Sickle cell anemia vs sickle cell disease:
- Sickle cell anemia (SCA) refers to the most severe forms of sickle cell disease
- Most commonly reserved for HbSS disease and HbSβ0-thalassemia
- Sickle cell disease (SCD) includes all sickling disorders, characterized by the predominance of HbS (e.g., HbSC, HbSβ+-thalassemia, HbSD, HbSE)
SCD affects EVERY organ! Chronic, severe hemolytic anemia has MANY effects:
- Brain: stroke, neurocognitive deficits
- Psych: depression, chronic pain
- Eyes: retinopathy
- Heart: cardiomyopathy
- Lungs: acute chest syndrome, pulmonary hypertension
- Renal: CKD
- GI: gallstones, hepatopathy
- GU/Endo: delayed puberty, poor growth, decreased fertility
- Spleen: infection, sequestration
- Bones: pain, avascular necrosis, osteomyelitis
- Skin: leg ulcers
Newborn screening for SCD:
- All infants screened at birth in the US, but targeted screening misses up to 20-25% of cases!
- SCD is the most commonly detected condition on NBS (1 in 2,000 births)
- vs. others: congenital hypothyroidism (1 in 3,000-4,000), CF (1 in 4,500), PKU (1 in 20,000)
The connection with malaria:
- “The gene for haemoglobin S (HbS), a structural variant of normal haemoglobin (HbA), is widely distributed in the developing world, having been selected to high frequencies by the protection afforded to carriers (HbAS; sickle cell trait) against malaria. HbS is the classic example of a balancing polymorphism, its frequency in populations reflecting the equilibrium between the historic degree of positive selection for heterozygotes (HbAS) and negative selection for homozygotes (HbSS), who suffer from a chronic form of haemolytic anaemia known as sickle cell disease (SCD).” —Williams TN, Obaro SK. Sickle cell disease and malaria morbidity: a tale with two tails. Trends Parasitol. 2011 Jul;27(7):315-20.
Globally, more than 300,000 infants with SCD are born every year. Most (~90%) are born in sub-Saharan Africa or India; only ~2% of births occur in the US and Europe.
Health Inequities in SCD
There are MANY disparities affecting patients with SCD:
- Decreased life expectancy
- Decreased access to high quality care
- ED: longer wait times and worse pain management
- Age: pediatric vs. adult
- Location: rural vs. urban, high- vs. low-resource country
- Lack of prioritization of SCD on local, national, global levels
More than 100,000 Americans live with SCD. Most (not all!) are Black or Latinx with African ancestry.
- In addition to challenges of a chronic illness, these patients live in a society where their skin color is an inherent disadvantage.
Consider the differences with another chronic disease, cystic fibrosis (CF). A 2020 study in JAMA asked whether differences in disease-specific funding between SCD and CF are associated with variations in drug development and research publications. The findings showed that disparities in funding between SCD and CF may be associated with decreased research productivity and novel drug development for SCD.
- FDA-approved drugs: 15 for CF vs 4 for SCD
- Comprehensive care centers: 120 for CF vs 0 for SCD
- Patient registries for CF but not for SCD
Another consideration is the care overlap between SCD and cancer:
- Heme/Onc is a combined discipline, but most SCD patients (especially adults) are treated in cancer centers
- Patients may feel “second rate” when receiving care at cancer centers, further exacerbating stigmatization and suboptimal care
- Many adults receive care from oncologists without adequate sickle cell expertise (or interest)
Routine Preventive Care… or the Lack Thereof
Early diagnosis and preventive care saves lives!
- Parental Education
- Vaccination and PCN prophylaxis
- Transcranial doppler (TCD) screening for stroke prevention
Another Disparity: Hydroxyurea
Hydroxyurea is a repurposed chemotherapy drug, able to reduce/prevent sickling by inducing fetal hemoglobin. It was the first FDA-approved drug for SCD (in 1994 for adults, 2017 for children).
- Reduces pain, prevents organ damage, improves mortality
- Significant notoriety due to “chemotherapy” label and tremendously underutilized despite well documented efficacy
Possible explanations for the above disparities:
- Notoriety as “chemotherapy”
- Inadequate provider education
- Inappropriate dosing (low dose may suggest minimal benefits)
- Starting too late in life
- Decreased tolerated dose
- Difficult to improve organ damage, chronic pain
- Myths about toxicity and fear of side effects…
Improving hydroxyurea uptake with appropriate conversations:
- Many reasons are not well-founded and historical due to “chemotherapy” categorization and other putative risks
- Hydroxyurea is within standard of care and we have very few patients/families who refuse (especially younger ones)
- Hydroxyurea conversations begin at first visit and treatment begins within first year of life
- Early initiation creating generation of asymptomatic patients
Increased Risks in Young Adults!
Mortality decreased substantially in children (67%), but increased in young adult groups.
Access to high-quality care is a challenge in young adults, and transition programs have had little effect.
- Age, financial insecurity, mental health, and clinic attendance are modifiable factors associated with admissions and readmissions
- Addressing these factors within truly comprehensive sickle cell centers can improve outcomes for adults with SCD
Despite many models and efforts to improve transition, none have worked very well. Many modifiable factors appear to be involved:
Transition processes should begin early. Potential role of Med-Peds physicians to bridge the gap!
Primary care in adult patients with SCD is a key element that is not well studied. Many patients do not have or do not utilize PCPs, and hematologists are not a substitute for a PCP.
New Therapies & New Challenges
Multiple new therapies are emerging, but the question remains whether they will be affordable and accessible.
- L-Glutamine (Endari)
- Voxelotor (Oxbryta)
- Crizanlizumab (Adakveo)
- Bone marrow transplantation
- Gene Therapy and Gene Editing
Sickle Cell Pain: Debilitating and Stigmatizing
Many sickle cell patients experience pain EVERY DAY, and often avoid the emergency room unless a visit is absolutely necessary.
- Key point: Vital signs, facial expressions, and the use of cell phones do NOT indicate the presence or lack of pain
The timing and extent of treatment in the ED are often inadequate because of systemic racism and stigma.
- Drug-seeking stigma by healthcare providers, leading to inadequate pain control
- “Sickler” is a dehumanizing and stigmatizing slur that reduces the existence of the individual to a disease
- Fear and mistrust in patients
NIH guidelines recommend 1st pain medication be given within 60 minutes of ED arrival, but the reality is much different:
- Only 48% of children received 1st dose within 60 min and only 15% received 2nd dose in recommended subsequent 30 min.
- Data for adults even worse
- Worse yet, there are no incentives to track data or improve outcomes
How Can We Do Better?
Strategies to treating pain in SCD:
- Listen to the patient! Most know what works best for them
- Labs, vital signs, texting, facial expressions, laughing, etc. should NEVER EVER be used to determine if a patient is in pain or how severe pain is
- Pain occurs much more frequently than number of hospitalizations, often part of daily life – the patient does not want to be there
- NEVER question a patient’s own report, don’t use terms like “frequent flyers” and do not stigmatize patient as “drug seeking”
- Treat, reassess, then treat again until the patient has relief
Reduce the impact of structural racism on patients with SCD:
- Improve federal funding
- Reintroduce comprehensive SCD centers
- Include SCD in quality metrics that drive hospital funding (US News & World Report)
- Ensure adequate access to psychosocial support for patients, including patient navigators, social workers, psychologists, etc.
Dismantle institutional racism with a focus on SCD:
- Develop formal, hospital-based reporting systems
- Include SCD patients/family on hospital task forces
- Develop SCD specific pain protocols in ED and monitor compliance
- Empower patients to safely report concerns
Address interpersonal racism with patients and providers:
- Speak explicitly about race within and across medical teams, emphasizing patient experiences
- Build partnerships with patients to educate providers
- Implicit bias training
- Avoidance of the term “sickler”
- Safe spaces to talk about race and racism
Bedside clinical care:
- Believe the patient, believe the patient, believe the patient!!!
- Take time to listen
- Do not make judgements before entering the room
- Check your own biases at the door and check them again
- Correct others when you hear comments or see actions that may seem inequitable or reflect implicit (or explicit) bias
- We are not perfect. Be okay noting your own faults/biases and learn from your mistakes
Lifespan Comprehensive Sickle Cell Center :
- Combined Pediatric and Adult Program for all RI SCD Patients
- Clinical Care
- Community Outreach
- Eliminating full “transition”
- Building Trust
- One team with a unified approach, shared values
- Anti-racist approach focusing on optimizing patient experiences and outcomes with continuous education across the system
Blog post based on Med-Peds Forum talk by Pat McGann MD, Director of the Pediatric & Adult Sickle Cell and Hemoglobinopathy Program at Rhode Island Hospital and Hasbro Children’s Hospital.