CMU-ISU Medical Corner FEVER Sir. Joseph Appleton Medical intern 18 April 2010

1. CMU-ISUMedical CornerFEVERSir. Joseph AppletonMedical intern18 April 2010

2. Lecture objectives • Definition of Fever • Mechanism of Fever • Causes of Fever • Types and patterns of Fever • Clinical Vignettes

3. What is Fever? • Fever or pyrexia is defined as the elevation of core body temperature above normal; in normal adults, the average oral temperature is 37°C (98.6°F). • Hyperpyrexia refers to extreme elevation in temp, above 41.1°C (106°F) • Hypothermia refers to an abnormally low temp below 35 °C (95°F) rectally.

4. Fever of an unknown origin (FUO) is defined as a febrile illness lasting more than 3 weeks, with temperatures exceeding 38.3°C on several occasions, and lacking a definitive diagnosis after 1 week of evaluation in the hospital. • Oral temp, rectal temp, axillary temp, and eardrum temperature. • Rapidly resp rates tend to increase the discrepancy b/w oral and rectal temps. In these situations, rectal temps are more reliable.

5. Mechanism of Fever The febrile response, of which fever is but one component, is a complex physiologic reaction to disease involving a cytokine-mediated rise in body temperature, generation of acute-phase reactants, and activation of numerous physiologic endocrinologic, and immunologic systems.

6. Body temperature depends on the balance b/w the production and dissipation of heat. How does the body generate heat? Which gland is responsible for thermoregulation in our body? How? What is set-point in physiology?

7. The hypothalamus (central to the process) • Function: thermostat controlling thermoregulatory mechanisms that balance heat production with heat loss • Integral to the process are the heat-sensitive receptors located in the pre-optic area of the anterior hypothalamus. • sensitive to elevations in blood temperature, increase signal output as the temperature rises above a fixed thermal set point (37.1°C average) and decrease output when the temperature drops below the set point.

8. Exogenous pyrogens (infectious agents, toxins, tumors) (+) Monocytes, macrophages, endothelial cells, other immune cells (+) Antipyretics (–) PGE2 NSAIDs (+) Anterior hypothalamus Elevated thermoregulatory set-point (+) (+) Heat conservation Heat production (vasoconstriction, (involuntary muscle behavior changes) contractions) FEVER

9. Cytokines Non-Ab proteins acting as mediators between cells • Monokines: produced by mononuclear phagocytes • Lymphokines: produced by activated lymphocytes, especially Th cells • Interleukins: cytokines that act as mediators between leukocytes • IL and a number

10. Cytokine network Complex system of interactions between cytokines wherein one cytokine can: • Induce or suppress its own synthesis • Induce or suppress synthesis of other cytokines • Induce or suppress synthesis of cytokine receptors • Antagonize or synergize with other cytokines

11. Properties of cytokines Can have similar actions (redundant) • Can share receptors or receptor components • Defect in a unique component: little effect • Defect in shared component: profound effect • IL-2Rγ defect X-linked SCID Genes encoding cytokines can produce variants through alternative splicing • Yield slightly different but biologically significant bioactivities

12. Cytokine receptors Most are formed as heterodimers. Many can be grouped into families based on common structural features • Type 1 (IL-2 or hematopoietin receptor family) • Type 2 (interferon receptor family) • TNF receptor family • IL-1 receptor family • Chemokine receptor family

13. Mediators of innate immune response • TNF-α • IL-1 • IL-10 • IL-12 • Type 1 interferons (IFN-α, IFN-β) • IFN-γ • chemokines

14. Tumor necrosis factor (TNF-α) • Produced by activated macrophages • Most important mediator of acute inflammation in response to microbes (esp gram negative bacteria) • Mediates recruitment of neutrophils and macrophages to site of inflammation by inducing ICAM, etc on endothelial cells • Stimulates endothelial cells and macrophages to produce chemokines • Acts on hypothalamus to produce fever • Promotes production of acute phase proteins

15. Interleukin 1 (IL-1) • Produced by activated macrophages • Effects similar to TNF-α • Helps activate Ts

16. Interleukin 10 (IL-10) Produced by activated macrophages and Th2 cells Function in both innate and adaptive immune response Inhibitory cytokine • Inhibits production of IFN-γ by Th1 cells • Shifts balance to Th2 • Inhibits cytokine production by activated macrophages • Inhibits expression of MHC class II and co-stimulatory molecules on macrophages

17. Causes of Fever • Bacterial infections • Viral infections • Parasitic Fevers • Trauma • Malignancy • Blood disorders (acute hemolytic anemia) • Drug reactions • Immune disorders (Collagen Vascular disease)

18. Patterns of Fever There exist specific fever patterns that can occasionally trace towards the diagnosis. • Continuous Fever : Body temperature in such instances remain above normal throughout the day and does not fluctuate more than 1 degree Celsius in 24 hrs. (Lobar pneumonia, typhoid, UTI, brucellosis) • Intermittent Fever: elevated temperature is present only for some hrs of the day and turns to normal for remaining hrs. ( Malaria, Kala-azar, Pyaemia, septicemia

19. Remittant Fever : temperature remains above normal throughout the day and fluctuates more than 1 degree Celsius in 24hrs, (infectious endocarditits). • Relapsing Fever: calls for another kind of everyday sort of illness, that reappears at times, in fact a number of times, during which it takes almost quite a few days for the body temperature to return back to normal. • A neutropenic Fever: also referred to as “ febrile neutropenia”, is a type of fever in the absence of normal immune system functionining.

20. Management of Fever • Non-Pharmacologic approach • Cold towel application method • Exercise? • Pharmacologic approach • NSAIDs • Antipyretics

21. Case 1 CC: Fever, cough, and chest pain HX/PE: • A 32-year of man comes to the emergency room with 5 days of fever, a cough that is sometimes productive of blood, and pleuritic chest pain. He is an active intravenous drug user and last used o the day before his presentation. He denies being HIV positive. Past medical history is significant for skin abscesses in the past, but he has been recently quite well. He uses no medications and has no allergies.

22. Tem: 39 degree Celsius (102F), BP: 112/72mmHg PR: 110/min. He is thin, weak appearing man lying on his side on the stretcher. Examination of the head, eyes, ears, nose and throat shows petechiae in his mouth and in his conjunctivae. Eye grounds are normal. His chest is bilaterally clear to border. There is no radiation of the murmur. His abdomen is benign, and his extremities do not have clubbing, but thin red lines are visible under the fingernails in the distal one-third.

23. Differential Dx • Pneumonia • Endocarditis • Sepsis • Bronchiectasis

24. Initial Dx plan • Blood cultures • Chest x-ray • Results: MRSA , Multiple nodular lesions visible bilaterally

25. Further Dx plan • Echocardiogram • Results:Vegetation visible on TV with tricuspid regurgitation • Tx Plan?

26. Case 2 Chief complaint: fever, chills, RUQ pain HX/PE: • A 78-year old woman is brought to the ER room with fever, chills, and RUQ pain. She was in her usual state of health until 1 week ago, when she began to develop intermittent pain in the RUQ associated with with darker colored urine. This morning the patient noticed feeling feverish and having a shaking chill. She denies any Hx of wt loss, any back pain, nausea, or vomiting. Her PMHX is significant for HTN for which she takes a beta-blocker.

27. She is frail appearing and in mild discomfort. Vital signs are: • Temp: 38.4 degree Celsius (101.1F). • BP: 90/60mmHg • PR: 100/min, RR: 16/min. • Sclera are icteric. Heart and lungs are normal. Abd examination is remarkable for being soft, with some RUQ tenderness and mild rebound tenderness. There is a well-healed scar on the RUQ. No masses are palpable. Rectal examination shows light-colored and Guaia-negative stool.

28. Differential Dx • Cholangitis • Common bile duct stones • Cholecystitis • Pancreatitis • Hepatitis

29. Initial Dx plan • CBC • BUN • Cr • Results: CBC, WBC 14,000, Bilirubin 4mg/dL, • Alkaline phospatase 300U/L, rest of LFT are normal.

30. Further Dx plan • Ultrasound of the RUQ • Results: Dilated common bile duct with common bile duct stones. No masses are appreciated in the liver or pancreas • TX plan? ERCP? Endoscopic retrograde cholangiopancreatograpy when stable.

31. Case 3 An 8-year old boy is brought in to the physician’s office with a 3-day Hx of fever and a rash. He has also had a mild sore throat and felt somewhat fatigued. His mother is concerns that could have “scarlet fever”. The rash started on his face and then spread to his arms and legs. He has only been given acetaminophen for the fever. He takes no other medications, has no known allergies, has no significant medical Hx, and has had no contact with anyone known to be ill.

32. On Examination: Temp: 37 degree Celsius, (99.8F) Other vital signs: normal His cheeks are notably red, almost as if they had been slapped. His pharynx is normal appearing, and the remainder of his head and neck exam is normal. On his extremities there is a fine, erythematous, maculopapular rash but no vesicles or petechiae. A rapid group A streptococcal Ag test done is the office negative.

33. Dx/Tx • What virus is the likely cause of this illness? • In which human cells does this virus cause lytic infection?