Sickle  Cell  Diseases  

Cage  S.  Johnson,  M.D.  Professor  Emeritus  of  Medicine    

Keck  School  of  Medicine  University  of  Southern  California  

Director,  Sickle  Cell  Center  Los  Angeles  County+USC  Medical  Center  

Acute & Chronic Manifestations of Sickle Cell Disease

•  Pain : ischemic, neuropathic, collapsed bone •  Brain: TIA, ischemic Stroke, hemorrhage •  Eye: retinopathy •  Bone: remodeling by marrow hyperplasia, bone infarct,

synovitis, osteonecrosis, collapse, osteomyelitis •  Lung: ACS, chronic restrictive lung disease (hypoxia) •  Heart : pulmonary hypertension •  Liver : gallstones, hepatitis, iron overload, sequestration •  Spleen : auto-infarction, sequestration, bacterial sepsis •  GU: infection, proteinuria, renal insufficiency,

obstetrical, priapism •  Skin: leg ulcers

Manifestations of Sickle Cell Disease

1.  Chronic Hemolysis 2.  Intermittent “crises” 3.  Frequent Infections 4.  End organ dysfunction 5.  Disorders unrelated to the Hbopathy

Neurologic Complications •  CVA: Acute neurological signs/symptoms lasting 24 h; ~ 1% per

year. Ct scan/MRI shows typical ischemic lesions. Rx with exchange transfusion immediately. Chronic transfusion therapy reduces recurrence by 90%; duration of therapy is unknown.

•  TCD ultrasonography: Velocity > 200 cm/sec in MCA/ICA is predictive of CVA. Chronic transfusion reduces the incidence by 90%. Screening begins at age 2. Values > 170 cm/sec require frequent testing for increase.

•  TIA: acute nuerological signs/symptoms lasting < 1 h with normal CT/MRI. Rx with chronic transfusion especially if there is an abnormal TCD.

•  Silent CVA: Incidence 13% in children and up to 35% in adults. MRI shows infarctive lesions without neurological symptoms, but neuropsychometric testing shows deficits in “executive functioning”.

Acute Chest Syndrome 1. Term recognizes the difficulty in

distinguishing among: a. Infection (bacterial, viral) b.  Sickle vaso-occlusion (± infarction) c.  Fat embolism d.  Thromboembolism 2. Fails to distinguish between

uncomplicated acute pulmonary disease and progressive disease

Arch Intern Med 139:67, 1979

Pulmonary Disease (CSSCD)

•  N = 318, > 18 y of age (mean 31 ± 10), 41 % male •  90 % abnormal

Restrictive - 74 %

Obstructive - 1 %

Mixed O/R - 2 %

↓ DLCO - 13 %

•  Association between lung & kidney disease

Am J Resp Crit Care Med epublished 23 Oct 2005

Graphic: SL Johnson

Pulmonary Hypertension

•  Surveys with echocardiography reveal an incidence of ~10% in children and 35% in adults.

•  Elevated pulmonary artery pressures are associated with shortened survival, pulmonary emboli/thrombosis, leg ulcers, priapism and increasing hemolysis

Gall Bladder

Br Med J 295:234, 1987

J Clin Epidemiol 45:893, 1992

Title

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Medicine 84:363, 2005

Adult Health Care •  Preventive Health Maintenance: •  Psychosocial Assessment: school achievement,

occupational Hx, depression, anxiety, financial resources

•  Education: tobacco, alcohol, recreational drugs, safe sex techniques, sickle cell related education – fever, dyspnea, pain management

•  Surveillance for complications of SCDz, as well as for disorders of adulthood

•  Referral network, early treatment of complications

Surveillance: (repeated annually)

•  H/O sickling related events: Pain-acute & chronic, CVA, PNA/ACS (ICU), Hepatitis, Cholelithiasis, Priapism, Retinopathy, Pregnancy, Leg Ulcer, Hematuria/Infection, Bone infections/AVN, Transfusion

•  Lab: CBC, Bun/Creatinine, Urine protein, Iron/Ferritin, Hepatitis markers, B12, Folate, RBC phenotype, pulse oximetry, allo-antibodies, EKG (QTc), Brain naturetic peptide, & additional assays based upon Hx/Px

•  X-ray: Chest, Hips, Shoulders, T/L Spines, etc.

CHALLENGES in MANAGEMENT

of the ADULT PATIENT •  Shorten the duration of acute complications

•  Reduce the frequency of acute complications

•  Reduce the frequency/severity of chronic complications

•  Improve survival

•  Enhance the Quality of Life

Options

•  Stem Cell Transplantation

•  Gene Therapy

•  Hydroxyurea

•  Transfusion/Chelation

Stem cell transplant in SCDz n ~ 600

•  Mortality 5-7% •  Engraftment >90%* •  Event free survival >85% •  Acute GVHD ~25%

Grade III-IV <5% Chronic GVHD ~20%

grade III-IV <10% * Some with partial chimerism

Gene Therapy

•  Clinical Trial in 5 Hb SS & 5 β Thal (Paris)

•  Self-inactivating lentiviral vector

•  βA-T87Q

Ann NY Acad Sci 1054:308, 2005

New Agents

•  GBT -440 •  Small molecule attaches to Hb S and

increases oxygen afinity •  In micromolar concentrations, n=8 for 28 days •  Reduces circulating ISCs from a mean of

57% to 7% , Indirect bilirubin BY 25%, , LDH by 12%, retic cts by 30%

•  Increases hgb by ~ 0.75 g/dL

New Agents

•  GMI-1070 •  Pan selectin inhibitor, IV q 12 h •  N = 43, placebo = 3 •  Decreased VAS faster than control,

5-10-fold decrease in opioid dose, 28% decrease in LOS

California  Birth  Rates  (~600k  per  yr)  

 FS    79/yr  

 FSC    39/yr  

 FSA    13/yr  

 FS  other    10/yr  

 FE    140/yr  Eur J Hum Genet 1994;2:262

6th position of Beta Chain Molecular Events in Hb S (Part 1)

MEMBRANE DAMAGE SECONDARY TO SS TACTOID

Membrane Damage in Hb S (Part I)

HEMOGLOBIN  COMPOSITION  IN  VARIOUS  CONDITIONS          Hb  A  Hb  A2  Hb  F  Hb  S  Hb  C    

 Normal  adult    96%  3%    <2%  -­‐  -­‐    Sickle  cell  trait  (Hb  AS)  58%  3%  <2%  38%  -­‐    Sickle  cell  anemia    -­‐  3%  2-­‐15%  80-­‐95%  -­‐    Hemoglobinopathy  SC  -­‐  3%  1-­‐2%  48%  48%    Sickle  βO  thalassemia    -­‐  5%  5-­‐20%  70-­‐85%  -­‐    Sickle  β+  thalassemia    10-­‐30%  5%  5-­‐20%  50-­‐70%  -­‐      

Manifesta[ons  of  Sickle  Cell  Disease  

1.  Chronic  Hemolysis  2.  Intermi]ent  “crises”  3.  Frequent  Infec[ons  4.  End  organ  dysfunc[on  5.  Disorders  unrelated  to  the  Hbopathy    

EXAMPLES  OF  TYPICAL  BLOOD  COUNTS  IN  VARIOUS  SITUATIONS      Condi[on                  Hb  AA/AS  Hb  SS  Hb  SC  Hb  SβO  thal    Hb  Sβ+  thal  Hemoglobin  (g/dl)  13-­‐15  7-­‐9  11-­‐14  8-­‐10                  9-­‐12        RBC  volume  (fl)    90±8  90±8  85±9  68±6                72±7  Re[culocyte  count  (%)  1.0  12.0  2.0  8.0                  5.0      

Acute  &  Chronic  Manifesta2ons  of  Sickle  Cell  Disease  

•  Pain  :  ischemic,  neuropathic,  collapsed  bone  •  Brain:      TIA,  ischemic  Stroke,  hemorrhage  •  Eye:    re[nopathy  •  Bone:  remodeling  by  marrow  hyperplasia,  osteonecrosis,  

 collapse,  osteomyeli[s  •  Lung:  ACS,  chronic  restric[ve  lung  disease  (hypoxia)  •  Heart  :  pulmonary  hypertension,  LV  dysfunc[on  •  Liver  :  gallstones,  hepa[[s,  iron  overload,  sequestra[on  •  Spleen  :  auto-­‐infarc[on,  sequestra[on,  bacterial  sepsis  •  GU:  infec[on,  proteinuria,  renal  insufficiency,      

 obstetrical,  priapism  •  Skin:  leg  ulcers  

Pain  Management  

•  Hydra[on:    D5+0.5  NS  @  1.5  x  maintenance  •  Analgesia:    IV  q  10-­‐15  min  un[l  pain  score  is  5  or  less  or  

respiratory  is  <  14  per  minute  (SQ  if  no  venous  access)  <50  kg:  morphine  0.1  to  0.15  mg/kg  or  hydromorphone  0.015  to  0.2  mg/kg  

>  50  kg:  morphine  5  to  10  mg  or  hydromorphone  1.5  mg  

Con[nue  50%  of  loading  dose  q  3-­‐4  h  ATC  Provide  a  rescue  dose  

Add  a  NSAID,  especially  if  there  is  bony  tenderness  

•  When  pain  is  controlled,  begin  oral  analgesic  with  rescue  dose  in  prepara[on  for  discharge  

 

 

Pain  Management  

•  Incen[ve  spirometry  q  2h  ATC  to  prevent  atelectasis  and  acute  chest  syndrome  

•  Monitor  pulse  oximetry  for  progressive  decrease  

•  Periodic  assessment  of  respiratory  effort,  cough,  sputum  produc[on  

•  DVT  prophylaxis    

PiSCES  FINDINGS    Pain,  Crises,  And  U.liza.on  

•  55%  of  pa2ents  had  pain  on  more  than  half  of  their  diary  days  

•   30%  had  pain  essen2ally  daily  •  4,429  crisis  days  (14.8%)  •  In  contrast,  pa2ents  reported  only  1,057  u2liza2on  days  (3.5%)    

Wally Smith et al. Virginia Commonwealth University

MULTICENTER HYDROXYUREA TRIAL

Group Hydroxyurea Placebo p value*

Pain Episodes 2.5 / year 4.5 / year p < 0.001Pain Admits 1.0 / year 2.4 / year p < 0.001Acute Chest 25 episodes 51 episodes p < 0.001Transfused 48 73 p < 0.001Total Units 336 586 p = 0.004

*Van der Waerden’s test.

Charache et al. N Engl J Med 322:1317, 1995.

Sickle  Cell  Diseases  

The  Acute  Chest  Syndrome:    A  new  chest  x-­‐ray  infiltrate  plus    One  or  more  pulmonary  signs/symptoms:    

   fever,  cough,  sputum  produc[on,    tachypnea,  dyspnea,  new  onset  hypoxia  

 In  contrast  to  the  general  popula[on,  mul[ple  lobe  involvement  and  delayed  clearance  of  infiltrates  (12  d)  is  more  common  is  SCDz.  

Acute  Chest  Syndrome  1.      Term  recognizes  the  difficulty  in  dis[nguishing  

among:  

a.        Infec[on  (bacterial,  viral)  

b.  Sickle  vaso-­‐occlusion  (±  infarc[on)  c.  Fat  embolism  

d.  Thromboembolism    

2.        Fails  to  dis[nguish  between  uncomplicated  acute  pulmonary  disease  and  progressive  disease  

 

     

Arch Intern Med 139:67, 1979

NACSSG  (NEJM  342:1855,  2000)  

•  671  episodes  in  538  pa[ents  •  27  pathogens  iden[fied      Chlamydia    -­‐  7.2%      Mycoplasma    -­‐  6.6%      Viral      -­‐  6.4%      Infarc[on    -­‐  16.1%      Fat  embolism  -­‐  8.8%  (most  common  cause  of  death)  

   S.  pneumonia  -­‐1.7%  (11  of  671)  •  48%  developed  ACS  as  inpa[ent  with  acute  pain  •  Physical  examina[on  was  normal  in  35%  of  cases  

Graphic: SL Johnson

Treatment  

•  Cephalosporin  (3  or  4th  genera[on)  plus  a  macrolide  

•  Alterna[ve  –  quinolone  or  macrolide  plus  a  betalactam  

•  Hydra[on  –  0.5  ns  @  1.5-­‐2.0  [mes  maintenance  

•  Incen[ve  spirometry  •  Bronchodilator  if  needed    

Treatment,  Goals  

•  Preven[on  of  alveolar  collapse  •  Maintenance  of  gas  exchange  

•  Preven[on  of  further  pulmonary  injury  (ARDS)  

Treatment,  transfusion  

•  Simple  transfusion  aimed  at  raising  the  oxygen  carrying  capacity  and  reducing  cardiac  workload.      

•  Exchange  transfusion  when  there  are  signs  of  worsening  pulmonary  func[on,  (i.e.,  considering  mechanical  ven[la[on)  

Exchange  Transfusion,  indica[ons  

•  Physical  examina[on:    a.    Altered  mental  status  

 b.    Persistent  tachycardia  >  125/min  

 c.    Respiratory  rate  >  30/min  or  increased  work  of  breathing  

 d.    Fever  >  400  C  

 e.    Hypotension  compared  to  baseline  

Exchange  Transfusion,  indica[ons  

•  Laboratory/Radiologic  findings    a.    Arterial  pH  <  7.35    b.    Oxygen  satura[on  <  88%  despite  aggressive  ven[latory  support    c.    Serial  decline  in  sPo2  or  increasing  A-­‐a  gradient  

 d.    Hemoglobin  falling  by  2  g/dl  or  more    e.    Platelet  count  <  200k/µl    f.    Evidene  for  mul[organ  failure  

 g.    Pleural  effusion    h.    Progression  with  addi[onal  lobar  infiltrates  

Pulmonary  Disease  (CSSCD)  

•  N  =  318,  >  18  y  of  age  (mean  31  ±  10),  41  %  male  

•  90  %  abnormal  

         Restric[ve    -­‐      74  %  

         Obstruc[ve    -­‐      1  %  

         Mixed  O/R  -­‐      2  %  

         ↓  DLCO  -­‐      13  %  

•  Associa[on  between  lung  &  kidney  disease  

Am J Resp Crit Care Med epublished 23 Oct 2005

Chronic  Organ  Damage  in  Hb  SS:    n  =  1,056;    11,427  pa[ent-­‐yrs  since  1959  

Organ   #  of  pts   %  pts   Age  at  Dx  (median)  

Gallbladder   297   28.1   28  

AVN   224   21.2   30  

Lung     165   15.6   32  

Leg  ulcer   152   14.4   30  

Priapism     71   13.5   29  

Renal   122   11.6   37  

CVA   116   11.0   20  

Re2na  (III,IV)   92   8.7   30  

Non-­‐sickle   30   2.8   24  

Composite   540   48.5   24  

Mortality   232   22.0   31  

Chronic  Organ  Damage  in  Hb  SC  

Organ   #  of  pts   %  pts   Age  at  Dx  (median)  

Re[na  (III,  IV)   65   23   28  

AVN   42   15   34  

Gall  bladder   22   8   32  

CVA   13   4.6   33  

Osteomyeli[s   12   4   29  

CLD   12   4   32  

Renal   8   3   52  

Priapism   7   2.5   26  

Leg  ulcer   6   3   33  

Composite   112   39   28  

Mortality   25   9   37  

Medicine 84:363, 2005

CHALLENGES  in  MANAGEMENT  of  the  ADULT  PATIENT  

•  Shorten  the  dura[on  of  acute  complica[ons  

•  Reduce  the  frequency  of  acute  complica[ons  

•  Reduce  the  frequency/severity  of  chronic  complica[ons  

•  Improve  survival  

•  Enhance  the  Quality  of  Life    

Op[ons  

•  Stem  Cell  Transplanta[on  

•  Gene  Therapy  

•  Hydroxyurea  -­‐  not  supported  by  Baby  HUG  

•  Transfusion/Chela[on  

Stem  cell  transplant  in  SCDz  n  ~  600  

•  Mortality          5-­‐7%  •  Engrayment        >90%*  •  Event  free  survival      >85%  •  Acute  GVHD      ~25%  

 Grade  III-­‐IV      <5%  Chronic  GVHD      ~20%    grade  III-­‐IV      <10%  

 *  Some  with  par[al  chimerism    

Gene  Therapy  

•  Clinical  Trial  in  5  Hb    SS  &  5  β  Thal  (Paris)  

•  Self-­‐inac[va[ng  len[viral  vector  

•  βA-­‐T87Q    

•  N  =  7  to  date  

Ann NY Acad Sci 1054:308, 2005

M Cavazzana-Calvo et al. Nature 467, 318-322 (2010) doi:10.1038/nature09328

Conversion to transfusion independence.

Gene  Edi[ng  

•  Cluster  Regularly  Interspaced  Short  Palindromic  Repeats  (CRISPR-­‐CAS-­‐9)  

•  CAS-­‐9  splits  DNA  for  repair  •  Has  corrected  the  defect  in  the  sickle  mouse  

•  Human  embryo  experiments  showed  mul[ple  sites  edited  

Transfusion/Chela[on  •  Allo-­‐immuniza[on:  

 Reduced  by  extended  phenotyping  

•  Iron  overload:    DFO  &  Exjade®  /Jadenu  ®  &  Deferipone  

•  Viral  Disease  Transmission:  

 Current  rates  are  extremely  rare  

Transfusion  Hemosiderosis  

•  Liver  fibrosis/cirrhosis  •  Diabetes  via  pancrea[c  fibrosis  •  Endocrine  organ  dysfunc[on      Growth  retarda[on      Gonadal  failure  

•  Cardiac  fibrosis/cardiomyopathy      

Hb  SS  (n=43)   Thal  (n=30)  

Cardiac   0  %   20  %  

Endocrine   0  %   37  %  

Gonadal  failure   0  %   33  %  

Viral  hepa22s   2  %   33  %  

Hepa2c  fibrosis   39  %   81  %  

Transfusion  Hemosiderosis  

Am J Hematol 80:70, 2005

New  Agents  

•  GBT  -­‐440  •  Small  molecule  a]aches  to  Hb  S  and  increases  oxygen  afinity  

•  In  micromolar  concentra[ons,  n=8  for  28  days  •  Reduces  circula[ng  ISCs  from  a  mean  of  57%  to  7%  ,  Indirect  bilirubin  BY  25%,  ,  LDH  by  12%,  re[c  cts  by  30%  

•  Increases  hgb  by  0.75  g/dL    

New  Agents  

•  GMI-­‐1070  •  Pan  selec[n  inhibitor,  IV  q  12  h  •  N  =  43,  placebo  =  3  •  Decreased  VAS  faster  than  control,  5  rp10-­‐fold  decrease    in  opioid  dose,  28%  decrease  in  LOS  

New  Agents  

•  SEL-­‐G1  humanized  monoclonal  an[body:  (SUSTAIN-­‐phase  II/III)  

•  P-­‐selec[n  inhibitor;  sickle  RBCs  have  a  PSGL-­‐1  receptor  

•  IV  q  4  wks  for  50  weeks,  •  N  =  174  •  Hi  dose,  low  dose,  placebo  

Clincal  Issues  in  Hb  AS  (sickle  cell  trait)  

• Hyposthenuria due to renal medullary damage • Hematuria due to renal papillary necrosis • Splenic infarction at altitude • Increased susceptibility to heat stroke • Sudden death due to myo-necrosis with extreme exertion • Importance of education regarding genetic transmission

Summary:  Goal  of  reducing  morbidity  &  mortality  

•  More  aggressive  use  of  Hydroxyurea:  www.ahrq.gov/clinic/tp/hydscdtp.htm  

•  Regular  Surveillance  •  Prompt  referral  

•  Individualize  therapy  to  the  pa[ent  

Graphic: SL Johnson

Days  in  Pain  

≤5

6-10

11-2526-50

51-75

76-95

96-100

0

5

10

15

20

25

30

35Pe

rcen

t of P

atie

nts

Percent of Days in Pain

30%  of  subjects  had  pain  nearly  every  day  Only  13%  of  subjects  almost  never  had  pain    

Neurologic  Complica[ons  •  CVA:  Acute  neurological  signs/symptoms  las[ng  24  h;  ~  1%  per  year.    

Ct  scan/MRI  shows  typical  ischemic  lesions.    Rx  with  exchange  transfusion  immediately.    Chronic  transfusion  therapy  reduces  recurrence  by  90%;  dura[on  of  therapy  is  unknown.  

•  TCD  ultrasonography:  Velocity  >  200  cm/sec  in  MCA/ICA  is  predic[ve  of  CVA.    Chronic  transfusion  reduces  the  incidence  by  90%.    Screening  begins  at  age  2.    Values  >  170  cm/sec  require  frequent  tes[ng  for  increase.    

•  TIA:    acute  neurological  signs/symptoms  las[ng  <  1  h  with  normal  CT/MRI.    Rx  with  chronic  transfusion  especially  if  there  is  an  abnormal  TCD.  

•  Silent  CVA:    Incidence  13%  in  children  and  up  to  35%  in  adults.    MRI  shows  infarc[ve  lesions  without  neurological  symptoms,  but  neuropsychometric  tes[ng  shows  deficits    in  “execu[ve  func[oning”.  

ACUTE Clinical Syndromes in SS (and Sickling Disorders) Due to Microvascular

Occlusion

Acute Pain

Hand-foot syndrome

Acute chest syndrome

Ischemic stroke

Splenic sequestration crisis

Acute priapism

Acute  Clinical  Events  in  Hb  SC  

Event   #  of  pts   %  of  pts  Incidence  per  100  pt-­‐yrs  

(mean)  

Hospitaliza2ons   202   71   47  

       Sickle  related   187   66   38  

       Uncomplicated  pain   157   55   30  

       20  sickle  pain   95   33   18  

     ACS   91   32   7  

     Bone  infarct   27   9.5   1.6  

Am J Hematol 70:206, 2002

J Clin Epidemiol 45:893, 1992

Causes  of  Tendini[s/Bursi[s  

•  Trauma  

•  Overuse  

•  Abnormal  biomechanics  

•  Differing  leg  lengths  

Treatment  

Lidocaine  5  mg    

Bupivacaine  1.25  mg    

Methylprednisolone  10  mg  

   

Diagnos[c  Criteria  

H.  Li]le:    CMAJ  120:456,  1979  

•  Localized  tenderness  (pinpoint)  •  Aggravated  by  ac[ve  mo[on  

 

Response  

1)  immediate  relief  of  pain    

2)  resump[on  of  range  of  mo[on  

3)  con[nuing  relief  for  6  months  or  more  

4)  failure  =  recurrence  of  symptoms  within  1  month  

Causes of Worsening Anemia in Patients with SS Disease

•  Aplastic crisis secondary to infection

•  Renal failure with erythropoietin deficiency

•  Hepatic or splenic sequestration crisis

•  Decreased folic acid (i.e. during pregnancy)

•  Iron deficiency in growing children or during pregnancy

Conclusions  

•  Tendini[s/Bursi[s  syndromes  are  common  in  the  general  popula[on,  age  25  to  50  with  a  female  preponderance      

•  Diagnosis  requires  clinical  suspicion  and  specific  maneuvers  on  physical  examina[on  

•  Local  anesthe[c  +  steroid  injec[on  is  both  diagnos[c  and  therapeu[c  

•  T/B  is  present  in  the  sickle  cell  pa[ent  popula[on,  but  the  incidence  is  unknown  

•  Response  to  anesthe[c  +  steroid  injec[on  in  SCD  is  similar  to  the  60-­‐70%  ini[al  response  rate  in  the  general  popula[on  

Br Med J 295:234, 1987

Pulmonary  Hypertension  

•  Surveys  with  echocardiography  reveal  an  incidence  of  ~10%  in  children  and  35%  in  adults.  

•  Elevated  pulmonary  artery  pressures  are  associated  with  shortened  survival,  pulmonary  emboli/thrombosis,  leg  ulcers,  priapism  and  increasing  hemolysis    

Int J Artif Organs 13:231, 1990