Pathophysiology

Fever

Fever

• Fever is defined as an elevation in body temperature resulting from disease

• "Fever is merely a symptom and we are not sure that it is an enemy. It may be a friend” Dubois (1946)

• "Fever, the Heat that Heals“ Benjamin (1959)

Body Temperature• “Core Temperature” = 37 ± 0.5oC– Aortic blood temperature– Esophageal temperature

• Clinical Approximates– Sublingual (oral) temperature = 0.7o F (0.3 oC ) < core– Axillary temperature = 1.8o F (1 oC ) < core– Rectal temperature = 0.9o F (0.5 oC ) > core

Normal Thermoregulation• Afferent Sensing– Cold receptors –> A delta fibers– Warm receptors –> C fibers– Integrated in spinal cord and CNS –> hypothalamus

• Central Integration– 20% each contribution from: skin, deep chest and abdomen, spinal

cord, CNS, hypothalamus– Skin input predominates behavioral responses

• Efferent Responses– Behavioral (clothing, adjusting environment)– Response to heat: sweat, cutaneous dilation– Response to cold: digital vasoconstriction (–agonism)

Nonshivering thermogenesis (–agonism) Shivering

Sessler DI: NEJM 336:1730–7, 1997.Sessler DI: NEJM 336:1730–7, 1997.

Endogenous Pyrogens• Interleukin–1 (alpha*, beta)• Interleukin–6• Interleukin–11• Tumor necrosis factor (alpha)• Interferon (alpha, beta, gamma)• Prostaglandin–E2• Platelet activating factor• Ciliary neurotropic factor (CNTF)• Oncostatin M• Cardiotropin–1• Leukemic inhibitory factor (LIF)

*first cloned by Auron PE: Proc Natl Acad Sci USA 81:7907–11, 1984.*first cloned by Auron PE: Proc Natl Acad Sci USA 81:7907–11, 1984.

Pyrogenic Cytokine Producing Cells• Monocytes, tissue macrophages• Keratinocytes• Gingival epithelium• Corneal epithelium• Renal mesangial cells• Brain astrocytes• Vascular endothelium• Vascular smooth muscle• NK cells• Fibroblasts

Fever and Host Defense Enhancement

• Neutrophil function– Enhanced migration– Enhanced superoxide production

• Mononuclear function– Enhanced interferon production• Enhanced interferon tumor and viral activity

– T–cell proliferation

The Structure of the Febrile State• Endocrine/Metabolic

CRH –> ACTH –> GCGHAldosteroneInsulin (if available)GlucagonAcute phase reactants

TSH

• AutonomicCutaneous vasoconstrictionPRBPSweating

• BehavioralSeek warmthShiveringAnorexiaSomnolenceMalaise

Cytokines Inducing Acute Phase Reactants

• Interleukin–1• Interleukin–6• Interleukin–11• Tumor Necrosis Factor• Oncostatin–M• Ciliary Neurotrophic Factor• Cardiotropin–1• Leukemic Inhibitory Factor

Dinarello CA: Sem Onc 24:288–98, 1997.Dinarello CA: Sem Onc 24:288–98, 1997.

Acute Phase Proteins(The concentration changes +/– 25%)

• Increased in Sepsis– Ceruloplasmin, ferritin, hemopexin, haptoglobin– 1–protease inhibitor, 1–antichymotrypsin, pancreatic secretory

trypsin inhibitor, inter––trypsin inhibitors– C3, C4, C9, C1 inhibitor, C4b–binding protein, C4b–binding lectin, factor B– Fibrinogen, plasminogen, TPA, urokinase, protein S, vitronectin,

plasminogen activator inhibitor–1– CRP, serum amyloid A, 1-acid glycoprotein, 2 macroglobulin,

phospholipase A2, fibronectin, manose binding protein, lipopolysaccharide–binding protein, IL–1 receptor antagonist, GCSF

• Decreased in Sepsis– Albumin, transthyretin, transferrin, 2-HS glycopreotein, FP, TBG,

insulin–like growth factor, Factor XII

Mackowiak PA: Arch IM 158:1870–81, 1998. Gabay C: NEJM 340:448-54, 1999Mackowiak PA: Arch IM 158:1870–81, 1998. Gabay C: NEJM 340:448-54, 1999

Afebrile Infections in the Elderly• Incidence– Bacteremia 5–31%– Endocarditis 7–21%– Pneumonia 20–56%– Meningitis 41%

• Mechanisms– Technical “pseudo-euthermia”

• Poorly taken oral/axillary temps– Chronic antipyretic drug ingestion– Physiologic changes

• Decreased BMR• Late, less efficient shivering• Autonomic neuropathy• Decreased temperature perception• Decreased production of endogenous pyrogens

Intrinsic Antipyretics• Somatostatin• Melanocyte–stimulating factor• Vasopressin• CRH–>ACTH–>GC• Thyroliberin (TRH,TRF)• GIP• Neuropeptide Y• Bombesin• IL–1ra, soluble TNF receptor

The Downside of Antipyresis• The febrile state is beneficial to the host• Fever is rarely harmful• Fever is a useful parameter to follow response to Rx• Intermittent defervescence is uncomfortable• Animal studies– decreased survival if febrile response to infection is ablated1–

5

• Human studies– slower healing of varicella6 and longer duration of malaria7

infection if antipyretics are given

11ARRD 130:857-62, 1984. ARRD 130:857-62, 1984. 22JID 155:991-7, 1987. JID 155:991-7, 1987. 33J Vet Pharm Ther 1:69-76, 1978. J Vet Pharm Ther 1:69-76, 1978. 44Fed Proc 36:511, 1977. Fed Proc 36:511, 1977. 55Brain Res Bull 5:69-73,1980. Brain Res Bull 5:69-73,1980. 66Doran TF: J Ped 114:1045-8, 1989. Doran TF: J Ped 114:1045-8, 1989. 77Brandts CH: Lancet 350:705–9, 1997.Brandts CH: Lancet 350:705–9, 1997.

Adverse Effects of Fever• Central Nervous System

oC oF Consequences 41 105.8 Delerium, seizures 42 107.6 Coma, CNS damage 41.6–42.0 106.9–7.6 Death (critical thermal max)*

Ox phos uncouples• Other Consequences– BMR 13-15% per 1oC– PR 7-10 bpm per 1oC **– Muscle proteolysis for acute phase reactant synthesis– Bone resorption –> hypercalcuria

**Bynum GD: Am J Phys 235:R228–36, 1978.Bynum GD: Am J Phys 235:R228–36, 1978.** Davies P:Emerg Med J 2009;26:9 641-643

Fever vs. Hyperthermia• Fever– Hypothalamic set–point increased by cytokines– Peripheral mechanisms generate and conserve heat– Response to antipyretics

• Hyperthermia– Hypothalamic set–point is normal– Peripheral mechanisms fail to match set–point– No response to antipyretics

Non–Infectious Etiologies of “Fever”

• CNS lesions– Stroke, trauma, encephalitis– High cord transection– Autonomic neuropathy

• Endocrine diseases– Pheochromocytoma– Thyrotoxicosis– Addison’s disease

• Skin Diseases– Ichthyosis– Absent sweat glands

• Miscellaneous– Severe CHF– Malignant hyperthermia– Neuroleptic malignant syndrome– Vasculitides– Malignancies– Inflammatory bowel disease

Causes of True Hyperthermia• Increased Heat Production– Exertional hyperthermia– Exertional heat stroke– Malignant hyperthermia– Neuroleptic malignant syndrome– Lethal catatonia– Thyrotoxicosis– Pheochromocytoma– Delerium tremens– Status epilepticus– Tetanus

• Drugs– ß–blockers– Sympathomimetics– Anti-cholinergics– Salicylate toxicity

• Decreased Heat Loss– Classic heat stroke– Occlusive dressings– Dehydration– Autonomic dysfunction

Clinically Benign Fevers• Diurnal variation• Meals• Ovulation• Smoking• Chewing gum/tobacco• Exercise

Weinstein L: RID 7:692, 1985.Weinstein L: RID 7:692, 1985.

Low Grade and High Grade FeversTemperature < 39o Temperature > 39o

Acute cholecystitis CholangitisAcute MI PericarditisSimple phlebitis PyophlebitisPulmonary emboli Septic pulmonary emboliAcute pancreatitis Abscess/infected pseudocystViral hepatitis (A–E) Leptospirosis/drug feverWound infection SubQ abscess/Strep., V. vulnificusGastrointestinal bleed Bowel infarctionCystitis PyelonephritisAtelectasis PneumoniaHematoma Infected hematoma

The Isolated Fever Spike• Manipulation of colonized surface– Wound debridement/irrigation– Flushing of drainage devices– Endoscopies– Foley in or out

• Blood/blood product transfusions• Contaminated infusates

Temperatures > 41o

• Central fever• Drug fever• Heat stroke• Malignant hyperthermia• Neuroleptic malignant syndrome• Malaria• Smallpox

Central Fever• Plateau fever curve• Poor response to antipyretics• Relative bradycardia• No sweating

Mechanisms of Drug Fever• Hypersensitivity Reactions– Drug as hapten, tissue binding, cell mediated

• Idiosyncratic Mechanisms– Malignant hyperthermia, neuroleptic malignant syndrome

• Altered Thermoregulatory Mechanisms– Thyroxine, sympathomimetics, anticholinergics, MAOI

• Cytolysis– Jarisch–Herxheimer reaction– Cancer chemotherapy– G6PD induced hemolysis

• Administration Related Fever– Endotoxin in drug/vaccine– Amphotericin B, bleomycin– Phlebitis, IM induced abscess

Tumors Commonly Causing Fever• Lymphomas– Hodgkin’s disease (IL–1, IL–6, TNF)– Non-Hodgkin’s lymphoma (IL–1)

• Leukemias – AML, ALL, CML, HCL (IL–1)– CLL (IL–1, IL–6)– Adult T–cell leukemia (IL–1)

• Multiple myeloma (IL–1, IL–6)• Renal cell carcinoma (IL–6)• Hepatoma, hepatoblastoma (IL–1)• Atrial myxoma (IL–6)• Melanoma (IL–1)• Ovarian CA (IL–1)• Transitional cell CA (IL–1)• Osteogenic SA (IL–1)• Malignant histiocytosis• Metastatic tumors to liver

Dinarello CA: Sem Onc 24:288–98, 1997.Dinarello CA: Sem Onc 24:288–98, 1997.