211 Fever, Chills, and Night Sweats

LAWRENCE DALL and JAMES F . STANFORD

Definition a thermometer, many will not have done so . Patients can

usually relate the sensation of feeling warm and the fre-
In health, body temperature is regulated around a set point quent nonspecific accompanying symptoms of fatigue,
of 371C, and a circadian temperature rhythm exists in myalgias, back pain, headache, and diaphoresis . Some pa-
which the highest temperature of each day occurs around tients, however, especially those with tuberculosis, occa-
6 P.M . The variance between the highest and lowest core sional patients with drug fevers, and patients with other
temperature in a given day is usually no more than 1 to distracting unpleasant symptoms, may be unaware of tem-
1 .5C . This circadian rhythm may differ among individuals peratures as high as 39 .4C . A history of accompanying
but should be consistent in each person . Relative to the core chills or night sweats should be sought . A sensation of chil-
(blood) temperature, oral temperature tends to be about liness is very common with fever from any cause and has
0 .4C lower and axillary temperature up to 1C lower, while little specificity, but an abrupt onset of fever with one or
rectal temperature, probably because of fecal bacterial me- two hard chills (rigors) of teeth-chattering, bed-shaking in-
tabolism, averages about 0 .5C higher . tensity suggests an acute bacterial infection such as pneu-
Fever is a physiologic disorder in which the temperature mococcal pneumonia .
is elevated above one's normal temperature . An elevated The pattern of temperature elevation and the specific
body temperature may accompany any condition in which details of other associated symptoms should be obtained
exogenous or endogenous heat gain exceeds mechanisms along with an accurate description of the initial onset of
of heat dissipation such as occurs with vigorous exercise, illness . Patients may begin their story with a recent dramatic
exposure to a warm ambient temperature, or the use of change in their condition (e .g ., high fever) when in actuality
drugs that cause excess heat production or limit heat dis- their illness began months earlier with, for example, weight
sipation . In these situations the hypothalamic "thermostat" loss, back pain, or other symptoms .
remains "set" in the normal range . In true fever, mecha- A careful travel history, exposure history (persons with
nisms to regulate the body temperature above the normal fever, known infectious disease, animals, ticks, fresh or sea
set point are actively operating . water, undercooked or unprocessed foods, toxins, etc .), sex-
In most patients with fever lasting 1 to 2 weeks, the ual history, and family history may provide vital clues . Has
etiology will be found or the fever will disappear . Occa- the patient had any recent visits to the dentist or another
sionally, despite the history, physical examination, labora- doctor? Is the patient a health care professional, and what
tory and radiologic procedures, fever (temperature above is their current state of mental health? Does the patient have
38 .3C) will continue beyond 2 to 3 weeks without diagnosis . any underlying conditions or take any medications that might
These patients are said to have fever of undetermined origin interfere with thermoregulation? (Table 211 .1) .
(FUO) . Although the classic Petersdorf and Beeson defi- When fevers persist and become fevers of undetermined
nition still has utility, in this era of prospective payment origin, the careful and detailed history and physical ex-
medicine it can be modified to include careful outpatient amination are the clinician's most valuable tools . These must
documentation of fever and lack of diagnosis after careful be performed repeatedly throughout the evaluation . Re-
outpatient evaluation . The critical aspects of any definition peated questioning may reveal information that was not
of FUO are documentation of fever (>38 .3C with a su- deemed pertinent by the patient on initial evaluation . Ques-
pervised electronic thermometer) and allowance of ade- tioning of a relative, friend, or former physician can be quite
quate time for the vast majority of self-limited viral illnesses enlightening . On physical examination particular attention
to run their course . should be given to skin lesions, funduscopic changes, or-
Chills are the subjective reports of shivering or shaking ganomegaly, nails, lymph nodes, heart auscultation, geni-
associated with rapid changes in body temperature . They talia, and rectal examination . Physical findings may change
result from involuntary muscle contractions that occur in dramatically during a hospitalization, and meticulous rep-
response to a sudden lowering of body temperature below etition may reveal the needed information .
the prevailing set point . In the patient with fever of undetermined origin, vague
Night sweats are subjective reports of nocturnal sweating or trivial complaints and minor physical findings are often
that results from an exaggeration of the normal circadian important . Avoid making the common mistake of over-
temperature rhythm . looking, disregarding, or rejecting an obvious clue .

Technique Basic Science

A carefully obtained and detailed history is invaluable in Fever has been recognized as one of the hallmarks of clinical
the evaluation of febrile conditions . The etiology is often disease since ancient times . Accurate recording of body tem-
evident from the history and physical examination alone . perature became possible in the eighteenth century when
While some patients will have taken their temperature with the Dutch inventor Farenheit introduced the thermometer .

944
 211 . FEVER, CHILLS, AND NIGHT SWEATS 945

Table 211 .1 indirectly via lymphokines secreted after interaction with

Drugs That Cause Fever sensitized lymphocytes .
Recently it has been discovered that there are actually
Most commonly three endogenous pyrogens that mediate fever-interleu-
Amphotericin B kin-1 (IL-1), tumor necrosis factor (TNF, cachetin), and
Antihistamines
interferon a . IL-1, which is identical to lymphocyte acti-
Asparaginase
Barbiturates
vating factor (LAF), in addition to inducing fever, modu-
Bleomycin sulfate lates a large number of host defense responses including a
Methyldopa mitogenic action on T lymphocytes, which results in in-
Penicillin creased generation of helper T cells, a reduction in plasma
Phenytoin sodium iron and zinc concentrations, neutrophilia, and increases in
Procainamide
acute phase plasma proteins . Since many organisms require
Quinidine sulfate
Salicylates
iron for growth, a fall in available plasma iron is to their
Sulfonamides detriment and has potentially great benefit to the host . TNF
is similar to IL-1 in many of its properties but does not
Occasionally
Allopurinol activate lymphocytes .
Azathioprine A number of factors (Table 211 .2) may alter the normal
Cephalosporins thermoregulatory response . They may lead directly to hy-
Cimetidine perthermia (heat-related illness) or, in the case of EP-me-
Cocaine derivatives diated fever, may be responsible for prolongation of fever
Hydralazine hydrochlori de and the development of extreme temperature elevations .
Iodides Excess heat is dissipated by radiation, conduction, and con-
Isoniazid
Nitrofurantoin sodium vection via hypothalamic-mediated cutaneous vasodilation
Para-aminosalicylic acid and increased cardiac output . Evaporation heat loss re-
Propylthiouracil quires an intact sweating mechanism as well as hypothalamic
Rifampin input . When ambient air temperature becomes 35 C or
Streptokinase higher, neither conduction nor radiation is effective . High
Streptomycin sulfate humidity limits heat loss by vaporization .
Vancomycin hydrochlori de
Almost never
Digitalis Clinical Significance
Chloramphenicol
Insulin
Tetracyclines Although the cause of fever is often evident from the his-
tory, physical examination, and initial laboratory and radio-
Source : Modified with permission of Lipsky BA, Hirshmann V . Drug logic studies, sorting through the myriad causes in an
fever . JAMA 198 1 ;245 :851-54 . organized approach is a formidable task for the clinician .
The approach should be directed and well thought out .
The clinical usefulness of fever patterns is dubious, al-
though there are some notable exceptions . There are five
In 1868, the German physician Wunderlich emphasized the patterns : intermittent, remittent, continuous or sustained,
clinical usefulness of recording body temperature based on hectic, and relapsing . With intermittent fever, the temper-
his observations of 25,000 patients . Fever accompanies in- ature is elevated but falls to normal (37 .2C or below) each
fectious as well as noninfectious diseases and holds a central day, while in a remittent fever the temperature falls each
role in the definition and pathogenesis of heat-related ill- day but not to normal . In these two patterns the amplitude
nesses such as heat stroke . The pathogenesis, pathophys- of temperature change is more than 0 .3C and less than
iology, and purpose of fever are becoming well delineated . 1 .4C . Either of the two patterns can be called hectic when
Most fevers are caused by infection, although many dis- the difference between peak and trough temperature is
ease states can be responsible (e .g ., central nervous system great (1 .4C or more) . Sustained fever is a pattern in which
lesions, neoplasms, endocrine abnormalities, connective tis- there is little change (0 .3C or less) in the elevated temper-
sue diseases) . Febrile states that are not secondary to dis- ature during a 24-hour period . In relapsing fever, a variant
ordered thermoregulation, like that seen in hypothalamic of the intermittent pattern, fever spikes are separated by
lesions, are due to the release of endogenous pyrogen . days or weeks of intervening normal temperature .
Endogenous pyrogen (EP) acts on receptors in the ther- Although not diagnostic, at times fever curves can be
moregulatory hypothalamus to cause fever. This fever pro- suggestive . Hectic fevers, because of wide swings in tem-
duction may be mediated by an increase in local perature, are often associated with chills and sweats . This
prostaglandin (PGE2) production, monoamines, cations such pattern is thought to be very suggestive of an abscess or
as sodium and calcium, or cyclic adenosine monophosphate . pyogenic infection such as pyelonephritis and ascending
Exogenous stimuli of EP release from its source in mono- cholangitis, but may also be seen with tuberculosis, hyper-
cytes, liver, spleen and lung macrophages, keratinocytes, nephromas, lymphomas, and drug reactions .
polymorphonuclear cells, vascular endothelial, and smooth Continuous or sustained fever is usually not associated
muscle cells, and kidney mesangial cells include : lipopoly- with true chills or rigors . It is characteristic of typhoid fever
saccharide (endotoxin) of gram-negative rods, viruses, other or typhus, although commonly seen in bacterial endocar-
bacterial products, fungi, etiocholanolone, antigen-anti- ditis, tuberculosis, fungal disease, and bacterial pneumonia .
body complexes, polynucleotides, and other antigens . Vi- Noninfectious etiologies include neoplasms, connective tis-
ruses, tumors, and hypersensitivity reactions to drugs and sue disease, and drug fever .
other substances may stimulate EP release from monocytes Relapsing fevers may be seen in rat-bite fever, malaria,
94 6 XVI . THE GENERAL EXAMINATION

Table 211 .2 Table 211 .3

Thermoregulatory Factors Associated with Fever and Causes of Relative Bradycardia
Heat-related Illness
Factitious fever
Exogenous heat gain Drug fever
High ambient temperature Legionnaires' disease
Extremes of age Psittacosis
Debilitating illnesses Typhoid fever
Alcohol (peripheral vasodilation) Mycoplasma pneumonia
Brucellosis
Increased heat production
Dengue
Exercise and exertion
Yellow fever
Improper training techniques
Tuberculous meningitis
Fever and acute infection
Blackwater fever (Falciparum malaria with profound hemolysis)
Agitated and tremulous states
Parkinson's disease
Acute psychosis/mania
Drug withdrawal : alcohol, barbiturates, meprobamate
Drug overdose
Amphetamines Contrary to widely held beliefs, the height of tempera-
Hallucinogens (LSD) ture elevation has little diagnostic significance . Although
Phencyclidine (PCP) thermoregulatory defects should certainly be thought of
Severe salicylate overdose when temperatures exceed 40 .5 C, infection, either alone
Hyperthyroidism and thyroid medication (39%) or coexisting with a thermoregulatory defect (32%),
Impaired heat dissipation has been found in 71% of patients with extreme (41 .1C or
Lack of acclimatization greater) pyrexia .
Salt and water depletion Drug fevers also may exceed 40 .5 C and may simulate
High ambient temperature
septicemia . Drugs causing fever (Table 211 .1) may do so by
High humidity
Moderate to severe obesity administration-related mechanisms (e .g ., amphotericin,
Heavy clothing phlebitis, fluid contamination), pharmacologic action of the
Cardiovascular disease drug (e .g., Jarish-Herxheimer reaction, tumor cell necrosis
Neurologic disease (autonomic dysfunction, dementia, stroke, with chemotherapeutic agents), alteration of thermoregu-
parkinsonism) lation (see Table 211 .2), idiosyncratic susceptibility (e .g.,
Drugs
malignant hyperthermia), or drug-specific hypersensitivity
Diuretics
Anticholinergics (e .g., penicillin, methyldopa, quinidine) . Patients with drug
Neuroleptics (phenothiazines, butyrophenones) fever may appear well or quite ill and may or may not have
Antidepressants a relative bradycardia . Rapid resolution of fever is seen with
Antihistamines discontinuation of the medication in the vast majority of
Antiparkinsonian agents cases .
Beta blockers, alpha-methyldopa
Monoamine oxidase inhibitors As a rule, the pulse rate rises about 15 beats/min for each
Sweat gland dysfunction degree centigrade of fever. When this expected rise is not
Cystic fibrosis seen, a relative bradycardia exists and, in the absence of
Scleroderma beta-adrenergic blockers, suggests one of the diseases listed
Ectodermal dysplasia in Table 211 .3 .
Extensive post-burn scarring Fever of undetermined origin is most often caused by
Miliaria
an unusual manifestation of a common disease rather than
Sweat gland necrosis secondary to barbiturate overdose or
previous heat stroke a more exotic condition . Although the causes of fever of
Potassium depletion undetermined origin broadly span the categories of infec-
Miscellaneous tious and noninfectious disease listed in Table 211 .4, two-
Diabetes mellitus thirds are caused by infectious and neoplastic diseases (30
Malnutrition
to 40% and 30% respectively), while another 15% are hy-
Source : Modified with permission of Stine RJ . Heat illness. JACEP
1979 ;8 :154-60 .

Table 211 .4
Causes of Fever of Unknown Origin
cholangitis, infections with Borrelia recurrentis, Hodgkin's
disease (Pel-Ebstein fever), and other neoplasms . Bacterial infections
Historically, some diseases are described as having char- Spirochetal infections
acteristic fever patterns . The double quotidian fever of Rickettsial infections
gonococcal endocarditis has two spikes in a 24-hour period . Chlamydial infections
Fever at 48-hour intervals suggests Plasmodium vivax or P . Viruses
Fungi
ovale; 72-hour intervals suggest P . malariae, while P . falci-
Parasites
parum often has an unsynchronized intermittent fever . Neoplasms
Most fevers follow the usual diurnal pattern . Dissemi- Hypersensitivity and autoimmune diseases
nated tuberculosis, typhoid fever, and polyarteritis nodosa Granulomatous diseases
are important exceptions in which reversal of the usual Inherited diseases
diurnal pattern ("typhus inversus" pattern) can be observed . Central nervous system causes
Drugs
A reversed pattern is also seen with old age and with sali-
Factitious fever
cylate ingestion .
 211 . FEVER, CHILLS, AND NIGHT SWEATS 947

persensitivity related, autoimmune, or granulomatous, 10% Table 211 .6

miscellaneous, and 10 to 15% remain undiagnosed. Clues to the Diagnosis of Factitious Fever
The etiology depends on age, duration of fever, and
immunologic status . In children less than 6 years of age an History
infectious etiology is the most common cause . In children Medical or paramedical training
between the ages of 6 and 16, collagen vascular disease and Complicated history with multiple or prolonged
hospitalizations (sometimes for FUO)
inflammatory bowel disease increase in prevalence . In the Inconsistencies in the history
elderly there is a higher percentage of patients with giant No weight loss
cell arteritis and "cryptic" disseminated tuberculosis . Fewer
Physical examination
cases are undiagnosed, and such diseases as atrial myxoma, Good general appearance or normal examination
systemic lupus, factitious fever, and adult Still's disease have Temperature >42C (106F)
not been reported to cause FUO in the elderly . Failure of temperature to follow normal diurnal variation
As a generalization, the longer the duration of an FUO, Absence of tachycardia despite high temperature
the less likely are infectious and neoplastic etiologies, whereas Wide swings in recorded temperature
factitious disease, granulomatous diseases, Still's disease, and Rapid defervescence with no diaphoresis
Cool skin
other, more obscure diseases become important consider- Morning "fever" only
ations . No response to antipyretics
The evaluation of the patient with FUO (Table 211 .5) is Elevated temperature that is always the same
challenging and should be guided by clinical observation, Hospital course
physical examination, and a knowledge of the common Refusal to cooperate with routine temperature-taking
causes . Diagnostic procedures should not substitute for daily procedures
reassessment . If the initial "FUO work-up" is negative, men- Associated puzzling disorders
tally "readmitting" the patient, carefully reviewing the data, Personality disorder
repeating technically inadequate or equivocal studies, dis- Bedside instruments (heating pad, lighter, hot liquids)
Refusal to use an IVAC electronic thermometer
cussing the case with consultants and colleagues, and con- Unrevealing FUO evaluation
sidering the possibility that you are being misled by a false- Polymicrobial bacteremia with no obvious source
negative or false-positive test result may help lead to the Temperature of simultaneous freshly voided urine is normal
diagnosis .
A comment is necessary on factitious fever and fraud- Source: Factitious or fraudulent fever . In : Murray HW, ed . FUO : fever
of undetermined origin . New York : Futura, 1983 ;87-107 . Reprinted with
ulent infection . A significant number of patients with FUO permission .
have self-induced disease . These patients are usually female
health professionals . Clues to the diagnosis are listed in
Table 211 .6 .
Night sweats may occur with any condition causing fever . heroic measures . Antipyretics and cooling blankets rarely
Although suggestive of tuberculosis or lymphoma, they also are adequate . Measures found to be efficacious include im-
occur in brucellosis, lung abscess, bacterial endocarditis, di- mersing the patient in a cold water bath ; placing wet ice
abetic autonomic neuropathy, nocturnal hypoglycemia, bags over the major arteries of the groin and axilla while
nocturnal angina, and diabetes insipidus . massaging the muscles with cool, wet sponges ; and evapo-
Except in patients with underlying heart disease, mod- rative cooling methods which utilize large fans and contin-
erate fever has no deleterious effects on the patient . Anti- uous spraying of the body surface with tepid water such as
pyretics, in addition to clouding the issue, make the patient with a body cooling unit . Although evaporative cooling tech-
uncomfortable because of periods of sweating when the niques have been touted as being "more physiologic" than
antipyretic is given and chills when the effect of the agent other techniques, have many practical advantages, and are
is wearing off . If antipyretics are used, they should be given now widely utilized, their superiority to ice-water immersive
around the clock (e .g ., every 3 to 4 hr) rather than as needed techniques in reducing morbidity and mortality in patients
in response to symptoms, to avoid this rollercoaster effect . with hyperthermia or extreme pyrexia remains unproven .
High fevers can be dangerous to the central nervous
system, particularly in children . A sustained temperature
greater than 42C may lead to permanent brain damage .
Febrile convulsions in children are common with temper-
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