#12: Sickle Cell Disease in Adolescence: Growing Pains

November 11, 2020 | By Justin Berk

Smells Like Heme Spirit with Dr. Lydia Pecker

Summary

Learn all about Sickle Cell Disease and the pediatric to adult transition in care from Dr. Lydia Pecker, a sickle cell doctor for young adults practicing in Baltimore, Maryland. In this episode we cover diagnosing sickle cell, detecting and managing complications, and the major treatments, including new drugs and bone marrow transplants. We’ll start with the basics and build up to expertise! 

Credits

• Written and produced, infographic by Martha Brucato MD, PhD
• Show notes by Martha Brucato and Joan Park, MD
• Cover Art: Chris Chiu MD
• Hosts: Justin Berk MD, Chris Chiu, Martha Brucato
• Editor: Justin Berk; Clair Morgan of nodderly.com
• Guest: Lydia Pecker MD

Time Stamps

• 2:25 Dr. Pecker’s one-liner
• 5:51 Case from Kashlak Children’s
• 6:20 How and when is sickle cell disease diagnosed
• 7:15 Genetic ancestry of sickle cell disease
• 8:32 Types of sickle cell disease and hemoglobinopathies
• 9:57 Lab work to obtain for a new patient with sickle cell disease
• 15:17 Early onset of renal dysfunction
• 18:34 Folic Acid Supplementation
• 21:37 Past Medical and Social Histories
• 28:41 Brain injury in SCD
• 31:49 Risk for Infections and the use of prophylactic penicillin
• 36:16 Vaccines
• 38:25 The transition from pediatric to adult care
• 43:10 Hydroxyurea vs Blood transfusions
• 49;10 When to acutely transfuse 
• 53:50 Bone Marrow Transplants
• 57:37 L-glutamine, voxelotor, and crizanlizumab
• 1:01:09 Reproduction and Fertility
• 1:05:38 Take home points

Sickle Cell Disease: Pearls

1. Hydroxyurea is indicated for all children and most adults with sickle cell anemia. But it is underprescribed, especially in adults. 
2. In patients with sickle cell disease whose current hemoglobin is below their baseline, a reticulocyte count can help guide how to respond to anemia 
3. Transcranial Dopplers screen for stroke risk in pediatric patients and, with red blood cell transfusions, any stroke risk can be significantly reduced.
4. Penicillin is thought to reduce the risk of severe infection in patients with SCD, though there is little evidence in the era of updated vaccinations
5. Despite the episode title: in SCD, vasoocclusive crisis is a diagnosis of exclusion and not an indication for transfusion.

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Diagnosis and Definition of Sickle Cell Disease

Newborn Screening

Newborn screening identifies all children born in the US with sickle cell disease. Universal newborn screening started first in New York state in 1974 (and then ramped up in 1979 with consistent follow-up). Universal newborn screening in all 50 states and DC has been in place since 2006. However, in other countries, newborn screening is not universal. Patients born in other countries may not have been diagnosed previously, and could be identified because of a complication or routine lab monitoring. 

Genetic Ancestry

Dr. Pecker thinks about risk for sickle cell disease being related to having genetic ancestry from a place where malaria served as an evolutionary pressure. This includes Africa, India, and the Middle East. Race (a social construct) is a poor proxy for genetics. 

Sickle Cell Genotypes 

Sickle cell disease is an umbrella term for a collection of diagnoses all linked by having at least one copy of a beta-globin gene mutation that leads to the production of hemoglobin S (for Sickle). Having the mutation in both copies of the beta-globin gene causes hemoglobin SS disease; one copy of S and one copy of a beta-thalassemia mutation causes sickle-beta thalassemia, and one copy of S and one copy of C leads to hemoglobin SC disease. 

Sickle cell anemia exists when hemoglobin is almost exclusively sickle hemoglobin. This is either hemoglobin SS disease and sickle-beta (0) thalassemia. 

Hemoglobin A is the wildtype hemoglobin. 

If you want to learn more about Sickle Cell Disease genetics, we talked about this in greater depth on the Curbsiders with Dr. Sophie Lanzkron! Check out the episode and show notes here.

What to do when meeting a patient for the first time

If you can’t confirm a diagnosis of sickle cell disease, sending a hemoglobin electrophoresis is your best first test. 

Baseline labs: CBC, reticulocytes, CMP, LDH, ferritin. What do their hemoglobin, MCV, platelet, and white counts look like? All are impacted by sickle cell disease. Reticulocyte count can help you understand if they compensate well for hemolyzing. Creatinine should be low in patients with sickle cell; if their value is within the “normal” range, they may actually have renal dysfunction. 

Liver enzymes are essential because SCD can cause hepatic dysfunction, but remember that AST may be slightly elevated as it’s also a marker of hemolysis. Total bilirubin is also a marker of hemolysis. Ferritin is helpful as a marker of total iron content, which may be elevated as a complication of recurrent transfusions. If you’re worried about iron deficiency, it’s also helpful to obtain other iron studies such as TIBC or serum iron. 

LDH is a hemolytic marker as well. It can be helpful to have a baseline LDH from when the patient is well to use for comparison if the patient is acutely ill in the future. 

Consider testing for the most common transfusion transmitted infections: HIV, Hep B, Hep C. 

Obtain a type and screen and notify your local blood bank about your new patient. Your blood bank will reach out to other blood banks to obtain records about what blood the patient has received in the past. This is helpful to make sure they give appropriately matched blood to the patient in the future. 

Renal Dysfunction

Kidneys are the first organ damaged by sickle hemoglobin. Hyperfiltration is a change in the kidney that occurs early in the disease course. The consequence of hyperfiltration is a low-for-age creatinine on the BMP. 

The BABY HUG trial found hydroxyurea was unable to prevent the onset of kidney disease. 

Folic Acid Supplementation

Folic acid is traditionally given to patients with hemolytic anemias because of concern that increased red cell turnover can lead to folic acid deficiency. This is rare in the US because our food is supplemented with folic acid. Most Americans live in a folate-rich environment. 

Many pediatric hematologists continue to prescribe folic acid despite low incidence of deficiency. Folic acid deficiency is more common in adults and so often co-prescribed with hydroxyurea. It can be helpful to prescribe because hydroxyurea itself causes macrocytosis (an increase in the MCV) like a folate deficiency would. If your patient is taking folic acid, then your clinical picture is not confounded. 

Children often love taking their folic acid because it’s sweet! 

Expert Opinion: Young adults may have good memories of taking this sweet medication. Parents and young adults may associate folic acid with being taken care of and may be more comfortable continuing to take it. 

Obtaining the Past Medical History

Sickle cell disease impacts every part of the body so a past medical history will be comprehensive. 

Expert Opinion: Big picture goal is to elicit a sense of how sickle cell disease has impacted a patient’s life and what their life goals are. This is important for thinking through what would be their best treatments. 

A Review of Affected Systems

• CNS: history of stroke (overt and silent), learning differences and educational attainment,  seizures, brain aneurysms
• Eyes: history of retinopathy, (do they have an ophthalmologist?)
• Dentistry: because patients with poor dentition have increased inflammation which can increase complications (Expert Opinion: can be a way to screen for dental insurance)
• Ears: balance, dizziness, hearing (patients with sickle cell disease may be at increased risk of hearing loss)
• Pulmonary: history of acute chest, sleep apnea, pulmonary emboli, asthma
• Cardiac: rare complication but there is increased risk of sudden cardiac death especially among adults, pulmonary hypertension
• Musculoskeletal: where do they have pain, what precipitates pain, how do they treat it, do they have any bony injuries (patients are at risk for “fish-mouth” deformity of the spine, which is biconcave intervertebral spaces due to end plate arching)
• Sexual history: sexual activity, reproductive life plans (are they parents, do they want to be parents), history of priapism, dysmenorrhea, contraceptive use
• History of blood clots or leg ulcers
• Sickle Cell treatment history

Complications of Sickle Cell Disease 

Brain injury in sickle cell disease

Dr. Pecker categories brain injury into the following categories:

1. Overt brain injury: the advent of transcranial dopplers  and subsequent treatment decreased the incidence of overt stroke from ~11% of children with SCD to 1% of children (Adams, 1998)
2. Insidious brain injury: silent cerebral infarcts cause learning differences
3. Cerebrovascular disease: vascular malformations 

Increased Transcranial Doppler velocities align with a higher risk of stroke. (Adams, 1997) Chronic blood transfusions can significantly lower the risk of stroke in children with elevated blood flow velocities. 

The SIT Trial (2014) looked at cognitive outcomes among transfused children. This study observed lower school performance in children with silent cerebral infarcts, but the effect size was smaller than having a mother with lower educational attainment. 

Risk of Infections

The Dallas Newborn Cohort suggested penicillin prophylaxis improved outcomes for patients with SCD.

PROPS I (1986): Penicillin for children with SCD < 5 years old prevented sepsis and deaths from sepsis. This study justified the need for universal newborn screening by providing evidence that early intervention can prevent deaths due to infection in patients with sickle cell disease. 

PROPS II (1995): follow-up study that looked at older children with sickle cell disease and seemed to show no benefit of penicillin.

Based on the results of PROPS II, most pediatric centers either discontinue penicillin at age 5 or discuss the option of discontinuing penicillin with the patient’s family for shared decision making. 

Vaccination schedules have been transformed since PROPS 1 in 1986 with the advent of H. influenza (fi1987) and pneumococcal (PCV7 in 2000; PCV13 in 2010) vaccines. It is unknown how crucial penicillin prophylaxis is in the context of updated vaccination schedules.

Refill data shows that adherence to penicillin prophylaxis is relatively low (only 18% of children received ≥300 days of antibiotics). 

Expert Opinion: Vaccines for sickle cell patients : 

1. Pneumococcal series including PPSV 23 every 5 years
2. Meningococcal vaccines–Meningitis B in adolescence and MCV4 (including 5 year booster)
3. Ensure that they have received at least one Haemophilus influenzae vaccine

Does mortality increase at the time of transition from pediatric to adult care? 

There is a spike in mortality among young adults with sickle cell disease in the United States. (Quinn 2010). However, this is not seen in every country.  Unclear if the increase in mortality is a universal phenomenon or a function of the fractured health care system in the US where transition coincides with the timing of major life changes. (Check out this great 2020 Lancet review for more).

Expert Opinion: Important to remember that for young adults, their disease may be catching up to them–they are middle-aged, based on the current life expectancy of late 40s to early 50s. 

Management

Hydroxyurea vs. Chronic Blood Transfusions

Blood transfusions are used to defend against very serious complications: stroke and acute chest syndrome. 

Indications for Blood Transfusions

1) Abnormal transcranial dopplers. Patients with sickle cell disease are screened annually to predict stroke risk. If dopplers show high blood velocity, there is an increased risk of stroke. 

Once dopplers normalize, patients can be transitioned to hydroxyurea based on TWiTCH, 2016.

2) History of overt stroke. Transfuse indefinitely. (SWiTCH, 2012 found transfusions were superior to hydroxyurea when managing patients with a history of stroke.)

3) Abnormal cerebral vasculature such as Moyamoya disease. Transfuse indefinitely. 

4) Patients who have had severe complications of SCD while on hydroxyurea (even if they were not taking it as prescribed).

5) Pregnancy (controversial). 

6) Chronic complex pain. “Takes sickle out of the picture while evaluating pain”–Dr. Lanzkron. 

Hydroxyurea

Hydroxyurea is relatively recently approved in children with SCD (BABY HUG, 2011). 

The 2014 NHLBI Guidelines recommend starting hydroxyurea at 9 months of age in children with Hgb SS disease or sickle-beta-null thalassemia regardless of disease severity. Though proven to be effective, hydroxyurea is under prescribed especially in adults.

Bone Marrow Transplants

Two cures for sickle cell disease exist now: bone marrow transplant and experimental gene therapy (here’s an NPR article discussing this). 

A bone marrow transplant is essentially destroying your bone marrow and replacing it with someone else’s stem cells. It requires myeloablative medications. 

One study (Gluckman et. al, 2017) examined the outcomes of patients with sickle cell disease who received BMTs and found a higher risk for individuals older than 16 (Dr. Pecker cites the inflection point for increased risk to be age 13). 

The New Drugs in Town

L-glutamine (2017): nitric oxide donor, shown in phase III trial to modestly decrease pain so approved by the FDA. It’s a powder you take twice a day so can be cumbersome for patients to take. 

Voxelotor (2019): anti-sickling agent, decreases hemolysis, main endpoint which justified FDA approval was mean increase in hemoglobin by 1 g/dL. No patient-reported outcome was used to justify FDA approval (compared to, for example, hydroxyurea, which decreases incidence of acute pain and acute chest syndrome, hospitalizations and transfusions). 

Crizanlizumab (2019): IV infusion, monoclonal antibody against P-selectin, FDA approval based on pain decreased by 50%. Unknown if it affects the extent to which the disease results in end organ damage.

Many insurances do not cover these new drugs because they are patented and have varying evidence. 

Reproduction and fertility 

Expert Opinion: For men with SCD: priapism and erectile disease are risks. Some men with SCD also have abnormal sperm counts; which seems to be a function of the disease (chronic testicular injury), but an open question is whether it’s also related to hydroxyurea treatment (possibly reversible, but unknown).

For women with SCD: pregnancy is high risk. Important for patients to be seen by Maternal-Fetal-Medicine if possible. Expert Opinion: There are thrombotic risks with estrogen-containing contraception in this population. 

Two recent studies (Multicenter Study of Hydroxyurea and London cohort) suggest that the reproductive lifespan of women with SCD is reduced. An open question is whether or how hydroxyurea would affect this reproductive lifespan. 

Links

• WYPR’s “The Realness”. Six part podcast on rapper Prodigy’s struggle with sickle cell disease.

Goal

Listeners will develop a systematic approach for the routine health maintenance of young adults with Sickle Cell Disease.

Learning objectives

After listening to this episode listeners will…  

1. Explain the pathophysiology of significant pediatric and young adult complications of sickle cell disease. 
2. Identify important components of history to obtain when establishing a relationship with a young adult patient with sickle cell. 
3. Describe how we screen for complications of sickle cell disease.
4. Recognize treatment options for decreasing pain and for primary and secondary prevention of complications of sickle cell disease

Disclosures

Dr. Pecker reports no relevant financial disclosures. The Cribsiders report no relevant financial disclosures. 

Citation

Pecker, L., Brucato, M., Chiu C, Berk J. “#12 Sickle Cell in Adolescence: Growing Pains”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ 11/12/ 2020.