Harrisons Manual of Medicine, 18th Ed.

CHAPTER 34. Fever, Hyperthermia, and Rash


• Temperature: The hypothalamic thermoregulatory center balances excess heat production from metabolic activity in muscle and liver with heat dissipation from the skin and lungs to maintain a normal body temperature of image image, with diurnal variation (lower in A.M., higher in P.M.).

• Fever: an elevation of body temperature (>37.2°C/98.9°F in the morning and >37.7°C/99.9°F in the evening) in conjunction with an increase in the hypothalamic set point

• Fever of unknown origin (FUO): generally refers to temperatures >38.3°C (>101°F) on several occasions over a defined period, with unrevealing investigations into its cause. FUO can be classified further into several categories:

– Classic FUO: fever lasting >3 weeks where 3 outpt visits, 3 days in the hospital, or 1 week of “intelligent and invasive” ambulatory investigation does not elucidate a cause

– Nosocomial FUO: at least 3 days of investigation and 2 days of culture incubation failing to elucidate a cause of fever in a hospitalized pt with no infection on admission

– Neutropenic FUO: at least 3 days of investigation and 2 days of culture incubation failing to elucidate a cause of fever in a pt whose neutrophil count is <500/μL or is expected to fall to that level within 1–2 days

– HIV-associated FUO: fever in an HIV-infected pt, lasting >4 weeks for outpatients or >3 days for hospitalized pts, where appropriate investigation (including 2 days’ incubation of cultures) does not reveal a cause

• Hyperpyrexia: temperatures >41.5°C (>106.7°F) that can occur with severe infections but more commonly occur with CNS hemorrhages

• Hyperthermia: an uncontrolled increase in body temperature that exceeds the body’s ability to lose heat without a change in the hypothalamic set point. Hyperthermia does not involve pyrogenic molecules.

• Pyrogen: any fever-causing substance, including exogenous pyrogens (e.g., microbial toxins, lipopolysaccharide, superantigens) and pyrogenic cytokines (e.g., IL-1, IL-6, TNF)


• Pathogenesis: The hypothalamic set point increases, causing peripheral vasoconstriction (i.e., heat conservation). The pt feels cold as a result of blood shunting to the internal organs. Mechanisms of heat production (e.g., shivering, increased hepatic thermogenesis) help to raise the body temperature to the new set point. Increases in peripheral prostaglandin E2 account for the nonspecific myalgias and arthralgias that often accompany fever. When the set point is lowered again by resolution or treatment of fever, processes of heat loss (e.g., peripheral vasodilation and sweating) commence.

• Etiology Most fevers are associated with self-limited infections (usually viral) and have causes that are easily identified.


• History: A meticulous history is essential, with particular attention to the chronology of events (e.g., in the case of rash: the site of onset and the direction and rate of spread; see below) and the relation of symptoms to medications, pet exposure, sick contacts, sexual contacts, travel, trauma, and the presence of prosthetic materials.

• Physical examination: A thorough physical examination should be performed. A consistent site for taking temperatures should be used. Temperature–pulse dissociations (relative bradycardia) should be noted, if present (sometimes present, for example, with typhoid fever, brucellosis, leptospirosis, factitious fever). Close attention should be paid to any rash, with precise definition of its salient features.

1. Lesion type (e.g., macule, papule, nodule, vesicle, pustule, purpura, ulcer; see Chap. 65 for details), configuration (e.g., annular or target), arrangement, distribution (e.g., central or peripheral)

2. Classification of rash

a. Centrally distributed maculopapular eruptions (e.g., viral exanthems, exanthematous drug-induced eruptions)

b. Peripheral eruptions (e.g., Rocky Mountain spotted fever, secondary syphilis, bacterial endocarditis)

c. Confluent desquamative erythemas (e.g., toxic shock syndrome)

d. Vesiculobullous eruptions (e.g., varicella, primary HSV infection, ecthyma gangrenosum)

e. Urticaria-like eruptions: in the presence of fever, usually due to urticarial vasculitis caused by serum sickness, connective-tissue disease, infection (hepatitis B virus, enteroviral, or parasitic infection), or malignancy (particularly lymphoma)

f. Nodular eruptions (e.g., disseminated fungal infection, erythema nodosum, Sweet’s syndrome)

g. Purpuric eruptions (e.g., meningococcemia, viral hemorrhagic fever, disseminated gonococcemia)

h. Eruptions with ulcers or eschars (e.g., rickettsial diseases, tularemia, anthrax)

• Laboratory tests: CBC with differential, ESR, and C-reactive protein; other tests as indicated by history and physical exam


• The use of antipyretics is not contraindicated in common viral or bacterial infections and can relieve symptoms without slowing resolution of infection. Withholding of antipyretics may be useful, however, in evaluating the effectiveness of a particular antibiotic or in diagnosing conditions with temperature–pulse dissociations or relapsing fevers (e.g., infection with Plasmodium or Borrelia species).

• Treatment of fever in pts with preexisting impairment of cardiac, pulmonary, or CNS function is recommended to reduce oxygen demand.

• Aspirin, NSAIDs, and glucocorticoids are effective antipyretics. Acetaminophen is preferred because it does not mask signs of inflammation, does not impair platelet function, and is not associated with Reye’s syndrome.

• Hyperpyretic pts should be treated with cooling blankets in addition to oral antipyretics.


• Etiology: The likely etiologies differ with the category of FUO.

– Classic FUO: Etiologies to consider include:

• Infection—e.g., extrapulmonary tuberculosis; EBV, CMV, or HIV infection; occult abscesses; endocarditis; fungal disease. Infections remain a leading diagnosable cause of FUO, accounting for ~25% of cases in recent studies.

• Neoplasm—e.g., colon cancer

• Miscellaneous noninfectious inflammatory diseases—e.g., systemic rheumatologic disease, vasculitis, granulomatous disease. In pts >50 years old, giant-cell arteritis accounts for 15–20% of FUO cases.

• Miscellaneous diseases—e.g., pulmonary embolism, hereditary fever syndromes, drug fever, factitious fevers

– Nosocomial FUO: More than 50% of cases are due to infection (e.g., infected foreign bodies or catheters, Clostridium difficile colitis, sinusitis). Noninfectious causes (e.g., drug fever, pulmonary embolism, acalculous cholecystitis) account for ~25% of cases.

– Neutropenic FUO: More than 50–60% of pts with febrile neutropenia are infected, and 20% are bacteremic. Candida and Aspergillus infections are common.

– HIV-associated FUO: More than 80% of pts are infected, with the specific infectious etiology dependent on the extent of immunosuppression and the geographic region. Drug fever and lymphoma are also possible etiologies.


The workup must consider the pt’s country of origin, recent and remote travel, environmental exposures associated with hobbies, and pets. An approach to diagnosis of FUO is illustrated in Fig. 34-1.


FIGURE 34-1 Approach to the patient with classic FUO. ANA, antinuclear antibody; CBC, complete blood count; CMV, cytomegalovirus; CRP, C-reactive protein; CT, computed tomography; Diff, differential; EBV, Epstein-Barr virus; ESR, erythrocyte sedimentation rate; FDG, fluorodeoxyglucose F18; NSAIDs, nonsteroidal anti-inflammatory drugs; PET, positron emission tomography; PMN, polymorphonuclear leukocyte; PPD, purified protein derivative; RF, rheumatoid factor; SPEP, serum protein electrophoresis; TB, tuberculosis; TIBC, total iron-binding capacity; VDRL, Venereal Disease Research Laboratory test.


The emphasis in pts with classic FUO is on continued observation and examination, with the avoidance of “shotgun” empirical therapy.

• Vital-sign instability, neutropenia, and immunosuppressive conditions may prompt earlier empirical anti-infective therapies.

• The use of glucocorticoids and NSAIDs should be avoided unless infection has been largely ruled out and unless inflammatory disease is both probable and debilitating or threatening.

Prognosis: When no underlying source of FUO is identified after prolonged observation (>6 months), the prognosis is generally good.


• Etiology: Exogenous heat exposure (e.g., heat stroke) and endogenous heat production (e.g., drug-induced hyperthermia, malignant hyperthermia) are two mechanisms by which hyperthermia can result in dangerously high internal temperatures.

– Heat stroke: thermoregulatory failure in association with a warm environment; can be categorized as exertional (e.g., due to exercise in high heat or humidity) or nonexertional (typically occurring in either very young or elderly individuals during heat waves)

– Drug-induced hyperthermia: caused by drugs such as monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, amphetamines, and cocaine and other illicit agents

– Malignant hyperthermia: hyperthermic and systemic response (e.g., muscle rigidity, rhabdomyolysis, cardiovascular instability) in pts with a genetic abnormality that causes a rapid increase in intracellular calcium in response to inhalational anesthetics or succinylcholine. This rare condition is often fatal.

– Neuroleptic malignant syndrome: caused by use of neuroleptic agents (e.g., haloperidol) or withdrawal of dopaminergic drugs and characterized by “lead-pipe” muscle rigidity, extrapyramidal side effects, autonomic dysregulation, and hyperthermia

– Serotonin syndrome: caused by selective serotonin reuptake inhibitors (SSRIs), MAOIs, and other serotonergic drugs. Serotonin syndrome can be distinguished clinically from neuroleptic malignant syndrome by the presence of diarrhea, tremor, and myoclonus rather than lead-pipe rigidity.

• Clinical Features: high core temperature in association with an appropriate history (heat exposure, certain drug treatments) and dry skin, hallucinations, delirium, pupil dilation, muscle rigidity, and/or elevated levels of creatine phosphokinase

• Diagnosis: It can be difficult to distinguish fever from hyperthermia. The clinical history is often most useful (e.g., a history of heat exposure or treatment with drugs that interfere with thermoregulation).

– Hyperthermic pts have hot, dry skin; antipyretic agents do not lower the body temperature.

– Febrile pts can have cold skin (as a result of vasoconstriction) or hot, moist skin; antipyretics usually result in some lowering of the body temperature.

TREATMENT Hyperthermia

• Physical cooling by external physical means (e.g., sponging, fans, cooling blankets, ice baths) or internal cooling (e.g., gastric or peritoneal lavage with iced saline). In extreme cases, hemodialysis or cardiopulmonary bypass with cooling of blood may be necessary.

• IV fluids, given the risk of dehydration

• Pharmacologic agents can be used, as appropriate.

– Malignant hyperthermia, neuroleptic malignant syndrome, and drug-induced hyperthermia should be treated with dantrolene (1–2.5 mg/kg IV q6h for at least 24–48 h); dantrolene may also be helpful in serotonin syndrome and thyrotoxicosis.

– Neuroleptic malignant syndrome also may be treated with bromocriptine, levodopa, amantadine, or nifedipine or by induction of muscle paralysis with curare and pancuronium.

– Tricyclic antidepressant overdose may be treated with physostigmine.


For a more detailed discussion, see Kaye KM, Kaye ET: Atlas of Rashes Associated With Fever, Chap. e7 and Dinarello CA, Porat R: Fever and Hyperthermia, Chap. 16, p. 143; Kaye ET, Kaye KM: Fever and Rash, Chap. 17, p. 148; and Gelfand JA, Callahan MV: Fever of Unknown Origin, Chap. 18, p. 158, in HPIM-18.