#136 Sickle Cell Disease Management & Complications

January 21, 2019 | By Justin Berk

A complete overview of sickle cell disease with hematologist, Sophie Lanzkron MD of Johns Hopkins.

Stuck on sickle cell disease? We hammer out the basics of diagnosis, common sickle cell variants and their manifestations, preventive medicine, acute and chronic pain management, opioid use, and how to recognize and treat common complications like anemia, fever and acute chest syndrome. Sickle cell expert, Sophie Lanzkron MD, Associate Professor of Medicine and Oncology and Director of the Sickle Cell Center for Adults at Johns Hopkins joins!

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Credits

Written (including CME questions) and produced by: Justin Berk MD, Martha Brucato MD PhD, Beth Garbitelli MS1

Hosts: Paul Williams MD, Justin Berk MD, Matthew Watto MD

Edited by: Matthew Watto MD

Guest: Sophie Lanzkron MD MHS

Sponsor

Time Stamps

• 00:00 Announcements, intro
• 02:30 A quick refresher on hemoglobinopathy
• 03:45 Guest bio
• 05:03 Guest one-liner, movie recommendation, career advice, picks of the week
• 10:53 ACP Internal Medicine Meeting 2019 (ad read)
• 12:33 Clinical case; defining sickle cell; pathophysiology
• 16:23 Different types of hemoglobinopathy genotypes and phenotypes
• 20:20 Preventive care for sickle cell disease
• 22:56 Taking a history at the initial visit in patient with sickle disease
• 26:40 Life expectancy in SCD
• 28:30 Hydroxyurea
• 30:40 Chronic red blood cell transfusion therapy; complications; monitoring
• 37:07 Silent cerebral infarcts and mild cognitive impairment in SCD 
• 40:10 Chronic pain management; opioid use disorder in sickle cell disease
• 46:00 Acute pain crisis management; PCAs vs bolus therapy
• 54:08 Reticulocyte count in sickle cell disease
• 55:40 Itching, opioids and naloxone?
• 58:10 Red blood cell transfusion threshold in sickle cell disease (anemia)
• 60:03 Acute fever in SCD
• 61:48 Acute chest syndrome
• 66:45 Transition from pediatrics to adult medicine in sickle cell
• 68:00 Incentive spirometry to prevent acute chest syndrome
• 68:45 Take home points
• 70:00 Outro

Sickle Cell Disease: Treatment Pearls

1. There is no clinical/laboratory standard for confirming an acute sickle crisis.  
2. There are several variants of Sickle Cell Disease (SCD) with treatment differences. Electrophoresis can confirm the diagnosis.
3. Hydroxyurea can decrease crisis frequency, acute chest syndrome (ACS) events, need for transfusions, hospitalizations, and death.
4. Indications for chronic red blood cell transfusion include: failed hydroxyurea therapy, severe disease with genoptyes other than HbSS, or secondary stroke prevention.
5. Patients with SCD often have non-functional spleens; this requires closer evaluation of fevers, which can be life-threatening.
6. Serum creatinine (Cr) is not a good indicator for monitoring renal function in patients with SCD because of hyperfiltration and secretion of Cr into the renal tubules. Instead, follow urine albumin or protein to creatinine ratio annually.
7. Silent cerebral infarcts and resulting neurocognitive dysfunction are commonly overlooked issues in sickle cell disease.
8. Each patient with SCD should have a pain plan to manage pain at home, in the ED, and in the hospital.

Sickle Cell Disease Show Notes

The Science Behind SCD

• Sickle cell disease is a genetic disorder of hemoglobin, specifically a single base substitution (valine for a glutamate) in the beta chain.
• The resulting malformed red blood cells are stiff and can have trouble moving through microvasculature causing a vaso-occlusive “crisis” and hemolysis.
• Hemolysis causes scavenging of nitric oxide. This triggers vasoconstriction and increased adhesion molecule expression. Consequently, the crisis worsens.

The Variants of Sickle Cell Disease

Typically, HbSS and HBS𝝱⁰ have a more severe phenotype (i.e. more severe clinical symptoms). However, some HbSC patients can present with very severe symptoms and some patients with HbSS that have few symptoms. Other complex variants also exist.

Sickle Cell trait will often not have significant clinical manifestations. [See a recent review of clinical outcomes in Naik et al. Ann Intern Med. 2018]

A hemoglobin HPLC (i.e. High Performance Liquid Chromatography, hemoglobin fracture, or hemoglobin electrophoresis) can quantify the percentage of each hemoglobin variant.

Case #1: Routine Health Maintenance for Sickle Cell

The most recent 2014 NHLBI Guidelines for Management of Sickle Cell Disease can be found here. Of note, our guest Dr. Lanzkron is a contributing author.

Vaccinations

Given functional asplenia, patients with SCD should get extra immunization against encapsulated organisms (namely pneumococcal and meningococcal vaccines). (Yawn et al. JAMA 2014)

Patients should also get the flu shot given an increased risk for flu complications. (Bundy et al. Pediatrics 2010).

Routine laboratory testing

Routine CBC, reticulocyte count and kidney/liver function tests are performed annually to monitor baseline hemoglobin and look for end-organ damage. Yawn et al. JAMA 2014). Of note, serum creatinine is a poor measure of renal function in sickle cell disease.

The renal medulla is the most hypoxic part of the body and the kidney is one of the earliest affected organs in Sickle Cell Disease. When creatinine begins to rise, a significant amount of function is already lost. As such, annual screening for proteinuria and/or microalbuminuria is recommended to gauge renal function.

Eye Exams

Patients with SCD are at high risk for visual complications and so should get annual eye exams to check for retinal disease. (Yawn et al. JAMA 2014)

Producer’s Note: Other recommendations included but not discussed: folate supplementation, ACE-inhibitors for microalbuminuria, and specific pediatric screening and prophylaxis (cf. Table 3 in Yawn et al. JAMA 2014)

Key Questions to Ask about Sickle Cell

Important questions to ask when taking the history of a patient with Sickle Cell Disease include:

1. What a typical crisis is like? (This can help identify red flag “atypical crises”)
2. What typically works for their pain at home? In the ED?
3. Do they have chronic pain?
4. Which complications have occurred?  
   (e.g. history of stroke, crises, acute chest, proteinuria, avascular necrosis, etc.)
5. What is their transfusion history? How many lifetime units? Any past challenges obtaining blood? Any antibodies to blood types?
   Patients with history of >20 units transfused are at risk for iron overload

Evidence-Based Interventions for Sickle Cell

Hydroxyurea

Hydroxyurea reduces reduces crisis frequency, ACS events, need for transfusions, and hospitalizations (Charache et al. NEJM 1995) and has been shown to improve survival (Voskaridou et al. Blood. 2010).

Hydroxyurea is indicated in use for people with HbSS. There is less evidence for those who have other variants of Sickle Cell Disease.

Hydroxyurea works by increasing fetal hemoglobin (therefore decreasing the proportion of HbS) and decreasing expression of adhesion molecules. Thus, it reduces vascular occlusion (Ware. Blood 2010).

Originally a chemotherapy medication, hydroxyurea can cause bone marrow suppression. CBCs should be monitored and the dose of hydroxyurea is titrated to an a Absolute Neutrophil Count of 2,000 to 4,000 while maintaining platelets above 90K and an absolute reticulocyte count above 90K (Yawn et al. JAMA 2014).

Chronic Red Blood Cell Transfusions

Indications to Consider Chronic Red Blood Cell Transfusions:

• Patients with variants other than HbSS and frequent crises (i.e. where there is less data for hydroxyurea).
• Patients that have failed hydroxyurea therapy.
• For secondary prevention in patients with a history of stroke (STOP Trial – Lee et al. Blood. 2006).

NOTE: Decreasing Hemoglobin S to below 30% reduces risk of stroke (STOP Trial – Lee et al. Blood. 2006). Chronic transfusion therapy seems to improve health related quality of life (Beverung et al. Am J Hematol. 2015).

Risks of chronic red blood cell transfusions:

• Increased exposure to blood product infection risk
• Development of antibodies to other blood cells (causing difficulty in future transfusions)
• Increased likelihood of iron overload

Iatrogenic hemochromatosis Iron Overload:

• Iron overload in the liver can result in end stage liver disease; in the pancreas, diabetes; and in the heart, cardiomyopathy.
• Monitor with “Iron MRIs” (Ferriscan for liver and Cardiac T2*). These quantify iron levels and ferritin trends.
• Switching to exchange transfusions is an option if iron overload occurs. These are net negative for iron balance. Unfortunately, they are more invasive and require a larger access.

Indication to Consider Acute Red Blood Cell Transfusion:

Acute transfusion is indicated for symptomatic anemia with low reticulocytes (Yawn et al. JAMA 2014).

Neurocognitive Dysfunction

Silent cerebral infarcts and resulting cognitive problems are common in this patient population. MRI imaging has demonstrated silent infarcts occurs in ~30% of patients with SCD before age 6 and ~40% before age 14 (DeBaun et al. Blood. 2012).

Pediatrics Pearl: Transcranial Dopplers are recommended to be performed annually from ages 2-16. Look for increased velocity, which is associated with cerebral infarcts (Yawn et al. JAMA 2014).

NOTE: These cognitive deficits can make patient care more challenging. Therefore, Dr. Lanzkron recommends sending patients for neurocognitive testing. Identifying deficits can provide insight for both patients and the treating clinician.

Case #2: Acute Pain Crisis and Chronic Pain

Triggers

Types of activity including swimming in cold water or exposure to cold environments can cause a crisis.

Labs

There is no lab finding or specific tool that definitively indicates an acute crisis. You may not see a drop in hemoglobin. During a crisis, Absolute Reticulocyte Count should be monitored to detect an aplastic crisis early. –Dr Lanzkron’s expert opinion

Acute Pain Treatment

Short-acting opioids or NSAIDs (if renal function allows) can be useful for managing an acute crisis.

Per Dr. Lanzkron: Patient-controlled analgesia (PCA) pumps are preferred over bolus therapy for narcotics. Check the PCA frequently (every 3 – 4 hours). Adjust dosing as needed for patient comfort. A typical crisis will require higher doses in the first 24 hours. Afterwards, doses can be weaned. Each day, it is important to calculate total opioid use in 24 hours.

NOTE: Blood transfusion may not be required for an acute crisis! The American Society of Hematology’s Choosing Wisely campaign includes this: “Don’t routinely transfuse patients with sickle cell disease (SCD) for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication.”

Planning

Ideally, each patient should have a pain plan for crises at home, in the ED, and in the hospital. During a crisis, it is important to remember to consider other causes of pain. In other words, don’t anchor on SCD and forget that another diagnosis may be the cause of pain.

Chronic Pain Treatment

Chronic opioid therapy has many harms. And, it may not cause benefits in pain management (for example, see Karafin et al. Hematology 2018). There are some patients (e.g. older patients with avascular necrosis without surgical options) where long acting opioids many be useful, but this should be a discussion with a pain management team.

If patients are on chronic pain management, it should be continued while treating an acute crisis (Yawn et al. JAMA 2014).

Other Acute Complications

Case #3: Fever

Having a non-functional spleen puts patients with sickle cell disease at risk for life-threatening complications from severe bacterial infections, particularly due to encapsulated bacteria (Booth et al. Int J Inf Disease. 2010). SCD patients are also at risk of serious complications from flu and other infections. Therefore, cultures and antibiotics are required if a patient appears toxic.

Case #4: Acute Chest Syndrome

Acute Chest Syndrome is a clinical diagnosis. Patients will have: new infiltrate on chest X-ray, along with chest pain/respiratory symptoms and/or fever. There is a spectrum of causes, including infection (i.e. community-acquired pneumonia) or fat embolism from bone marrow infarcts.

NOTE: Not everyone with Acute Chest Syndrome, particularly those with mild symptoms, requires transfusion. Remember. It is a spectrum.

People who are hypoxic require transfusion (Vichinsky et al. Blood. 1997). Use of an incentive spirometer in the hospital can help prevent acute chest syndrome (Niss et al. Blood. 2017; Bellet et al. NEJM 1995).

Goals and Learning Objectives

Goal

Listeners will develop a systematic and evidence based approach to common acute complications and routine health maintenance of Sickle Cell Disease.

Learning objectives

After listening to this episode listeners will:

1. Define Sickle Cell Disease (SCD) and identify the most common forms of hemoglobinopathy
2. Identify common acute complications of SCD
3. Describe priorities for management of acute pain crises
4. Identify common chronic complications of SCD
5. Describe available therapies for improving outcomes for patients with SCD

Disclosures

Dr. Lanzkron reports research grants or contracts from Pfizer, Ironwood, Global Blood, and Prolong. The Curbsiders are sponsored by the ACP Internal Medicine Meeting 2019 for this episode.

Links from the show

Links are included in the show notes above.  

1. Fever Pitch (IMDB)
2. Pokémon Go
3. Thoroughbreds (IMDB)
4. Indefensible by David Feige
5. Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review
   (Naik et al. Ann Intern Med. 2018)
6. 2014 Guidelines for Management of Sickle Cell Disease (Yawn et al. JAMA 2014.)
7. Burden of influenza-related hospitalizations among children with sickle cell disease.
   (Bundy et al. Pediatrics 2010).
8. MSH Trial – Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. (Charache et al. NEJM 1995)
9. LaSHS Trial 17 year follow-up – The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes (Voskaridou et al. Blood. 2010)
10. How I use hydroxyurea to treat young patients with sickle cell anemia. (Ware RE. Blood 2010)
11. STOP Trial – Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results (Lee et al. Blood. 2006)  
12. Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia. (DeBaun et al. Blood. 2012)
13. Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease. (Vichinsky et al. Blood. 1997).
14. Prevention of Acute Chest Syndrome By Implementing a Standardized Process to Improve Incentive Spirometry Use in Hospitalized Patients with Sickle Cell Disease (Niss et al. Blood. 2017)
15. Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases. (Bellet et al. NEJM 1995)
16. GotTransitions.org for Healthy Pediatric to Adult Transitions of Care https://www.gottransition.org/
17. American Society of Hematology’s Transition Toolkit http://www.hematology.org/Clinicians/Priorities/5573.aspx
18. NEJM Review Article on SCD (Piel et al. NEJM. 2017)