Fever: pathogenesis, patho physiology, and purpose.

·         Fever appears to have evolved in vertebrate hosts as an adaptive mechanism for controlling infection.

·         This phenomenon is produced by certain exogenous (largely microbial) stimuli that activated bone-marrow-derived phagocytes to release a fever-inducing hormone (endogenous pyrogen).

·         Endogenous pyrogen, in turn, circulates to the thermoregulatory center of the brain (preoptic area of the anterior hypothalamus) where it causes an elevation in the "set-point" for normal body temperature.

·         Warm blooded animals produced fever by increasing heat production (through shivering) or reducing heat loss (by peripheral vasoconstriction), whereas cold blooded animals do so only by behavioral mechanisms (seeking a warmer environment).

Fever

·         Fever is elevated body temperature (> 37.8° C orally or > 38.2° C rectally) or an elevation above a person’s known normal daily value. Fever occurs when the body's thermostat (located in the hypothalamus) resets at a higher temperature, primarily in response to an infection. Elevated body temperature that is not caused by a resetting of the temperature set point is called hyperthermia.

 

·         Symptoms are due mainly to the condition causing the fever, although fever itself can cause chills, sweats, and discomfort and make patients feel flushed and warm.

 

Pathophysiology

·         During a 24-h period, temperature varies from lowest levels in the early morning to highest in late afternoon. Maximum variation is about 0.6° C.

 

·         Body temperature is determined by the balance between heat production by tissues, particularly the liver and muscles, and heat loss from the periphery.

·         Normally, the hypothalamic thermoregulatory center maintains the internal temperature between 37° and 38° C.

·         Fever results when something raises the hypothalamic set point, triggering vasoconstriction and shunting of blood from the periphery to decrease heat loss; sometimes shivering, which increases heat production, is induced.

·         These processes continue until the temperature of the blood bathing the hypothalamus reaches the new set point.

·         Resetting the hypothalamic set point downward (e.g., with antipyretic drugs) initiates heat loss through sweating and vasodilation.

·         The capacity to generate a fever is reduced in certain patients (e.g., alcoholics, the very old, the very young).

 

·         Pyrogens are substances that cause fever.

·         Exogenous pyrogens are usually microbes or their products.

·         The best studied are the lipopolysaccharides of gram-negative bacteria (commonly called endotoxins) and Staphylococcus aureus toxin, which causes toxic shock syndrome.

·         Fever is the result of exogenous pyrogens that induce release of endogenous pyrogens, such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), IL-6 and other cytokines, which then trigger cytokine receptors, or of exogenous pyrogens that directly trigger Toll-like receptors.

 

·         Prostaglandin E2 synthesis appears to play a critical role.

 

Consequences of fever

·         Although many patients worry that fever itself can cause harm, the modest transient core temperature elevations (i.e., 38 to 40°C) caused by most acute illnesses are well tolerated by healthy adults.

 

·         However, extreme temperature elevation (typically > 41° C) may be damaging. Such elevation is more typical of severe environmental hyperthermia but sometimes results from exposure to illicit drugs (e.g., cocaine, phencyclidine), anesthetics, or antipsychotic drugs. At this temperature, protein denaturation occurs, and inflammatory cytokines that activate the inflammatory cascade are released. Thus, cellular dysfunction occurs, leading to malfunction and ultimately failure of most organs; the coagulation cascade is also activated, leading to disseminated intravascular coagulation.

 

·         Because fever can increase the BMR by about 10 to 12% for every 1° C increase over 37° C, fever may physiologically stress adults with preexisting cardiac or pulmonary insufficiency. Fever can also worsen mental status in patients with dementia.

 

·         Fever in healthy children can cause febrile seizures.

 

Etiology

Many disorders can cause fever. They are broadly categorized as

·         Infectious (most common)

·         Neoplastic

·         Inflammatory (including rheumatic, nonrheumatic, and drug-related)

 

·         The cause of an acute (i.e., duration ≤ 4 days) fever in adults is highly likely to be infectious. When patients present with fever due to a noninfectious cause, the fever is almost always chronic or recurrent. Also, an isolated, acute febrile event in patients with a known inflammatory or neoplastic disorder is still most likely to be infectious. In healthy people, an acute febrile event is unlikely to be the initial manifestation of a chronic illness.

 

 

Infectious causes

Virtually all infectious illnesses can cause fever. But overall, the most likely causes are

 

·         Upper and lower respiratory tract infections

 

·         GI infections

 

·         UTIs

 

·         Skin infections

 

·         Most acute respiratory tract and GI infections are viral.

 

·         Specific patient and external factors also influence which causes are most likely.

 

·         Patient factors include health status, age, occupation, and risk factors (e.g., hospitalization, recent invasive procedures, presence of IV or urinary catheters, use of mechanical ventilation).

 

·         External factors are those that expose patients to specific diseases—e.g., through infected contacts, local outbreaks, disease vectors (e.g., mosquitoes, ticks), a common vehicle (e.g., food, water), or geographic location (e.g., residence in or recent travel to an endemic area).

 

 

·         Some Causes of Acute Fever

(Predisposing Factor)

 

Cause

In Healthy Patients

·         Upper or lower respiratory tract infection

·         GI infection

·         UTI

·         Skin infection

Hospitalization

·         IV catheter infection

·         UTI (particularly in patients with an indwelling catheter)

·         Pneumonia (particularly in patients using a ventilator)

·         Atelectasis

·         Surgical site infection (postoperatively)

·         Deep venous thrombosis or pulmonary embolism

·         Diarrhea (Clostridium difficile–induced)

·         Drugs

·         Hematoma

·         Transfusion reaction

·         Decubitus ulcers

Travel to endemic areas

·         Coccidioidomycosis

·         Dengue fever (less common)

·         Diarrheal disorders

·         Hantavirus

·         Histoplasmosis

·         Legionnaires' disease

·         Malaria

·         Multidrug resistant bacteria

·         Plague

·         Tularemia

·         Typhoid fever

·         Viral hepatitis

·         Zika virus infection

Vector exposure

·         Ticks: Rickettsiosis, ehrlichiosis, anaplasmosis, Lyme disease, babesiosis, tularemia

·         Mosquitoes: Arboviral encephalitis

·         Wild animals: Tularemia, rabies, hantavirus infection

·         Fleas: Plague

·         Domestic animals: Brucellosis, cat-scratch disease, Q fever, toxoplasmosis

·         Birds: Psittacosis

·         Reptiles: Salmonella infection

·         Bats: Rabies, histoplasmosis

 

 

 

 

 

 

 

 

 

 

 

 

 

Vector species	Pathogens		Diseases Transmitted
Mosquitoes
Anopheles species		Plasmodium species	Malaria
Culex quinquefasciatus Ochletorotatusus nivieus Mansonia annulifera, M. Indiana, M. uniformis		Wuchereria bancrofti Wuchereria bancrofti Brugia malayi	Nocturnal periodic bancroftian filariasis Sub-periodic bancroftian filariasis Nocturnal periodic malayan filariasis
Aedes aegypti, Ae. albopictus		Dengue virus serotypes I, II, III, IV   Chikungunya virus	Dengue fever and its two complicated manifestations -  dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) Chikungunya fever
Culex. tritaeniorhynchus, Cx. vishnui, Cx. vishnui Cx. pseudovishnui, Cx. gelidus, & Cx. fuscocephala		Japanese encephalitis virus	Fever, acute encephalitis
Culex species		West Nile virus	Viral encephalitis
Sand flies
Phlebotomus argentipes		Leishmania donovani	Visceral leishmaniasis
Ph. papatasi, Ph. sergentii		Leishmania tropica, Leishmania major	Cutaneous leishmaniasis
Phlebotomus species		Chandipura virus	Chandipura viral encephalitis
Other Vectors
Xenopsylla cheopis (Oriental rat flea) is ecto-parasite on rats, which are reservoirs for the pathogen		Yesrsinia pestis (bacteria)	Bubonic plague,Murine typhus(endemic typhus)
Leptotrombidium deliense & Schoengastiella ligula (mites) are ecto-parasites on rats		Orienta tsutsugamushi (bacteria)	Scrub typhus (tropical typhus)
Pediculus humanus (body lice)		Bacteria	Lice-borne relapsing fever, and skin infections (secondary)
Ornithodorus sp (Soft ticks)		Bacteria	Tick-borne relapsing fever
Haemaphysalis spinigera-major vector (ticks)		Virus	Kyasanur forest disease
Hyalomma species (Hard-bodied ticks)		Virus	Cremian-congo haemorrhagic fever
Fruit bats and pigs		Virus	Nipah fever

 

Immunocompromise

·         Viruses: Varicella-zoster virus or cytomegalovirus infection

 

·         Bacteria: Infection due to encapsulated organisms (eg, pneumococci, meningococci), Staphylococcus aureus, gram-negative bacteria (eg, Pseudomonas aeruginosa), Nocardia sp, or Mycobacteria sp

 

·         Fungi: Infection due to Candida, Aspergillus, Histoplasma, or Coccidioides sp; Pneumocystis jirovecii; or fungi that cause mucormycosis

 

·         Parasites: Infection due to Toxoplasma gondii, Strongyloides stercoralis, Cryptosporidium sp, microsporidia, or Cystoisospora (previously Isospora) belli

 

Drugs that can increase heat production

·         Amphetamines

·         Cocaine

·         Methylenedioxymethamphetamine (MDMA, or Ecstasy)

·         Antipsychotics

·         Anesthetics

 

Drugs that can trigger fever

·         Beta-lactam antibiotics

·         Sulfa drugs

·         Phenytoin

·         Carbamazepine

·         Procainamide

·         Quinidine

·         Amphotericin B

·         Interferons

Evaluation

Two general issues are important in the initial evaluation of acute fever:

·         Identifying any localizing symptoms (e.g., headache, cough): These symptoms help narrow the range of possible causes. The localizing symptom may be part of the patient’s chief complaint or identified only by specific questioning.

 

·         Determining whether the patient is seriously or chronically ill (particularly if such illness is unrecognized): Many causes of fever in healthy people are self-limited, and many of the possible viral infections are difficult to diagnose specifically. Limiting testing to the seriously or chronically ill can help avoid many expensive, unnecessary, and often fruitless searches.

 

History

·         History of present illness should cover magnitude and duration of fever and method used to take the temperature. True rigors (severe, shaking, teeth-chattering chills—not simply feeling cold) suggest fever due to infection but are not otherwise specific. Pain is an important clue to the possible source; the patient should be asked about pain in the ears, head, neck, teeth, throat, chest, abdomen, flank, rectum, muscles, and joints.

 

·         Other localizing symptoms include nasal congestion and/or discharge, cough, diarrhea, and urinary symptoms (frequency, urgency, dysuria). Presence of rash (including nature, location, and time of onset in relation to other symptoms) and lymphadenopathy may help.

 

·         Infected contacts and their diagnosis should be identified.

 

·         Review of systems should identify symptoms of chronic illness, including recurrent fevers, night sweats, and weight loss.

 

·         Past medical history should particularly cover the following:

 

·         Recent surgery

 

·         Known conditions that predispose to infection (e.g., HIV infection, diabetes, cancer, organ transplantation, sickle cell disease, valvular heart disorders—particularly if an artificial valve is present)

 

·         Other known disorders that predispose to fever (e.g., rheumatologic disorders, SLE, gout, sarcoidosis, hyperthyroidism, cancer)

 

·         Questions to ask about recent travel include location, time since return, locale (e.g., in back country, only in cities), vaccinations received before travel, and any use of prophylactic antimalarial drugs.

 

·         All patients should be asked about possible exposures (e.g., via unsafe food or water, insect bites, animal contact, or unprotected sex).

 

·         Vaccination history, particularly against hepatitis A and B and against organisms that cause meningitis, influenza, or pneumococcal infection, should be noted.

 

·         Drug history should include specific questions about the following:

 

·         Drugs known to cause fever

·         Drugs that predispose to increased risk of infection (e.g., corticosteroids, anti-TNF drugs, chemotherapeutic and antirejection drugs, other immunosuppressants)

 

·         Illicit use of injection drugs (predisposing to endocarditis, hepatitis, septic pulmonary emboli, and skin and soft-tissue infections)

Physical examination

·         Physical examination begins with confirmation of fever. Fever is most accurately diagnosed by measuring rectal temperature. Oral temperatures are normally about 0.6° C lower and may be falsely even lower for many reasons, such as recent ingestion of a cold drink, mouth breathing, hyperventilation, and inadequate measurement time (up to several minutes are required with mercury thermometers). Measurement of tympanic membrane temperature by infrared sensor is less accurate than rectal temperature. Monitoring skin temperature using temperature-sensitive crystals incorporated into plastic strips placed on the forehead is insensitive for detecting elevations in the core temperature.

 

·         Other vital signs are reviewed for presence of tachypnea, tachycardia, or hypotension.

·         The patient’s general appearance, including any weakness, lethargy, confusion, cachexia, and distress, should be noted.

 

·         All the skin should be inspected for rash, particularly petechial or hemorrhagic rash and any lesions or areas of erythema or blistering suggesting skin or soft-tissue infection. Neck, axillae, and epitrochlear and inguinal areas should be examined for adenopathy.

 

·         In hospitalized patients, presence of any IVs, NGTs, urinary catheters, and any other tubes or lines inserted into the body should be noted. If patients have had recent surgery, surgical sites should be thoroughly inspected.

 

·         Tympanic membranes: Examined for infection

·         Sinuses (frontal and maxillary): Percussed

·         Temporal arteries: Palpated for tenderness

·         Nose: Inspected for congestion and discharge (clear or purulent)

·         Eyes: Inspected for conjunctivitis or icterus

·         Fundi: Inspected for Roth spots (suggesting endocarditis)

·         Oropharynx and gingiva: Inspected for inflammation or ulceration (including any lesions of candidiasis, which suggests immunocompromise)

·         Neck: Flexed to detect discomfort, stiffness, or both, indicating meningismus, and palpated for adenopathy

 

·         The lungs are examined for crackles or signs of consolidation, and the heart is auscultated for murmurs (suggesting possible endocarditis).

·         The abdomen is palpated for hepatosplenomegaly and tenderness (suggesting infection).

·         The flanks are percussed for tenderness over the kidneys (suggesting pyelonephritis).

·         A pelvic examination is done in women to check for cervical motion or adnexal tenderness; a genital examination is done in men to check for urethral discharge and local tenderness.

·         The rectum is examined for tenderness and swelling, suggesting perirectal abscess (which may be occult in immunosuppressed patients).

·         All major joints are examined for swelling, erythema, and tenderness (suggesting a joint infection or rheumatologic disorder). The hands and feet are inspected for signs of endocarditis, including splinter hemorrhages under the nails, painful erythematous subcutaneous nodules on the tips of digits (Osler nodes), and nontender hemorrhagic macules on the palms or soles (Janeway lesions).

·         The spine is percussed for focal tenderness.

·         Neurologic examination is done to detect focal deficits.

 

Red flags

The following findings are of concern:

 

·         Altered mental status

·         Headache, stiff neck, or both

·         Petechial rash

·         Hypotension

·         Dyspnea

·         Significant tachycardia or tachypnea

·         Temperature> 40° C or < 35° C

·         Recent travel to an area where serious diseases (e.g., malaria) are endemic

·         Recent use of immunosuppressants

 

Interpretation of findings

 

Red flag findings strongly suggest a serious disorder. as in the following:

 

·         Headache, stiff neck, and petechial or purpuric rash suggest meningitis.

 

·         Tachycardia (beyond the modest elevation normally present with fever) and tachypnea, with or without hypotension or mental status changes, suggest sepsis.

 

·         Malaria should be suspected in patients who have recently traveled to an endemic area.

 

·         Immunocompromise, whether caused by a known disorder or use of immunosuppressants or suggested by examination findings (e.g., weight loss, oral candidiasis), is also of concern, as are other known chronic illnesses, injection drug use, and heart murmur.

 

·         The elderly, particularly those in nursing homes, are at risk of serious bacterial infection.

 

·         Generalized adenopathy may occur in older children and younger adults who have acute mononucleosis; it is usually accompanied by significant pharyngitis, malaise, and hepatosplenomegaly. Primary HIV infection or secondary syphilis should be suspected in patients with generalized adenopathy, sometimes accompanied by arthralgias, rash, or both. HIV infection develops 2 to 6 wk after exposure (although patients may not always report unprotected sexual contact or other risk factors). Secondary syphilis is usually preceded by a chancre, with systemic symptoms developing 4 to 10 wk later. However, patients may not notice a chancre because it is painless and may be located out of sight in the rectum, vagina, or oral cavity.

 

·         Fever and rash have many infectious and drug causes. Petechial or purpuric rash is of concern; it suggests possible meningococcemia, Rocky Mountain spotted fever (particularly if the palms or soles are involved), or, less commonly, some viral infections (e.g., dengue fever, hemorrhagic fevers). Other suggestive skin lesions include the classic erythema migrans rash of Lyme disease, target lesions of Stevens-Johnson syndrome, and the painful, tender erythema of cellulitis and other bacterial soft-tissue infections. The possibility of delayed drug hypersensitivity (even after long periods of use) should be kept in mind.

 

·         If no localizing findings are present, healthy people with acute fever and only nonspecific findings (e.g., malaise, generalized aches) most likely have a self-limited viral illness, unless a history of exposure to infected contacts, to disease vectors, or in an endemic area (including recent travel) suggests otherwise.

 

·         Patients with significant underlying disorders are more likely to have an occult bacterial or parasitic infection. Injection drug users and patients with a prosthetic heart valve may have endocarditis. Immunocompromised patients are predisposed to infection caused by certain microorganisms.

 

·         Drug fever (with or without rash) is a diagnosis of exclusion, often requiring a trial of stopping the drug. One difficulty is that if antibiotics are the cause, the illness being treated may also cause fever. Sometimes a clue is that the fever and rash begin after clinical improvement from the initial infection and without worsening or reappearance of the original symptoms (e.g., in a patient being treated for pneumonia, fever reappears without cough, dyspnea, or hypoxia).

 

 

 

Testing

 

If localizing findings are present:

·         Mononucleosis or HIV infection: Serologic testing

 

·         Rocky Mountain spotted fever: Biopsy of skin lesions to confirm the diagnosis (acute serologic testing is unhelpful)

 

·         Bacterial or fungal infection: Blood cultures to detect possible bloodstream infections

 

·         Meningitis: Immediate lumbar puncture and IV dexamethasone and antibiotics (head CT should be done before lumbar puncture if patients are at risk of brain herniation; IV dexamethasone and antibiotics must be given immediately after blood cultures are obtained and before head CT is done)

 

·         Specific disorders based on exposure (e.g., to contacts, to vectors, or in endemic areas): Testing for those disorders, particularly a peripheral blood smear for malaria

 

·         If no localizing findings are present in otherwise healthy patients and serious illness is not suspected, patients can usually be observed at home without testing. In most, symptoms resolve quickly; the few who develop worrisome or localizing symptoms should be reevaluated and tested based on the new findings.

 

·         If serious illness is suspected in patients who have no localizing findings, testing is needed. Patients with red flag findings suggesting sepsis require cultures (urine and blood), chest x-ray, and evaluation for metabolic abnormalities with measurement of serum electrolytes, glucose, BUN, creatinine, lactate, and liver enzymes. CBC is typically done, but sensitivity and specificity for diagnosing serious bacterial infection are low. However, WBC count is important prognostically for patients who may be immunosuppressed (i.e., a low WBC count may be associated with a poor prognosis).

 

·         Patients with certain underlying disorders may need testing even if they have no localizing findings and do not appear seriously ill. Because of the risk and devastating consequences of endocarditis, febrile injection drug users are usually admitted to the hospital for serial blood cultures and often echocardiography. Patients taking immunosuppressants require CBC; if neutropenia is present, testing is initiated and chest x-ray is done, as are cultures of blood, sputum, urine, stool, and any suspicious skin lesions. Because bacteremia and sepsis are frequent causes of fever in patients with neutropenia. Febrile elderly patients often require testing.

 

 

 

Treatment

·         Specific causes of fever are treated with anti-infective therapy; empiric anti-infective therapy is required when suspicion of serious infection is high.

 

·         Whether fever due to infection should be treated with antipyretics is controversial. Experimental evidence, but not clinical studies, suggests that fever enhances host defenses.

 

·         Fever should probably be treated in certain patients at risk, including adults with cardiac or pulmonary insufficiency or with dementia.

 

Geriatrics Essentials: Fever

·         In the frail elderly, infection is less likely to cause fever, and even when elevated by infection, temperature may be lower than the standard definition of fever. Similarly, other inflammatory symptoms, such as focal pain, may be less prominent. Frequently, alteration of mental status or decline in daily functioning may be the only other initial manifestations of pneumonia or UTI.

 

·         Despite their less severe manifestations of illness, the febrile elderly is significantly more likely to have a serious bacterial illness than are febrile younger adults. As in younger adults, the cause is commonly a respiratory infection or UTI, but in the elderly, skin and soft-tissue infections are among the top causes.

 

·         Focal findings are evaluated as for younger patients. But unlike younger patients, elderly patients probably require urinalysis, urine culture, and chest x-ray. Blood cultures should be done to exclude septicemia; if septicemia is suspected or vital signs are abnormal, patients should be admitted to the hospital.

 

Key Points

·         Most fevers in healthy people are due to viral respiratory tract or GI infections.

·         Localizing symptoms guide evaluation.

·         Consider underlying chronic disorders, particularly those impairing the immune system.