INFECTIOUS

 DISEASES    
SOURCE:  Dr.  General’s  Lecture  2    
  ELEVATION  OF  HYPOTHALAMIC  SET  POINT  BY  CYTOKINES  
“Approach  to  a  Patient  with  Fever”    

  PGE2  
VALUES      
Elevation  in  the  hypothalamic  tissue  and  the  third  cerebral  ventricle  during  
    •
• Core  body  temperature  –  36.5  -­‐  37.5°C   fever  
• Mean  oral  temperature  –  36.8  ±  0.4°C  (18-­‐40  years  old)   • Found  highest  near  circumventricular  vascular  organs  –  enlarged  capillaries  –  
• Maximal  normal  oral  temperature  –  6AM=  37.2°C,  4PM=  37.7°C   destruction  of  organs  –  reduced  fever  
  • First  step  in  initiating  fever  –  exogenous  pyrogens  +  pyrogenic  cytokines  
FEVER:   interact  with  the  endothelium  
• AM  temperature  of  >37.2°C  (>98.9°F)   • Increased  PGE2  in  periphery  –  non  specific  myalgias  and  arthralgias    
• PM  temperature  of  >37.7°C  (>99.9°F)    
  MYELOID  AND  ENDOTHELIAL  CELLS  
ELDERLY:    
• Can  exhibit  a  reduced  ability  to  develop  fever   • Primary  cell  types  that  produce  pyrogenic  cytokines  
   
RECTAL:   EP-­‐3  
• Generally  0.4°C  higher  than  oral  readings    
  • PGE2    3rd  receptor  essential  for  fever  
UNADJUSTED  MODE  TYMPANIC  MEMBRANE:    
• 0.8°C  lower  than  rectal  temperatures    
   
  PRODUCTION  OF  CYTOKINES  IN  CNS  
WOMEN  WHO  MENSTRUATE:    
• AM  temperature  is  generally  lower  in  the  2  weeks  before  ovulation   • Cytokines  produced  in  the  brain  –  account  for  the  hyperpyrexia  of  CNS  
• Rises  by  0.6°C  (1°F)  with  ovulation  and  remains  at  the  level  until  menses  occur   hemorrhage,  trauma,  or  infection  
  • Viral  infections  of  the  CNS  induce  microglial  and  possibly  neuronal  production  
POSTPRANDIAL  STATE   of  IL-­‐1,  TNF,  IL-­‐6  
• Elevated  body  temperature    
   
   
   
  FEVER  VS  HYPERTHERMIA  
 
   
FEVER    
   
• Elevation  of  body  temperature  that  exceed  the  normal  daily  variation    
• Occur  in  conjunction  with  an  increase  in  the  hypothalamic  set  point  (from  37°C    
to  39°C)    
   
HYPERPYREXIA    
   
• A  fever  of  >41.5°C    
• Occurs  in  patients  with:    
∗ Severe  infections    
∗ CNS  hemorrhages  (most  common)    
   
HYPERTHERMIA    
   
• Heat  stroke    
• Uncontrolled  increase  in  body  temperature  that  exceeds  the  body’s  ability  to    
lose  heat    
• Hypothalamic  thermoregulatory  center  is  unchanged    
• Does  not  involve  pyrogenic  molecules    
• Exogenous  heat  exposure  and  endogenous  heat  production  –  dangerously  high    
internal  temperatures     APPROACH  TO  PATIENT  WITH  FEVER  
• Rapidly  fatal    
• Does  not  respond  to  antipyretics   PHYSICIAL  EXAMINATION  
• Systemic  sepsis  –  can  result  to  hyperpyrexia    
**Diagnosed  on  the  basis  of  the  events  immediately  preceding  the  elevation  of  core    
temperature**   • Chronology  of  events  preceding  fever,  exposure  to  other  infected  individuals  or  
• Skin  is  HOT  but  not  dry  (in  fever  –  skin  can  be  cold;  due  to  vasoconstriction)   to  vectors  of  disease  
  • Same  site  should  be  used  consistently  to  monitor  a  febrile  disease  (oral,  
  tympanic  membrane,  or  rectal)  
   
 
PATHOGENESIS  OF  FEVER    
  MAY  HAVE  ACTIVE  INFECTION  IN  THE  ABSENSE  OF  FEVER  
PYROGENS    
  • Newborns  
• Exogenous  pyrogens  –  microbial  products,  microbial  toxins,  or  whole   • Elderly  
microorganisms,  including  virus   • Chronic  liver  disease  
• Lipopolysaccharides  (endotoxin)  produced  by  all  gram  negative  bacteria   • Renal  failure  
• Enterotoxins  of  Staphylococcus  aureus;  superantigens  of  group  A  and  B   • Taking  glucocorticoids  
streptococcus   • On  treatment  with  anticytokine  
• Endotoxin  –  fever,  leukocytocis,  acute  phase  protein,  and  generalized  symptoms    
of  malaise    
  LABORATORY  TEST  
PYROGENIC  CYTOKINES    
  • CBC  
• Regulate  immune,  inflammatory,  and  hematopoietic  processes   • Juvenile  or  band  forms,  toxic  granulations,  and  Dohle  bodies  –  bacterial  
• Interleukin  (IL)  1  and  6  –  leukocytosis  seen  in  infections   infection  
• IL-­‐1,  IL-­‐6,  TNF  and  ciliary  neurotropic  factor   • Neutropenia  –  viral  infection  
• Fever  –  prominent  side  effect  of  IFN-­‐α  used  in  the  treatment  of  hepatitis   • Levels  of  cytokines  such  as  IL-­‐1  and  TNF  –  not  advised  below  the  detection  
• Fever  –  can  be  manifestation  of  disease  in  the  absence  of  microbial  infection   limit  of  the  assay  
• Inflammatory  process,  trauma,  tissue  necrosis,  and  antigen  antibody  complexes   • C  –  reactive  protein  level,  ESR  –  markers  of  inflammatory  processes  are  
  particularly  helpful  in  detecting  occult  disease  
  • Circulating  IL-­‐6  –  useful  because  it  induces  C-­‐reactive  protein  
                       
♥ KTD    .    1
                     
 
    
   
  FEVER  IN  PATIENTS  RECEIVING  ANTICYTOKINE  THERAPY     REGIMENS  FOR  THE  TREATMENT  OF  FEVER  
   
• Crohn’s  diease,  rheumatoid  arthritis,  or  psoriasis   • Reduced  the  elevated  hypothalamic  set  point  
• Blocking  of  cytokine  activity  –  lower  the  level  of  host  defenses  against  both   • Facilitate  heat  loss  
routine  bacterial  and  opportunistic  infections   • Reduced  systemic  symptoms  of  headache,  myalgias,  and  arthralgias  
• Receiving  high  dose  glucocorticoid  therapy  or  anti-­‐inflammatory  agents  such  as   • Oral  aspirin  and  NSAIDS  –  reduce  fever  but  can  adversely  affect  platelet  and  the  
ibuprofen  –  blunted  fever   GIT  
  • ASPIRIN  –  increases  the  risk  of  Reye’s  syndrome  in  children  
**low  grade  fever  is  of  considerable  concern  in  patients  receiving  anticytokine   • Fever  increase  the  demand  for  oxygen  
therapies**   ∗ For  every  increase  of  1°C  over  37°C,  there  is  a  13%  increase  in  oxygen  
  consumption  
  ∗ Aggravate  preexisting  impairment  of  cardiac,  pulmonary  or  CNS  function  
   
  DECISION  TO  TREAT  FEVER   • Children  with  a  history  of  febrile  or  nonfebrile  seizure  should  be  aggressively  
  treated  to  reduce  fever  
• Bacterial  infections,  the  withholding  of  antipyretic  therapy  can  be  helpful  in    
evaluating  the  effectiveness  of  particular  antibiotic    
• Temperature  pulse  dissociation:    
∗ Enteric  fever    
∗ Brucellosis    
∗ Leptospirosis    
∗ Drug  induced  fever    
∗ Factitious  fever    
 
• Hypothermia  –  can  develop  in  patients  with  septic  shock  
• Characteristic  patterns  of  febrile  episode  
∗ Plasmodium  vivax  –  cause  fever  every  third  day  
∗ Fever  occurs  every  fourth  day  with  malariae  
∗ Borrelia  infection  –  with  days  of  fever  followed  by  several  day  afebrile  
period  and  then  replapse  into  additional  days  of  fever  
∗ Pel  –  Ebstein  pattern,  Hodgkin’s  disease,  lymphoma  –  fever  lasting  3-­‐10  
days  followed  by  afebrile  peroids  of  3-­‐10  days  
∗ Cyclic  neutropenia  –  fever  occurs  every  21  days  and  accompany  the  
neutropenia  
∗ No  periodicity  of  fever  in  patients  with  familial  Mediterranean  fever  
 
 
 
  FEVER  IN  AUTOINFLAMMATORY  DISEASES  
 
• Recurrent  fever  
• Neutrophilia  
• Serosal  inflammation  
• Blocking  of  IL-­‐1β  –  reduce  the  fever  
• Respond  to  antipyretics  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MECHANISM  OF  ANTIPYRETIC  AGENTS  
 
 
• The  reduction  of  fever    by  lowering  of  the  elevated  hypothalamic  set  point  –  a  
direct  function  of  reduction  of  the  PGE2    
• Synthesis  of  PGE2  depends  on  cyclooxygenase  
• Inhibitors  of  cyclooxygenase  are  potent  antipyretics  
• Aspirin,  acetaminophen,  NSAIDs  
• Ibuprofen  and  COX  2  inhibitor  reduce  IL-­‐1  induced  IL-­‐6  production  –  contribute  
to  the  antipyretic  activity  of  NSAIDs  
 
Glucocorticoids:  
• Reduce  the  PGE2  synthesis  by  inhibiting  the  activity  of  phospholipase  A2  
• Block  the  transcription  of  the  mRNA  for  the  pyrogenic  cytokines  
 
 
 
 
 
 
 
 
                       
♥ KTD    .    2