SEVERE  INFECTIONS  in  LUPUS    as  a    

RHEUMATOLOGIC  EMERGENCY    

Regina Berba MD MSc Sections of Adult Medicine & Infectious Diseases

ARE  LUPUS  PATIENTS  AT  HIGHER  RISK  FOR  MORE  SEVERE  INFECTIONS?  

Overview of the Pathogenesis of Systemic Lupus Erythematosus.

Tsokos GC. N Engl J Med 2011;365:2110-2121

PATHOGENESIS  OF  SLE  

Chromosome Loci and Genes Associated with SLE.

Tsokos GC. N Engl J Med 2011;365:2110-2121

Chromosomal  and  Genetic  Uniqueness  in  SLE  

SLE.

Tsokos GC. N Engl J Med 2011;365:2110-2121

Translates  to  a  massive  aberrant  in#lammatory  &  immunocompromised  

response  

Treatment Approaches for SLE.

Tsokos GC. N Engl J Med 2011;365:2110-2121

Treatment  of  SLE  also  contributes  to  additional  risks  for  infections  

Increased  susceptibility  of  LUPUS  patients    to  infections:    •  IMMUNE  DYSFUNCTION  FROM  ILLNESS  

•  Phagocy7c  dysfunc7on  •  Lymphopenia  •  Decreased  cytokine  produc7on  •  Decreased  immunoglobulin  •  Impaired  func7oning  of  complement  system  •  Func7onal  asplenia  

•  IMMUNOSUPPRESSION  FROM  TREATMENT  •  Glucocor7coids  •  Other  immunosuppressive  drugs  

“SLE  as  an  Emergency”  

“An  emergency  in  medicine  can  be  defined  as  a  situa7on  that  endangers  life,  or  an  organ  system,  or  quality  of  life.    In  that  sense,    SLE  ITSELF  IS  AN  EMERGENCY.”  

hOp://www.apiindia.org/pdf/pg_med_2004/chapter_46.pdf  

Among  the  emergencies,  infections  are  probably  the  most  commonly  encountered  •  Infec7ons:  59/100  pa7ent-­‐years  •  Usually  mul7ple  sites  • May  overlap  with  disease  ac7vity/flare  • Most  common  sites:  

•  UTI  •  Pneumonia  •  Joint  infec7ons  •  CNS  infec7ons  •  Abdominal  infec7ons  •  Skin  

hOp://www.apiindia.org/pdf/pg_med_2004/chapter_46.pdf  

Bacteria  accounts  for  80-­‐90%  

•  Streptococcus  pneumoniae  •  Staphylococcus  aureus  •  Ecoli  •  Salmonella  • Klebsiella  • Pseudomonas    • Mycobacterium  tuberculosis  

hOp://www.apiindia.org/pdf/pg_med_2004/chapter_46.pdf  

Bacterial  causes  of  SLE  infections  

GRuiz-­‐Irastorza,  NOlivares,  I  Ruiz-­‐Arruza,  A  Mar6nez-­‐Berriotxoa,  MV  Egurbide,  Caguirre  Predictors  of  major  infec7ons  in  systemic  lupus  erythematosus    Arthri&s  Research  &  Therapy  2009,  11:R109        

Salmonella  infections  •  Bacteremia  with  extraintes7nal  manifes7ona7ons  •  UTI  •  Myco7c  aneurysm  •  Arthri7s  •  Pericardi7s  •  Osteomylei7s  •  Sob  7ssue  abscesses  

•  Mortality  as  high  as  25%  

hOp://www.apiindia.org/pdf/pg_med_2004/chapter_46.pdf  

• September  1996  to  May  1997  • Mexico  City  •  180  pa7ents  visited  ER  •  164  females    

•  Mean  age:  31.7    •  Mean  Mex  SLEDAI  score  3.8  •  Mean  SLICC-­‐ACR  1.3  •  Most  common  CC:      Fever  •  49  SLE  pa7ents  admiOed:  2  deaths  

Hospitalized  vs  non-­‐hospitalized:  Risk  Factors  

• Compliance  (7.6  vs  9  p<0.0001)  • Malar  Rash  (57%  vs  82%  p<0.0008)  • Disease  severity  in  Physician  global  assessments                (5.6  vs  2.1  p<0.0001)  

• Beck  depression  inventory  (21  vs  16  p<0.01)  • Pa7ents  level  of  formal  educa7on  • Chloroquine  daily  dose  intake  (45  vs  77  mg  p<0.04)  

2007-­‐2010  China  131  SLE  ER  visits  16.8%  mortality        

Clinical  Rheumatology  2011  

Predictors  of  mortality  • Older  age  >45  years  •  Longer  dura7on  of  disease  • Presence  of  pulmonary  hypertension  • Presence  of  renal  insufficiency  • Presencey  of  invasive  infec7on  • Higher  organ  damage  index  (SLICC  3.86  vs  0.93  p<0.001)  •  Lower  diseas  ac7vity  (SLE-­‐DAI  11.5  vs  16.5,  p=0.015)    

Chen  et  al  “Severe  systemic  lupus  erythematosus  in  emergency  department:  a  retrospec7ve  single-­‐center  study  from  China”    Clinical  Rheumatology  2011  

Canadian  experience  single  center:  Cohort  of  665  SLE  patients  5  yrs  

 •  124  deaths  (18.6%)  •  The  overall  survival  rates:  

•  5  year:  93%  •  10  year:  85%  •  15  year:  79%  •  20  year:  68%  

•  Most  common  causes  of  deaths:    •  Infec7on  40  (32%)  •  SLE  in  20  (16%)  •  Acute  vascular  event  19  (15.4%)  •  Malignancy  8  (6.5%)  •  Organ  failure  6  (4.8%)  

 Abu-­‐Shakra  M,  Urowitz  MB,  Gladman  DD,  Gough  J  J  Rheumatol  1995,  22(7):1259-­‐1264    

Risk  of  Death  in  SLE  due  to  Infections  

•  7  Countries  in  Europe  •  At  the  end  of  10  years,  68  pa7ents  have  died  (6.8%)    •  Causes  of  death:    

•  SLE  26.5%;    •  Thromboses  26.5%,  •   infec7ons  25%  

 

SLE  admissions  to  ICU:  Infection  

Lash  A  and  B  Lusk  “Systemic  Lupus  Erythematosus  in  the  Intensive  Care  Unit”      Crit  Care  Nurse  2004,  24:56-­‐65.  hOp://www.cconline.org      

MOST  COMMON  REASON  FOR  ICU  ADMISSION:  INFECTION  •  Thong  series  1999-­‐2000:    62%  admission  due  to  infec7on  •  Noel  et  al:  66%  of  SLE  pa7ents  for  admission  were  due  to  infec7on;  14%  needed  ICU  •  Use  of  steroids  (p<0.005)  •  Use  of  pulse  treatment  with  cyclophosphamide  (p<0.003)  •  Plasmapheresis  (p<0.01)  

•  Ansell:  37%  of  SLE  admissions  to  ICU  were  due  to  infec7on:  pneumonia,  UTI,  meningi7s  

 

   

 Noel  V,  Lortholary  O,  Cassassus  P,  et  al.  Risk  factors  and  prognos7c  influence  of  infec7on  in  a  single  cohort  of  87  adults  with  systemic  lupus  erythematosus.  Ann  Rheum  Dis.  2001;60:1141-­‐1144.    Thong  BY,  Tai  DY,  Goh  SK,  Johan  A.  An  audit  of  pa7ents  with  rheuma7c  disease  requiring  medical  intensive  care.  Ann  Acad  Med  Singapore.  2001;30:254-­‐259.    Ansell  SM,  Bedhesi  S,  Ruff  B,  et  al.  Study  of  cri7cally  ill  pa7ents  with  systemic  lupus  ery-­‐  thematosus.  Crit  Care  Med.  1996;24:981-­‐986.    

Survival  curves  of  SLE  at  ER  

Chen  et  al    “Severe  systemic  lupus  erythematosus  in  emergency  department:  a  retrospec7ve  single-­‐center  study  from  China”  Clinical  Rheumatology  2011  

Approach  to  SLE  Patients  with  Severe  Infections  

RECOMMENDATIONS  FOR  SEPTIC  LUPUS  PATIENTS  

- Dellinger RP, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med. Feb 2013; 41(2): 580-637.

Annals  of  Emergency  Medicine  Volume  63,  Issue  1,  Pages  35-­‐47  (January  2014)  DOI:  10.1016/j.annemergmed.2013.08.004  

 

Review Article: Critical Care Medicine Severe Sepsis and Septic Shock

Derek C. Angus, M.D., M.P.H., and Tom van der Poll, M.D., Ph.D.

N Engl J Med Volume 369(9):840-851

August 29, 2013

†National Center for Health Statistics, 2001.  §American Cancer Society, 2001. *American Heart Association. 2000.  ‡Angus DC et al. Crit Care Med. 2001;29(7):1303-1310.

AIDS* Colon Breast Cancer§  

CHF†   Severe Sepsis‡  

Cas

es/1

00,0

00

0

50

100

150

200

250

300

Incidence of Severe Sepsis Mortality of Severe Sepsis

0

50,000

100,000

150,000

200,000

250,000

Deaths/Year

AIDS*   Severe Sepsis‡  

AMI†  Breast Cancer§  

SEPSIS  in  comparison  with  other  major  diseases  

The  OVERARCHING  MESSAGE  OF  THE    SEPSIS  GUIDELINES:  

• The  SPEED  and  APPROPRIATENESS  of  therapy  administered  in  the  INITIAL  hours  aOer  severe  sepsis  develops    

• …significantly  INFLUENCE  clinical  outcomes.  

WHAT  IS  APPROPRIATE  SEPSIS  MANAGEMENT  FOR  VERY  ILL  SLE  PATIENTS?  

Recognizing  Sepsis  among  SLE  patients  

               

TERMINOLOGY  " Systemic  Inflammatory  Response  Syndrome  (SIRS)  

" Temp  >  38  or  <  36  " HR  >  90  " RR  >  20  or  PaCO2  <  32  " WBC  >  12  or  <  4  or  Bands  >  10%    

" Sepsis  " The  systemic  inflammatory  response  to  infec7on.  

 

" Severe  Sepsis  " Organ  dysfunc7on  secondary  to  Sepsis.  " e.g.    hypoperfusion,  hypotension,  acute  lung  injury,  encephalopathy,  acute  kidney  injury,  

coagulopathy.  

" Sep6c  Shock  " Hypotension  secondary  to  Sepsis  that  is  resistant  to  adequate  fluid  administra7on  and  

associated  with  hypoperfusion.  

Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest, 101(6), 1644–1655."

TWO  out  of  four  criteria  acute  change  from  baseline  

Infection,  SIRS,  Sepsis  

Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest, 101(6), 1644–1655."

SEPSIS  PATHOGENESIS  Unbalanced  Immune  Reac7on  

Tissue  Factor  

Procoagulant  State  

Microvascular  Thrombosis  

Mediators  of    Inflamma7on  

ROS  

Vasodila7on   Capillary  Leak  

Angus DC, van der Poll T. N Engl J Med 2013;369:840-851

HOST  RESPONSE  IN  SEVERE  SEPSIS  

Angus DC, van der Poll T. N Engl J Med 2013;369:840-851

Organ  Failure  in  Severe  Sepsis  and  Dysfunction  of  the  Vascular  Endothelium  and  Mitochondria.  

Organ  failure  in  SEPSIS  

Vincent, J.-L., Sakr, Y., Sprung, C. L., Ranieri, V. M., Reinhart, K., Gerlach, H., Moreno, R., et al. (2006). Sepsis in European intensive care units: results of the SOAP study. Critical Care Medicine, 34(2), 344–353."

P/F  Platelets  Bili  BP  GCS  Cr/UOP  

MAJOR  CHANGES  IN  THE  NEW  SEPSIS  GUIDELINE  • Use  of  protocolized  quan7ta7ve  resuscita7on  with  specific  physiologic  targets  

• Preferen7al  use  of  crystalloids  (with  or  without  albumin)  for  volume  resuscita7on  

• Preferen7al  use  of  norepinephrine  • Addi7on  of  lactate  clearance  as  a  marker  of  7ssue  hypoperfusion  

• Decreased  emphasis  on  the  use  of  cor7costeroids  

Figure  2  

Source:  Annals  of  Emergency  Medicine  2014;  63:35-­‐47  (DOI:10.1016/j.annemergmed.2013.08.004  )  Copyright  ©  2014  American  College  of  Emergency  Physicians  Terms  and  Condi7ons  

Surviving  Sepsis  Bundle  

ESSENTIALS  IN  SEPSIS  MANAGEMENT  OF  LUPUS  PATIENTS  •  Initial  Resuscitation  

•  Fluids  •  Pressors  

• Microbial  Diagnosis  •  Antimicrobial  Therapy  

•  Primer  on  Antibiotics  •  Source  Control  •  Infection  Prevention  

INITIAL  RESUSCITATION  FOR  SEPTIC  LUPUS  PATIENTS  •  1)  Protocolized  quan7ta7ve  resuscita7on  of  pa7ents  with  sepsis-­‐induced  7ssue  hypoperfusion  (defined  as  hypotension  persis7ng  aber  ini7al  dluid  challenge  or  blood  lactate  concentra7on  >  4mmol/L).  Goals  during  the  first  6  hours  of  resuscita7on:  •  A)  Central  venous  pressure  8-­‐12  mm  Hg  •  B)  Mean  arterial  pressure  (MAP)  >/=  65mm  Hg  •  C)  Urine  output  >/=  0.5ml/kg/hr  •  D)  Central  venous  or  mixed  venous  O2  satn  70%  or  65%  respec7vely  (Grade  1C)  

•  In  pa7ents  with  elevated  lactate  levels  targe7ng  resuscita7on  to  normalize  lactate  (Grade  2C)  

FLUID  THERAPY  OF  SEVERELY    SEPTIC  LUPUS  PATIENTS  • 1)  Crystalloids  as  the  ini7al  fluid  of  choice  (1B)  • 2)  Against  the  use  of  hydroxyethyl  starches  (1B)  • 3)  Albumin  may  be  used  when  pa7ents  require  substan7al  amounts  of  crystalloids  (2C)  

• 4)  Ini7al  fluid  challenge  with  sepsis-­‐induced  hypoperfusion  with  suspicion  of  hypovolemia  to  achieve  a  minimum  of  30ml/kg  of  crystalloids  (1C)  

 

Use  of  Vasopressors  •  1)  Vasopressor  therapy  to  target  MAP  65mmHg  (1C)  •  2)  Norepinephrine  is  the  first  choice  vasopressor  (1B)  

•  3)  Epinephrine  added  to  or  poten7ally  subs7tuted  when  addi7onal  agent  is  needed  to  maintain  adequate  BP  (2B)  

•  4)  Vasopressin  0.03  units/min  can  be  added  to  NE    

AntimicrobialTherapy  

MICROBIAL  DIAGNOSIS  •  1)  Cultures  as  clinically  appropriate  BEFORE  an7microbial  therapy  if  no  significant  delay  (>45min)  in  the  start  of  an7microbial  (Grade  1C).    •  At  least  2  sets  of  blood  CS  be  obtained  before  an7bio7cs  (Grade  1C)  

•  2)  Imaging  studies  performed  promptly  to  confirm  a  poten7al  source  of  infec7on  (UG).  

Inadequate  antibiotic  therapy:    A  RISK  FACTOR  FOR  MORTALITY    

Vallés et al. Chest 2003 123:1615–1624

Hospital  Mortality  by  Time  to  Antibiotics  

Variable   Odds Ratio   95% CI   P Value  

Broad-spectrum antibiotics  

0–1 hours   0.67   0.50–0.90   0.008  

1–3 hours   0.80   0.60–1.06   0.127  

3–6 hours   0.87   0.62–1.22   0.419  

No antibiotic in the first 6   1  

Fluid challenge in the event of hypotension  

1.01   0.73–1.39   0.966  

Low-dose steroids for persistent hypotension despite fluid resuscitation and/or lactate .36 mg/dl  

1.04   0.85–1.28   0.688  

Impact  of  timely  antibiotic  interventions  in  severe  sepsis  on  hospital  mortality  

Am J Respir Crit Care Med Vol 180. pp 861–866, 2009

2154 patients with septic shock, 78.9% got effective antimicrobial therapy

Delay in treatment (hours) from onset of hypotension to effective antimicrobial therapy

-Kumar et al. Crit Care Med. 2006:34

Duration  of  hypotension  before  appropriate  therapy  and  association  with  mortality      

Surv

ivia

l (%

)

0

10

20

30

40

50

60

70

80

90

0.5 1 2 3 4 5 6

Each hour of delay carries 7.6% reduction in

survival

Antibiotic  timing  and  mortality  

" No randomized-controlled data

Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department*. Critical Care Medicine 2010;38(4):1045–53. "

Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*. Critical Care Medicine 2006;34(6):1589–96. "

Time  from  EDGT  qualifica7on  to  ABX  Time  from  hypotension  to  appropriate  ABX  

•  Intravenous  an7bio7c  therapy  be  started  as  early  as  possible  and  within  the  first  hour  of  recogni0on  of  sep7c  shock  (1B)  and  severe  sepsis  without  sep7c  shock  (1C).  

Antibiotic  Therapy  for  Septic  LUPUS  Patients  

Empiric  Antibiotic  Therapy  • 1)  Start  effec7ve  IV  an7bio7cs  within  the  first  hour  of  recogni7on  of  sep7c  shock  (1B)  and  severe  sepsis  without  sep7c  shock  (1C)  

• 2)  Ini7al  empiric  an7bio7c  therapy  of  one  or  more  drugs  that  have  ac7vity  against  all  likely  pathogens  (bacterial  /or  fungal/or  viral)  and  that  penetrate  in  adequate  concentra7on  into  7ssues  presumed  to  be  the  source  of  sepsis  (1B)  

Empiric  Antibiotic  Therapy  •  3)  Combina7on  empirical  therapy  for  neutropenic  pa7ents  with  severe  sepsis  92B)  and  for  pa7ents  with  difficult-­‐to-­‐treat  mul7drug  resistant  bacterial  pathogens  such  as  Acinetobacter  or  Pseudomonas  (2B).    

•  4)  For  pa7ent  with  sever  infec7ons  asociated  with  respiratory  failure  and  sep7c  shock,  combina7on  therapy  with  an  extended  spectrum  beta  lactam  and  either  aminoglyocside  or  fluroquinolone  is  for  P  aeruginosa.  

•  5)  A  combina7on  of  betalactam  and  macrolide  should  e  given  to  pa7ents  with  sep7c  shock  from  bacteremic  Streptococcus  pneumoniae  infec7ons  (2B).  

OTHER  SUPPORTIVE  MEASURES  • Ven7latory  support  • Renal  replacement  therapy  • Bicarbonate  therapy  • Blood  products  • Seda7on,  pain  relief  • Glucose  control  • DVT  prophylaxis  • Stress  ulcer  prophylaxis  • Nutri7on  

IS  IT  AN  INFECTION  OR  A  LUPUS  FLARE?  

 THE  REAL-­‐LIFE  CHALLENGES  

IS  IT  CNS  INFECTION  OR  LUPUS  CEREBRITIS?    •  In  Korea,  1420  SLE  pa7ents  were  followed  

•  20  pa7ents  with  CNS  infec7on  •  11/20  :  Cryptococcus  neoformans  

•  Predictors:    •  Older  age  group  (p=  0.025)  •  Altered  mental  status  (p<0.005)  •  Plasma  leukocytosis  (p  =  0.037)  •  Neutrophila  (p  =  0.020)  •  CSF  pleocytosis  (p  =  0.044)  •  Low  CSF  Glucose  (p=  0.036)  

Lupus  April  2011  vol.  20  no.  5  531-­‐536    

Is  it  TB  or  is  it  Lupus?  

Philippines  :  Retrospec7ve  study  390  pa7ents  with  SLE  •  13.8%  ac7ve  TB  •  74%  Pulmonary  TB  •  Disseminated  TB  =  higher  lupus  ac7vity  index  and  more  aggressive  disease  •  Victorio-­‐Navarra  ST,  Dy  EE,  Arroyo  CG,  Torralba  TP.  Tuberculosis  among  Fil  ipino      pa7ents  with  systemic  lupus  erythematosus.  Semin  Arthri7s  and  Rheum.    

 1996;26:628–34.    

When  to  do  Tuberculin  Testing  

How  to  interpret:  what  to  do  • There  should  be  no  sign  of  ac7ve  TB  • TREAT  with  9mos  Isoniazid  when:  

•  If  PPD  is  >10mm    •  If  PPD  is  >5mm  in  those  who  will  take  15  mg  prednisone  daily  for  at  least  3  mos  

•  In  endemic  countries:  regardless  of  PPD,  treatment  of  Latent  TB  decreases  risk  of  ac7ve  TB  by  70%  if  prednisone    at  least  15mg/day  will  be  given  for  >  3mos  

American  Thoracic  Society  

Barber  et  al  Current  Opin  Rheumatolo  2011;  23(4):358-­‐365.    

Is  it  infective  endocarditis  or  Libman-­‐  Sacks?  

IS  IT  HIV  OR  LUPUS  ARTHRITIS  OF  THE    ARYTENOIDS?  

HIV  and  Lupus  Erytheamtosus  Indian  J  Dermatolog  2008;  53(2):80-­‐82  

NO  Guideline  for  Lupus  Patients!  PROPOSED  CHECKLIST  TO  PREVENT  INFECTIONS:  

ü Yearly  influenza  shot    ü Pneumococcal  vaccina7on    ü Regular  pap  smears  to  screen  for  cervical  dysplasia  caused  by  HPV  ü HPV  vaccina7on  as  per  recommenda7ons  for  the  general  popula7on  ü TB  skin  test/PPD  prior  to  star7ng  immunosuppressive  agents  and  treatment  with  isoniazid  (INH)  for  pa7ents  with  latent  TB  infec7on.  

ü Hepa77s  B  serology  at  baseline  in  all  pa7ents.  ü Hepa77s  C  serology  at  baseline  in  pa7ents  with  risk  factors.  ü HIV  serology  at  baseline  in  pa7ents  with  risk  factors.  ü Screening  for  strongyloides  in  pa7ents  from  endemic  areas  (strongyloides  serology)  prior  to  star7ng  immunosuppressive  agents  and  treatment  with  ivermec7n  if  infected.  

Barber  C,  LGWayne,  PRFor7n.  Infec7ons  in  the  Lupus  Pa7ent:  Perspec7ves  on  Preven7on.  Curr  Opin  Rheumatol.  2011;23(4):358-­‐365.      

Is  it  possible  to  do  all  these  in  the  Philippines  and  in  our  institution?    Of  course    

OF  COURSE!  

In  summary:  • Infec6ons  represent  14-­‐50%  of  cause  of  all  hospitaliza6ons  of  SLE  pa6ents  

• Infec6ons  represent  significant  cause  of  mortality  

• Aggressively  diagnose  and  treat  infec6ons,  even  in  situa6ons  where  dilemma  exists  

• Preven6on  of  some  infec6ons  may  be  possible.  

Let’s  Save  Lives!  Make  Our  Lupus  Patients  Survive  Sepsis