of analgesic management for emergency department patients with sickle cell disease and renal colic. Clin. J. Pain 26, 199–205 (2010).

4. Abdallah, K. et al. Emergency Department Utilization for Patients Living With Sickle Cell Disease: Psychosocial Predictors of Health Care Behaviors. Ann. Emerg. Med. 76, S56–S63 (2020).

5. Solomon, L. R. Treatment and prevention of pain due to vaso-occlusive crises in adults with sickle cell disease: an educational void. Blood 111, 997–1003 (2008).

Sickle cell disease

Cite this article as:
Rowenne Smith. Sickle cell disease, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.27598

Abigail is a 10 month-old female presenting to the Emergency Department with a history of profound lethargy, pallor and a mildly distended abdomen over the last few hours. She has no past medical history, her immunisations are up to date, and she has no known allergies. Her parents report that she is usually well, however they have noticed recent swelling of her hands and feet over the last month. Her parents are originally from Nigeria. In the Emergency Department she is pale and flat. 

She is tachycardic with a heart rate of 180bpm and afebrile. On examination she has a prolonged capillary refill time of 5 seconds and cool peripheries. She has a soft systolic murmur. Her spleen measures 7cm below the costal margin and she squirms on abdominal palpation. There is no history or evidence of trauma. 

Intravenous (IV) access is obtained and bloods are sent including a venous blood gas, blood culture, FBE, blood group and cross match, LFT and UEC. 

Abigail is given a 10ml/kg fluid bolus of 0.9% sodium chloride and commenced on broad-spectrum antibiotics. After a second 10ml/kg bolus her capillary refill time and heart rate improve but she remains very lethargic. 

You are notified by pathology that Abigail’s formal haemoglobin is 64 g/L and she is thrombocytopaenic with a platelet count of 80 x 109/L. The white cell count is within normal limits. 

You send for an urgent blood transfusion and arrange a PICU review.

The treating team is contacted by the haematologist who has reviewed her blood film and noted the presence of target cells, Howell-Jolly bodies and sickle cells. 

What is the diagnosis? Abigail has presented in hypovolaemic shock secondary to splenic sequestration as a first presentation of sickle cell disease. 

What is sickle cell disease?

Sickle cell disease (SCD) is a genetic disorder of haemoglobin synthesis.

Haemoglobin is a tetramer comprised of four polypeptide globin chains, each containing a haem molecule (which reversibly binds oxygen). Beyond infancy, adult haemoglobin (HbA) replaces foetal haemoglobin (HbF) as the predominant haemoglobin molecule. HbA consists of two alpha and two beta globin chains. 

SCD is caused by a point mutation in the beta globin gene resulting in a structurally abnormal haemoglobin molecule, HbS. 

The primary event in sickle cell pathology is polymerisation of HbS, distorting the red cell shape and leading to the characteristic sickle appearance.  Polymerisation can occur in the setting of deoxygenation, acidosis, pyrexia and dehydration. Recurrent episodes of sickling cause red blood cell (RBC) membrane damage and an irreversibly sickled cell.

Sickled RBCs adhere to the vascular endothelium and circulating RBCs causing occlusion of the microvascular circulation (vaso-occlusion). Sickled RBCs also undergo haemolysis, with an average RBC lifespan of only 17 days.

The physiological changes in RBCs result in a multisystem disease with the following key features:

  • Chronic haemolytic anemia
  • Painful vaso-occlusive episodes
  • Multi-organ damage from micro-infarcts (including cardiac, skeletal, splenic and central nervous system).

Inheritance and incidence

Sickle cell anaemia is inherited in an autosomal recessive pattern.

It is one of the most common, severe monogenic disorders worldwide. The prevalence of the disease is high among individuals of sub-Saharan African, Indian, Saudi Arabian and Mediterranean descent. 

It is estimated that 312 000 neonates are born with sickle cell anaemia globally each year, over 75% of whom are born in sub-Saharan Africa.

Terminology

SCD refers to a group of disorders characterised by the presence of at least one HbS allele in addition to a second beta globin gene mutation. 

In sickle cell anaemia, individuals are homozygous for HbS (HbSS). This is the most frequent and severe form of the disease. Other variants of SCD include sickle β thalassaemia (HbSβ0 or HbSβ+ thalassaemia) and haemoglobin SC disease (HbSC)

Individuals with sickle cell trait are benign carriers for the condition, inheriting HbS and a normal beta globin gene (HbAS). Sickle cell trait confers a survival advantage in malaria endemic areas. 

Diagnosis

Universal newborn screening for SCD has been implemented in the United States and United Kingdom. SCD is not part of the newborn screening program in Australia.

SCD can be diagnosed through the identification of haemoglobin variants using haemoglobin electrophoresis, high-performance liquid chromatography (HPLC) or isoelectric focusing. 


Clinical manifestations 

Symptom onset usually occurs within the first year of life, often at around 5 months. The delay in clinical signs and symptoms is due to the higher levels of HbF in infancy preventing the polymerisation of HbS.

Clinical manifestations include:

Anaemia

  • Patients have a chronic, compensated haemolytic anaemia.
  • Major causes of an acute drop in haemoglobin include splenic sequestration and aplastic crisis. 
  • Aplastic crisis is caused by a transient arrest in erythropoiesis. This is typically caused by infection, commonly human parvovirus B19.

Vaso-occlusive pain episodes

  • This is the cardinal feature of SCD and accounts for the majority of hospital admissions.
  • Acute pain occurs due to ischaemic tissue injury secondary to vaso-occlusion of sickled cells.
  • The majority of episodes have no identifiable cause, however common triggers include infection, fever, acidosis, hypoxia, dehydration and exposure to temperature extremes. 
  • Common sites of pain include the chest, abdomen, back and extremities. Dactylitis is a common presentation in infants and toddlers, with back and abdominal pain more common in older children.
  • Management of vaso-occlusive episodes involves early and aggressive pain relief.

Splenic sequestration 

  • Splenic sequestration occurs when large quantities of sickled RBCs pool within the spleen. This is a potentially life threatening complication of SCD, with a risk of hypovolaemic shock.
  • Splenic sequestration is characterised by the sudden enlargement of the spleen, an acute drop in haemoglobin (>20 g/L), thrombocytopaenia and an increase in reticulocytes.
  • It typically occurs between the ages of 6 months and 2 years.
  • Management includes: 
    • Restoration of circulating blood volume with a blood transfusion. This increases the haemoglobin level directly and promotes the release of trapped RBCs by the spleen. 
      • Always discuss transfusion targets with the on-call haematologist, as autotransfusion will occur if haemoglobin is increased excessively or too quickly thereby increasing the risk of hyperviscosity syndrome. 
    • Active fluid resuscitation for hypovolaemia while awaiting a blood transfusion.

Infection

  • Functional hyposplenism occurs early in life due to splenic infarction.
  • Patients are at an increased risk of invasive bacterial infections, particularly by encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type B and Neisseria meningitidis).
  • Children with SCD presenting with a febrile illness require prompt assessment and empiric IV antibiotics.
  • Prevention strategies include: 
    • Prophylactic penicillin for all young children, ideally by the age of 2-3 months. This has been shown to significantly reduce the morbidity and mortality of pneumococcal infections.
    • Vaccinations as per the functional asplenia/hyposplenia guidelines.

Acute chest syndrome (ACS)

  • This is the leading cause of mortality in patients with SCD.
  • ACS is defined as a new infiltrate on chest x-ray associated with new respiratory symptoms (chest pain, respiratory distress, hypoxia or cough) and/or fever. 
  • The majority of patients do not have a single identifiable cause. Possible aetiologies include infection, atelectasis, vaso-occlusion and fat emboli from infarcted bone marrow.
  • Management includes supplemental oxygen, IV antibiotics, exchange transfusion, analgesia, physiotherapy and early PICU involvement if hypoxia or respiratory distress.

Stroke

  • Prior to routine screening with transcranial doppler ultrasound (TCD), clinically evident strokes occurred in up to 11% of patients with SCD by the age of 20 years.
  • Silent cerebral infarcts (evidence of infarction on neuroimaging in the absence of overt neurological symptoms) occur in up to 20% of children with sickle cell anaemia.
  • Management includes: 
    • Prompt neuroimaging – MRI is the modality of choice, however if unavailable non-contrast CT should be performed (contrast increases the risk of hyperviscosity).
    • Exchange transfusion.
  • Primary prevention strategies include:
    • Regular TCD assessment starting from the age of 2 years. 
    • Prophylactic regular transfusions for children with persistently elevated TCD velocity.

Priapism

  • Priapism is an unwanted, persistent erection in the absence of sexual activity.
  • The majority of episodes occur due to impaired venous outflow from the penis causing increased pressure, preventing normal arterial circulation.
  • Prolonged episodes of priapism (>4 hours) may lead to permanent tissue damage, with a risk of erectile dysfunction.
  • The optimal treatment is unknown. 
  • Management strategies include hydration, analgesia, oxygen therapy, showering, short aerobic exercise and urination (consider catheterisation if unable to empty bladder). Ice should not be used as cold temperatures may exacerbate sickling. 
  • Priapism extending beyond 4 hours is a urological emergency and consultation with the on-call haematologist and general surgical/urology team is required.

Avascular necrosis

  • Avascular necrosis occurs at a higher rate in children with SCD.
  • It commonly affects the femoral and humeral heads.

Sickle cell disease and COVID-19


There is limited data on the relationship between SCD and COVID-19. Children with sickle cell disease, thalassaemia and rare anaemias without other risk factors do not seem to be at increased risk of having severe disease. 

Emergency department management

Examination

  • Vital signs
  • Pallor or jaundice
  • Hydration status
  • Respiratory examination
  • Spleen examination, with comparison to baseline
  • Neurological examination
  • Localising signs of infection

Investigations

  • FBE and reticulocyte count
    • Splenic sequestration: haemoglobin below baseline, thrombocytopaenia, reticulocytosis
    • Aplastic anaemia: haemoglobin below baseline, decreased reticulocyte count (<1%)
  • Blood group and cross match
  • UEC and LFT (if jaundice or dehydrated)
  • Based on assessment
    • If febrile 🡪 blood and urine culture
    • If respiratory symptoms 🡪 consider chest x-ray
    • If neurological findings 🡪 urgent neuroimaging

Acute management

  • Prompt review and early discussion with the on-call haematologist.
  • Aggressive pain management – all patients with SCD presenting with pain should initially be managed as a vaso-occlusive episode, with the exception of chest pain, which should be treated as ACS.
  • Oxygen therapy for hypoxia or respiratory distress, aiming for SaO2 >96% or for comfort.
  • Fluid management:
    • Encourage oral fluids.
    • Consider IV fluids for fluid resuscitation or maintenance fluids if unable to tolerate oral intake.
    • It is important to recognise that excessive fluid administration can increase the risk of ACS.
  • A blood transfusion may be required, however this should always be in consultation with the on-call haematologist to discuss both the type of transfusion and transfusion targets. 
    • There is a risk of hyperviscosity if the haemoglobin is increased significantly over the patient’s baseline.
  • If febrile, commence IV antibiotics with a third generation cephalosporin, in addition to atypical coverage if there is a significant respiratory component. 
  • If respiratory symptoms, suspect ACS.

Chronic management

Blood transfusions are used to treat and prevent the complications of SCD. Types of transfusions include simple, manual partial exchange and automated red cell exchange (erythrocytapheresis).  

Hydroxyurea is a myelosuppressive agent used in the management of individuals with SCD, which has been shown to reduce the vaso-occlusive complications. 

A life-long cure for SCD is only available through haematopoietic stem cell transplantation.

Prognosis

Individuals with SCD have reduced overall life expectancy. In high-income countries, the survival of individuals with SCD is improving steadily through measures such as newborn screening, early initiation of antibiotic prophylaxis, immunisations and screening for children at high risk of stroke.

This is not the case worldwide. The majority of countries where SCD is a major public health concern lack national programs and key public health interventions. As a result, sickle cell anaemia-related childhood mortality in Africa is as high as 50-90%, with less than half of affected children reaching the age of five. The World Health Organization (WHO) estimates that 70% of sickle cell anaemia deaths are preventable with simple, cost-effective interventions. 

Key messages

SCD is a multisystem disease characterised by haemolytic anemia, painful vaso-occlusive episodes and multi-organ damage from micro-infarcts.

Early diagnosis, simple prophylactic measures and parental education improves the morbidity and mortality of SCD.

Always discuss with the on-call hematologist prior to transfusing a sickle cell patient due to the risk of hyperviscosity. 

References

Arlet JB, de Luna G, Khimoud D, et al. Prognosis of patients with sickle cell disease and COVID-19: a French experience [published online ahead of print, 2020 Jun 18]. Lancet Haematol. 2020;S2352-3026(20)30204-0. doi:10.1016/S2352-3026(20)30204-0

Bainbridge R, Higgs DR, Maude GH, Serjeant GR. Clinical presentation of homozygous sickle cell disease. J Pediatr. 1985;106(6):881-885. doi:10.1016/s0022-3476(85)80230-4

Brousse V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. Br J Haematol. 2014;166(2):165-176. doi:10.1111/bjh.12950

Dick M, Rees D. Sickle Cell Disease in Childhood: Standards and Recommendations for Clinical Care (3rd edition, 2019). Available at https://www.sicklecellsociety.org/wp-content/uploads/2019/11/SCD-in-Childhood_Final-version-1.pdf [accessed 24 June 2020]

Grosse SD, Odame I, Atrash HK, Amendah DD, Piel FB, Williams TN. Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am J Prev Med. 2011;41(6 Suppl 4):S398-S405. doi:10.1016/j.amepre.2011.09.013

Meier ER, Miller JL. Sickle cell disease in children. Drugs. 2012;72(7):895-906. doi:10.2165/11632890-000000000-00000

Odunvbun ME, Okolo AA, Rahimy CM. Newborn screening for sickle cell disease in a Nigerian hospital. Public Health. 2008;122(10):1111-1116. doi:10.1016/j.puhe.2008.01.008

Pace BS, Goodman SR. Sickle cell disease severity: an introduction. Exp Biol Med (Maywood). 2016;241(7):677-678. doi:10.1177/1535370216641880

Piel FB, Patil AP, Howes RE, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013;381(9861):142-151. doi:10.1016/S0140-6736(12)61229-X

Therrell BL Jr, Lloyd-Puryear MA, Eckman JR, Mann MY. Newborn screening for sickle cell diseases in the United States: A review of data spanning 2 decades. Semin Perinatol. 2015;39(3):238-251. doi:10.1053/j.semperi.2015.03.008

World Health Organization. Geneva. World Health Organization – 59th World Health Assembly resolutions; 2006. Sickle-cell anaemia. https://apps.who.int/gb/archive/pdf_files/WHA59/A59_9-en.pdf [Accessed on 30th June 2020]