Sickle Cell Disease in the Military What Do We Know?

COL Margot R. Krauss, MD, MPHAccession Medical Standards Analysis

and Research ActivityWalter Reed Army Institute of Research

AFEB 22 May 2002

Sickle Cell Disease

Group of diseases characterized by the production of Hb S resulting from the inheritance of a beta S gene and a gene for other abnormal hemoglobin which polymerizes with Hb SHb S molecules co-polymerize most effectively with other Hb S molecules and then in decreasing order Hb C, D, O, A, J, and F 70% Hb S and 30% Hb F not associated with clinical

disease

AFEB 22 May 2002

Sickle Cell Disease

Sickle cell anemia (Hb SS) Sickle-C disease (Hb SC)Sickle beta-thalassemia (S-thal) “o” type no normal beta globin is produced “+” some normal beta globin is produced

Other abnormal hemoglobins may not cause disease D (except D-Punjab), E, G, O

AFEB 22 May 2002

Sickle Cell Anemia

Homozygous sickle cell (Hb SS) 5-50% cells are permanently sickled Anemia moderate to severe

Average Hb 8.0g/dl (6-10) Retic count 10% (4-24%) Crisis not associated with increased anemia

Low MCV and high MCHC

Common sx: abdominal or bone pain Crisis generally 5-7 days

AFEB 22 May 2002

Sickle Cell Anemia

Newborn screening for sickle cell disease First started in NY 1975 Currently in > 40 states

Predisposition toward infection, pneumococcal pneumonia, staph or salmonella osteomyelitis PCN prophylaxis until age 5 for Hb SS or Hb S

betao thalassemia1989 - 85% survival rate at 20 yrs of age

AFEB 22 May 2002

Sickle Cell and Alpha Thalassemia

Co-inheritance of sickle cell anemia and alpha thalassemia is not unusual 30% black Americans have a single alpha gene

deletion Approximately 2% have deletion of 2 of the 4

alpha globin genes

Difficult to differentiate from Hb SS Relatively more Hb A2 Decreased mortality

AFEB 22 May 2002

Sickle C (Hb SC) disease

Anemia mild to moderate20% do not have anemia and are asymptomaticHemoglobin “crystals” noted regularly

Clinical disease much like SS - usually milderHb SC unusual aspectsAseptic necrosis of head of femur is common

(can occur in SS but not as frequently)Splenomegaly (palpable spleen in 65-80%)

AFEB 22 May 2002

Sickle Beta -Thalassemia Disease

Hb S betao thalassemia No beta globin synthesis Virtually indistinguishable from HbSS clinically and on

electrophoresis (HA2 >3%)

Hb S beta+ thalassemia Beta globin present but reduced Mild to moderate anemia Somewhat milder than Hb SC disease Hb S predominates Hb A 5-30%, HbA2 >3%

AFEB 22 May 2002

Estimates of Sickle Cell Disease

Sickle Cell Disease*African-American 1 / 375Native American 1 / 3,000

Hispanic 1 / 20,000Whites 1 / 60,000

*Agency for Health Care Policy and Research (AHCPR) 1993 Guidelines for Sickle Cell Disease: Screening, Diagnosis, Management, and Counseling

AFEB 22 May 2002

Sickle Cell Disease Among Black Americans

American Black Population**Sickle cell anemia 1/625 live births

Sickle-C disease 1/835 –1,100 live birthsS-Beta thalassemia 1/1,667 live births

Sickle-D disease 1/20,000 Sickle -persistent high F Hb 1/25,000

**Interpretation of Diagnostic Tests, 7th Ed Jacques Wallach 2000

AFEB 22 May 2002

Prevalence of Hemoglobin Disorders Among Black Americans

634 hemoglobin variantsAlpha thalassemia minor 57/1,000All homozygous S conditions 3.7/1,000Sickle cell anemia 1/1,000

* Wintrobe’s Clinical Hematology, 10th ed, 1999

AFEB 22 May 2002

Standard from DoDI 6130.4

The causes for rejection for appointment, enlistment, or induction are:

E1.2.1. Anemia. Any hereditary (282), acquired (283), aplastic (284), or unspecified (285) anemia that has not been permanently corrected with therapy.

AFEB 22 May 2002

SCD Found Among Early Loss (EPTS) Due to Anemia

ICD9: 282 (hereditary hemolytic anemia): Thalassemias (ICD9: 282.4)

Thalassemia minor Sickle cell thalassemia

Sickle cell anemia (ICD9: 282.6) Hb SS Hb SC

Other hemoglobinopathies (ICD9: 282.7) Sickle cell trait (ICD9: 282.5)

ICD9: 285 (other and unspecified anemia)

AFEB 22 May 2002

HbS Conditions Not Disqualifying Asymptomatic forms of hemoglobinopathiesHb SD (except D-Punjab)Hb SG

Approximately 20% of Hb SC diseaseSCT

AFEB 22 May 2002

Early Loss Due to Anemia,All Components, 1998-2000

219 EPTS with any mention of anemia119 (hereditary hemolytic anemia): (ICD9:282) 24% (23/94) of sickle disorders in the Army

98 (other and unspecified anemia): (ICD9:285) 50% (49/98) Army

1 each of aplastic anemia & acquired anemiaArmy represents 36% of all accessions43% (94/219) of all anemia related to SCD (ICD 9: 282.6)

AFEB 22 May 2002

MethodsDescriptive Enlisted accessions 1998 to 2000 Active duty only

Reserve and NG # not accurate for denominatorNot able to follow Reserve and NG after initial training

Confirmed SCD cases by EPTS record review - ICD9 282

Comparison of Services by EPTS (Existing Prior to Service <6mo) Hospitalizations (PASBA- original data)

Chart review Disability (service disability boards)

AFEB 22 May 2002

Laboratory Diagnosis SCD Sickle Cell Anemia No Hb A, Hb A2 normal Predominant Hb S Hb F in varying amounts

Hb S beta 0 thalassemia Virtually indistinguishable from Hb SS Hb A2 >3%

Hb S beta + thalassemia Hb A 5-30%, Hb A2 4-6% MCV<78

AFEB 22 May 2002

Other Diagnosis

Sickle cell trait - (Hb A> Hb S)Persistent Hemoglobin F

Approx Hb S 70% Hb F 30%Not associated with clinical disease

Hb SG - clinically silent

* Wintrobe’s Clinical Hematology, 10th ed, 1999

AFEB 22 May 2002

Army Policy on SCDNo screen for sickle disease or anemiaIdentified by clinical presentation

AFEB 22 May 2002

SCD in the Army, 1998-200040 EPTS coded hereditary anemia (ICD 9 282)17 other anemias 10 thalassemia minor7 other

18 AD records confirmed as SCDExcluded 5 Reserve and NG with SCD

AFEB 22 May 2002

SCD in the Army, 1998-200012/18 AD (67%) hospitalized for SCD6 PASBA record confirmed by EPTS record

5 in crisis (262.62)6 reported hospitalized by EPTS record only

Abdominal painBack pain, painful joints RhadomylosisAnemia

AFEB 22 May 2002

SCD Diagnosis on Army EPTS records

5 + Sickledex, type based on history/smearElectrophoresis- Full results usually not recorded on EPTS forms…best guess as to type below SS - 4SC - 6S-thalassemia - 7

7 with Hgb or Hct provided only 1 with a Hgb >12 (12.7 g/dl)

AFEB 22 May 2002

SCD in the Army, 1998-2000

No documented denial of disease16 (88%) gave history of SCT/SCD– not divulged on pre-screening at MEPS 13 gave a positive history of SCD/crisis 3 reported thinking they had SCT - had Hb SC

Safe to assume some are not identified No screening May be coded under 285 (other anemia) Some Hb S + conditions are asymptomatic

AFEB 22 May 2002

SCD Hospitalizations After Serving At Least 6 Months on AD: 1996-2000

Population # LOS Loss

Army 43 M11-Y18 22

Navy 7 M07-Y9 3

AF 6 Y3-Y18 1

Marines 6 Y01-Y09 3

Total 62 29

AFEB 22 May 2002

Hospitalization for SCD10 Army hospital records requested 4 locations: 2/3 confirmed (282.62) Hb SS/SC with crisis

Hb SC, Reported electrophoresis c/w Hb SS Death – electrophoresis Hb AS

1/1 confirmed (282.63) Hb SC Hb SC

2/5 confirmed (282.60) SCD, NOS Hb SC, S-thal Hb AS 2 sickledex + (no hemoglobin electrophoresis)

1/1 confirmed (282.69) Other hemoglobinopathies Hb SC

AFEB 22 May 2002

Hospitalizations

6/10 (60%) hospitalizations for SCD confirmed by chart review

Consistent with 60% loss after hospitalizations reported in the Army after 6 months on AD

AFEB 22 May 2002

Air Force Policy on SCT/SCD

Screens for SCT/SCDHemoglobin electrophoresis doneThose with SCT can leave the service under admin separationThose with SCD receive EPTS

AFEB 22 May 2002

SCD in the Air Force 1998 - 2000

18; 17 by screen / 1 symptomaticHemoglobin electrophoresis1 - SS11 - SC2 - S beta thal2 - Hb S plus another abnormal Hb 1 - SCT (symptomatic)1 - No lab provided

AFEB 22 May 2002

SCD in the Air Force1998 - 2000

50% (9/18) gave negative prior history at presentation All Hb SC or S-thalassemia One from West Africa had fought successfully in

several wars (in his country)5 gave history of SCD/crisis at presentation – not divulged on pre-screening at MEPS 1 Hb SS & 4 Hb SC 1-2 pain crisis/yr, hospitalization Mildest reported arthritic pains with running

AFEB 22 May 2002

Estimates of SCD Not Disclosed at MEPS

Expected: Used a high prevalence of SCD in an unscreened population than is probably real Based on reported incidence of disease at birth

Expect some may have died (Hb SS) from infection Reported incidence of disease by sub-types (Hb SS Hb SC

HbS-Thal) overestimate prevalence If incidence added together estimate is much higher than the

prevalence of all SCD among the black population

Observed: Used only confirmed SCD cases –if data was unclear they were excludedThis approach would overestimate the ability of the MEPS exam process to deny enter to those with SCD

AFEB 22 May 2002

SCD in the AF: Expected (no screening) vs Observed, 1998-2000

Black Pop Incid Exp Obs Diff?

18,328Hb SS 1/675 27 1 P<.001

Hb SC 1/8351/1100

2116

11 NS

Hb S -thal 1/1667 11 3 P<.001

Other SCD ? 2Total SCD 1/305 60 17 P<.001

AFEB 22 May 2002

Navy Policy on SCT/SCD

Screens SCD/SCTTwo-tier hemoglobin electrophoresisThose with SCD are dischargedThose with SCT remain on AD unless Hb S >45%EPTS reporting appears fairly complete

AFEB 22 May 2002

SCD in the Navy 1998 - 2000

69 EPTS records coded 282 8 thalassemias/ 2 Hb CC/ 1 ITP

18 coded SCT- 12 (67%) with documented SCD 6 SCT- 2 symptomatic

47 EPTS for sickle cell disease (SCD) confirmedAll but 1 case (Native Indian) in blacks 5 records not found- likely SCD Potential additional case

1 hospitalization due to SCD- lost to service

Probably 53+ cases of SCD in three year period

AFEB 22 May 2002

SCD in the Navy 1998-2000

EPTS records did not document whether the individual knew about his or her SCD prior to entry on to active duty

AFEB 22 May 2002

SCD in the Navy: Expected (no screening) vs Observed, 1998-2000

Incid Exp Obs

Hb SS 1/675 42 9 P<.0001Hb SC 1/835-

1/11003426

22 NS

Hb S -thal 1/1667 17 8 NSOther SCD ? 8TOTAL 1/ 304 93(H) 47(L) 51% (36-72%)

Black pop28272

AFEB 22 May 2002

SCD in the Navy: Estimate of SCD Not Detected at MEPS, 1998-2000

6Prob SCD71% (50%-100%)53751/375Total SCD

62% (43%-90%)47751/ 375Confirmed

Not detectedObsExpPrev28272Black pop

AFEB 22 May 2002

Estimate of SCD Not Detected at MEPS, 1998-2000

Population Army Navy AF Marine

Black 45,734 28,272 18,328 12,072

Prev=1/375

SCD (exp) 122 75 49 32

SCD EPTS 18 47 17 11

Approx % not identified at MEPS

15% 63% 35% 34%

AFEB 22 May 2002

Why does the Navy identify more SCD than the AF?

AF allows those with SCT to be administratively discharged (may actually have disease) Many incorrectly coded as SCT on Navy EPTS paperwork Generally those miscoded as SCT had S-thal If used only those originally coded as SCD

37-47% not identified at MEPS in the Navy (similar to % in AF)

AFEB 22 May 2002

Great Lakes Lab Report on Sickle Screening, 2001

Recruit screening tests: 50,993 Reserve screening tests: 6,084

Total screening tests: 57,077Positive sickle screens: 939 (1.6%) False positive 32/939 (3.4%)

Positive SCD 17/939 (1.8%) Approx 17 SCD/yr confirms what was found in

EPTS review H/H drawn on 2/17 with SCD

LCDR Brian T. McNamara, MSC, USNOIC Clinical Pathology Naval Hospital Great Lakes

AFEB 22 May 2002

Observation

Navy data provide most accurate numbers for SCD Initial coding not accurate, BUT Electrophoresis results generally fully described

allowing accurate determination of hemoglobinopathy

HOWEVER, no hx/o SCD or documented anemia Air Force & Army data provide history of SCD prior to service

AFEB 22 May 2002

SCD Impact to DoDDoD loses ~33 by EPTS/yr for SCD Navy ~17 Army ~6 Air Force ~ 6 Marine ~ 4

Maximum number of 4 additional losses per year following hospitalization for SCD after 6 months on AD (Army) Total ~8 hospitalizations occur every year due to SCD

(Army)2.8 SCD lost/10,000 accessions/yr

AFEB 22 May 2002

Cost Estimate of Testing for SCD at MEPS

Approx $1 million for testing alone if done at MEPS ~240,000 applicants receive physicals/yr $1.25 (GL) to $4 (CHPPM)/SCT screen $300K to $960K to identify 3,840 +SCT

Assume 1.6% +SCT (Navy’s prevalence) Assume $14/hemoglobin electrophoresis for +SCT $53,760 to identify 69 with SCD

Approximate cost: $6K to $14K per SCD identifiedOther costs not considered Counseling for +SCT Loss of those +SCT who might misunderstand the significance of the

test

AFEB 22 May 2002

Confusion Is Common Between SCT and SCD

Incorrect EPTS code: 67% SCT reported on EPTS (Navy) actually was due to SCDIncorrect history: At least three recruits in the Army thought they had SCT when they had disease (Hb SC)Incorrect Hospitalization discharge diagnosis code: 2/10 with hospitalization discharge diagnosis for SCD (Army) had SCT 2 additional cases with SCT (without hemoglobin electrophoresis)

AFEB 22 May 2002

Not All SCD is Clinically Significant

50% of those identified with screening program in the AF gave no history of SCDOver 80% in Army gave a positive history

Some with SC disease (Army) on AD for up to 18 yearsAt least two with apparent SCD (by hospitalization discharge diagnosis Army) found fit for duty at PEB

AFEB 22 May 2002

ConclusionsSCD is a rare disorder in the military currently identified by screening in the AF, Navy & Marines at basic training and usually by clinical presentation in the ArmyCurrent screening at MEPS does not identify at least 50% of those with SCD, perhaps moreScreening specifically for SCT/SCD at MEPS would be expensive and possibly falsely discourage applicants with SCT from entering ADUncorrectable anemia is the true disqualifying condition

AFEB 22 May 2002

Questions ?

AFEB 22 May 2002

Results Depend on Type of Electrophoresis

Navy (GL) uses Alkaline/Acid Electrophoresis Beckman Coulter Paragon Kits Excellent ability to differentiate variant Hb

Unknown what type of electrophoresis used in the AF or Army Some systems Hb A and F can not be reliably

separated Some electrophoresis do not detect Hb A 2

AFEB 22 May 2002

Estimate of SCT Among Black Recruits

3.4%3.5%6%1.5%Approx % SCD/SCT

11174718SCD EPTS

3224897541212SCT (exp)

Prev=8%

40246,1099,42415,247Black

MarineAFNavyArmyPopulation

AFEB 22 May 2002

Great Lakes Lab Report on Sickle Screening, 2001

Rate for est black pop 17/9424 (.18%)Obs/Exp =17/25 67% “missed” at MEPS95% CI includes 100% Possible that no one self-defers for SCD More likely some with Hb SS do self-defer (p<.001) SC and S-thal coming in at expected rate

Probably > half of these are unaware of SCD Based on review of AF EPTS records Might be able to stay on AD