Patients with a fever - Clinical Tree

Introduction

Fever is one of the most common presenting features in the practice of any doctor who sees patients with acute illness. It is the hallmark of the body’s response to infection or inflammation. Before looking at the causes of fevers it is important to understand what we mean by that term and how the reaction to it is generated in the body.

Fever is an increase in the core body temperature (the temperature within the deep tissues of the body) above the daily range for an individual. The daily range of core body temperature is between 35.6°C and 37.8°C (97.0°F and 100.4°F). The closest to core body temperature we can measure is rectal temperature. Because this is usually not easily performed and is less acceptable to patients, the next best is ear (tympanic) temperature. This requires a specific device that can be inserted into the ear using disposable covers. Oral temperature is about 0.5°C less than ear temperature and axillary temperature a further 0.5°C lower than oral temperature.

The normal core temperature of any individual does not remain static but varies according to certain rhythms and characteristics. It is affected by time of the day (known as diurnal variation), age, gender, height, time in the menstrual cycle, as well as with exercise and meals.

The diurnal variation of core body temperature is usually up to 0.6°C, but can be exaggerated with a variation of 2°C to 3°C. Core body temperature is at its highest in the late afternoon and evening, with lowest point in the early hours of the morning ( Fig. 10.1 ).

Figure 10.1, Diurnal variation of core body temperature.

How is normal core body temperature regulated?

Control of body temperature is termed thermoregulation. Under normal circumstances the body temperature will be in a state of stable internal temperature, or in homeostasis.

The temperature of the body depends on the balance between heat production and heat loss. Core body temperature is regulated by a system of control mechanisms affecting heat generation and heat loss. These include the autonomic nervous system, the endocrine system, musculoskeletal system and behavioural responses. The centre of this mechanism is called the thermoregulatory centre. It lies in the hypothalamus and acts like a thermostat in controlling the systems to produce the right balance of heat production and loss. The thermoregulatory centre has heat-sensitive receptors that respond to changes in body temperature by switching on and off systems to keep the balance within normal range. The range of temperature considered normal by the hypothalamus is termed the set point ( Fig. 10.2 ). Damage to the hypothalamus can lead to loss of its thermostat control and result in very high or low core body temperatures.

Figure 10.2, Regulation of core body temperature.

Heat is gained and lost by the body through normal body functioning. Heat is produced all the time in the tissues of the body as a product of their metabolic processes. Heat is also produced by increased activity of skeletal muscles, such as during exercise or when shivering.

Normally, this heat is lost to the environment through transfer from deep tissues, via the blood stream, to body areas in contact with the outside. This is mostly through the skin, but also occurs through the lungs. Heat loss occurs through four main mechanisms called evaporation, convection, conduction and radiation as described in Box 10.1 .

Box 10.1

Mechanisms of bodily heat loss

Evaporation : Sweating and panting cool by increasing heat loss
Convection : Increasing blood flow to body surfaces leads to heat loss
Conduction : Losing heat by being in contact with a colder surface (e.g. swimming in cold water or lying on a cold floor)
Radiation : Increased exposure of the body surface will lead to increased heat loss

The amount of heat lost from the skin via the above mechanisms depends on environmental conditions, with more heat loss occurring in cold, dry and windy environments. When the temperature of the environment is higher than body temperature or when there is a lot of humidity, heat cannot easily be lost, leading to a rise in body temperature ( Fig. 10.3 ).

Figure 10.3, Mechanisms of thermoregulation and dysregulation.

What effects on thermoregulation lead to fever?

Despite fever being an indicator of an abnormal clinical finding, it is a normal physiological response. Although fever is an increase above normal in the core body temperature, it is not an indicator that the thermoregulatory system has lost control of its thermostatic function. It is rather a function of the up-regulating or resetting of the set point of the thermoregulatory centre to a higher level, much like turning up the thermostat to a higher temperature. So long as the reset temperature remains below the range of the normal function of the thermoregulatory centre (<41.5°C) it will function to keep the body at this higher temperature. Above this temperature, the centre can no longer function to control body temperature and the fever is termed hyperpyrexia, a medical emergency requiring immediate and rapid cooling of the body.

Hyperthermia, on the other hand, is an example of a high temperature that is not a fever. It differs from a fever in that it is not associated with a change in the set point of the thermoregulatory centre, but occurs owing to raising the body temperature above the normal set point. It can be caused by heatstroke, neuroleptic malignant syndrome, malignant hyperthermia and stimulants such as amphetamines and cocaine.

Fever is produced when a stimulus from either outside (external) or inside (internal) the body is detected by the body’s immune system as foreign, and a host of immune responses occur. External stimuli are usually in the form of infectious agents or drugs, whereas internal stimuli may be in the form of antibodies or damaged tissue. These (perceived) foreign objects activate the cells of the immune system to release chemical mediators called cytokines, including tumour necrosis factor alpha (TNF-α), interferon, IL-1 and IL-6. These cytokines act on the hypothalamus to reset the set point to a higher temperature or to ‘turn up the thermostat’. Some bacterial proteins can act directly on the thermoregulatory centre in the hypothalamus to cause the same effect.

Elevation of the internal set point results in a higher core body temperature and causes the individual to feel cold. This leads to increased generation of heat and reduction of heat loss in the form of peripheral vasoconstriction and shivering. Rigors are a form of severe shivering.

Should you always treat a fever?

Because fever is a physiological response of the body, it must have some inherent value, and so is there always a need to be so quick to reduce it? Benefits of having a high temperature include an increase in the phagocytic and bactericidal activity of neutrophils and the cytotoxic effects of lymphocytes, impairment of the growth and virulence of bacteria and evidence of survival benefit for individuals with an elevated body temperature in response to infection.

On the other hand, there are negative effects of a raised body temperature. Oxygen consumption and fluid and calorie requirements increase; increased metabolic activity can increase stress if organs are failing; inflammatory cytokines increase muscle breakdown; and fever can reduce mental acuity, cause delirium and trigger convulsions, especially in children.

Therefore, there is an indication to treat fever in those who are pregnant, in children, in those with impaired organ function or those with a very high temperature of >41.5°C.

Fever can be treated by increasing heat loss through physical cooling or by resetting the upregulated hypothalamic set point using antipyretics.

The patterns of fever

Fever can reveal a characteristic pattern in some diseases and this pattern of rise and fall of temperature may be a clue for diagnosis ( Fig. 10.4 ).

Approach to a patient with a fever—causes of fever

Fever is one of the most common presenting features at acute medical facilities around the world. Although it is a characteristic sign of infection, not all fever has an associated infectious cause. It is also a feature of a number of non-infectious inflammatory diseases (autoimmune connective tissue and autoinflammatory disease and vasculitis) and neoplasms. It may also occur as a drug reaction. In a significant number of cases, the temperature subsides spontaneously and no cause is identified ( Box 10.2 ).

Box 10.2

Causes of fever

▪
Infections
▪
Non-infectious inflammatory diseases
- −
  Autoimmune inflammatory
- −
  Autoinflammatory
- −
  Vasculitis
▪
Malignancy
▪
Miscellaneous causes such as drug reactions
▪
Undiagnosed

The likelihood that fever is caused by an infection differs from one area of the world to another and reflects the burden of disease in the particular country ( Fig. 10.5 ). It is also important to remember that the very young and the very old may have a serious infection without producing a fever.

Figure 10.5, Causes of fever in India and Europe.

History

As with any medical condition, the starting point of diagnosis is a detailed and meticulous history. The history taking should follow a logical scheme to ensure important questions are not missed; causes of fever have a broad aetiology and can present as multisystem diseases. Taking a ‘fever history’ is unlike most other history taking, as it does not focus on a particular body system. Aspects of the personal, general and specific histories of all other systems need to be explored.

All histories should begin with an introduction, stating clearly your designation as a trainee, student or observer. Ensure you have the correct patient and that the patient understands the language. If the patient is a minor or a guardian or parent is present, be aware that certain sensitive questions may have to be asked at a later time when you are alone with the patient.

Main presenting complaint

Patients presenting with fever will often have a raft of associated complaints, many or all of which may be perceived as the main problem to the patient. It is therefore prudent to refer to the fever as the main presenting complaint and the associated complaints as part of the systematic history.

History of the presenting complaint

Details of the fever itself should be taken and the pattern described as continuous, intermittent or recurrent as noted above. Ask whether the fever is worse in the morning or at night. Some open-ended questions should be followed by direct questions to elicit the finer distinguishing characteristics of the fever. Remember that the taking of antipyretics, anti-inflammatories or antibiotics can mask a fever, so ask the patient if he has taken any medication. Enquire as to the duration of fever, which should reflect when the patient first noticed having a fever. This differs from the onset of fever that may be sudden or gradual; the former more likely to represent a more virulent disease, whereas the latter suggests a more indolent one. A description of the fever should include the presence or absence of rigors (profound chills associated with exaggerated shivering and chattering of teeth), which usually indicates a rapidly rising temperature found in malaria or severe bacterial sepsis.

High fever of more than 39°C is the initial symptom in most patients with adult onset Still’s disease (AOSD). The classic fever pattern is one or two daily febrile spikes exceeding 39°C, usually occurring late in the day. At times the fever is continuous or, less commonly, there is an early morning spike.

Personal history

Although the patient’s name, age and date of birth are used as identifiers, the country of birth and countries of residence are the first questions of the infection history. These are important both in respect to disease exposures and disease protection in the form of childhood and other vaccinations. Rates of diseases such as tuberculosis (TB) are higher in people who were born or resided in a country with a high incidence of tuberculosis, even if they have left the country. Vaccination schedules differ among countries and because of this, immunity to certain childhood diseases may vary.

History of associated and constitutional symptoms

These include the presence of any of the following:

▪
Headache is a non-specific symptom and does not differentiate the cause of the fever. A severe headache associated with photophobia or vomiting could indicate meningitis. Vasculitides affecting the head and neck vessels may present with headache.
▪
Muscle ache (myalgia) is again a non-specific finding present in all causes of fever. If infectious, myalgia is more suggestive of infection with intracellular pathogens, particularly viral infections and malaria.
▪
Joint pain (arthralgia) is an additional non-specific symptom, which may be caused by multiple infectious and non-infectious aetiologies. In a patient complaining of arthralgia, one should distinguish between mono-arthralgia (single joint) and poly-arthralgia (multiple joint) involvement.
▪
Presence or absence of a rash is particularly important to enquire about, because many infections and autoimmune disorders are associated with a typical rash, both in pattern and evolution. The rash may not be present at the time of consultation or it may have changed over the course of the illness. Ask details about the rash history, finding out where on the body it began, its associations, where it spread, whether the lesions changed over time and, if no longer present, how it resolved. Further details to help the diagnosis include details on the colour, type of lesion (e.g. vesicle, pustule, lacey) and whether it was pruritic, painful or neither. If the rash is intermittent, patients can be asked to photograph it with their mobile phone, and may have done so of their own accord.
▪
Weight loss in a patient with a fever suggests a more chronic process and is a classic feature of YB (consumption) or malignancy.
▪
A full systematic history should be included looking for a pattern of disease in systemic infectious or non-infectious disease, or a specific organ source of infection (e.g. cough, abdominal pain, dysuria, diarrhoea and redness or pain of skin or soft tissue).

History of behaviours and exposures are important in infectious diseases

▪
Contact with anyone having similar symptoms or living with someone who has been treated for an infection. It is also useful to know about close contacts who have not been ill.
▪
Living arrangements, including access to clean water and sanitation, proximity to animals or rodents. A history of insect or animal bite or scratches.
▪
Occupation, hobbies and sports, especially those involving exposure to water, animals or health care.
▪
Recreational habits, especially illicit drug use or tattoos.
▪
Sexual habits are vitally important and patients may need some encouragement to be open and honest about these risks. Unprotected sexual practices increase the risk of both sexually transmitted diseases and blood-borne viruses.
▪
Food habits, including ingestion of unpasteurized milk or cheese.
▪
Taking of appropriate prophylaxis, including vaccinations, either when travelling or at home.
▪
Travel is one of the most important histories to explore. Details of the destinations include whether the stay was in an urban or rural setting, stay was with family or friends, in a hotel or without facilities ( Box 10.3 ).

Box 10.3

Infections to consider if there is a history of travel

Sub-Saharan Africa —malaria, reproductive tract infection (RTI), diarrhoeal illness, HIV, rickettsia, haemorrhagic fevers, TB, hepatitis

South East Asia —dengue, malaria, diarrhoeal illness

Sub-Continent Asia/India —enteric fever, dengue, malaria, diarrhoeal illness, hepatitis

South America —diarrhoeal illness, RTI, dengue, malaria, mosquito-borne viruses

Central America/Caribbean —diarrhoeal illness, RTI, dengue, malaria, mosquito-borne viruses

North America/Europe —influenza, HIV, Lyme, tick-borne viruses, TB (eastern Europe)

Past medical and surgical history

Although all past history is important to obtain, certain aspects play a more important role as risks for infections.

▪
Infections are more frequent and more serious in patients with diabetes. A past history of rheumatic heart disease increases the risk for infective endocarditis. Previous TB assumes a risk of recurrence.
▪
Immune compromise increases the risk, severity and scope of infections. The patient’s immune status should be determined, specifically by asking about underlying diseases, such as human immunodeficiency virus (HIV); medications, such as steroids or chemotherapy; or a history of a splenectomy.
▪
Recent hospitalization is associated with hospital-acquired multiresistant pathogens.
▪
Surgery, invasive procedures, medical devices, implants and transfusions all provide a means for introduction of infectious agents.
▪
Antibiotic use may select for more resistant pathogens and increases the risk of antibiotic-associated diarrhoea. Antibiotics may also provide protection against infection in certain groups of immune compromised patients.
▪
A history of immune compromise, radiation, toxin exposure or certain chronic infections may increase the risk of certain malignancies.
▪
A family history of non-infectious inflammatory diseases can indicate a genetic predisposition that may increase the risk of developing a non-infectious inflammatory disease.

Systematic history

Symptoms focusing on specific organ systems will provide direction towards the likely diagnosis when considering infectious causes of fever. Malignancies may also be found in any organ system. Non-infectious inflammatory diseases tend to affect multiple systems together, although a single system may predominate. The following detail focuses on infectious causes of fever.

Respiratory tract

▪
Upper respiratory tract infection is suggested by rhinorrhoea, nasal stuffiness, sneezing, sore throat, cough and a hoarse voice.
▪
Sinusitis is likely to cause facial pain and headache.
▪
Otitis is associated with ear pain, ear discharge with or without auditory symptoms such as deafness.
▪
Lower respiratory tract infections present with a cough, productive of purulent sputum, shortness of breath, wheeze or chest pain. Haemoptysis (coughing blood) suggests invasion of or damage to the blood vessels of the lung. This is present in TB, invasive fungal infection or non-infectious causes, such as lung cancer or vasculitis.

Genitourinary tract

▪
Lower urinary tract infection classically presents with a combination of dysuria, frequency, urgency and change in smell and colour of urine.
▪
Upper urinary tract infection may have the above (or a history of the above) with additional loin or back pain.
▪
Sexually transmitted infections and pelvic inflammatory disease can present with the same symptoms as a lower or upper urinary tract infection, but may have the additional symptoms of a vaginal or urethral discharge, dyspareunia (pain during intercourse), anogenital ulcers, genital warts, painful swelling of the scrotum, pubic itch or swelling of lymph glands in the groin.
▪
Vaginal candidiasis is not uncommon in women, particularly those who use vaginal douches or after a course of antibiotics. It may present as urinary tract infections do with a whitish vaginal discharge and vaginal itching.
▪
Bacterial vaginosis is not considered a true infection, but rather an imbalance of normal vaginal flora and overgrowth of anaerobes. It presents with watery, foul-smelling vaginal discharge.

Gastrointestinal tract

Abdominal pain may be present with almost all gastrointestinal causes of infections, but may be less prominent than pain caused by inflammatory or malignant gastrointestinal diseases. It is important to characterize the pain, including the site and radiation, associated abdominal symptoms and relieving and aggravating factors.

▪
Gastroenteritis , the most common gastrointestinal infection, is associated with abdominal pain and diarrhoea, with or without vomiting. Characterizing the diarrhoea may help in narrowing the aetiology owing to the characteristic pathogenesis of some of the gastrointestinal pathogens. Determining whether the diarrhoea is acute or chronic can distinguish infective from non-infective causes. Direct questions to ask about diarrhoea include frequency, colour and consistency, presence of mucus and/or blood in the stool (rather than just on the paper).
▪
Hepatitis is usually caused by viral agents, but can also occur as a complication of medications or other toxins. Jaundice is the classic sign of hepatitis, along with a history of exposure to risk factors involving contact with body fluids or excretions. Leptospirosis, a rare cause of jaundice, is caused by an organism that is carried by rats.
▪
Cholecystitis and cholangitis classically present with pain in the right upper quadrant of the abdomen associated with nausea with or without jaundice.
▪
Other forms of intra-abdominal infection, including bowel perforation and peritonitis, present with varying abdominal symptoms, including generalized or localized abdominal pain, bowel distension, diarrhoea, constipation or vomiting.

Nervous system

Headache, photophobia, vomiting, altered consciousness, fits, fainting, muscle weakness, numbness, paralysis, tremor, abnormal sensation and change of behaviour can all suggest an infection of the central nervous system. In neonates and young children the symptoms of infection are mostly non-specific.

Patients with multisystem non-infectious inflammatory diseases can have central and peripheral nervous system symptoms. A variety of neurological complications can be present, including spinal cord involvement in rheumatoid arthritis, neuropsychiatric involvement in systemic lupus erythematosus and neurological sequelae in vasculitic disorders.

Certain predisposing factors play a role in various forms of nervous system infection. A history of immune suppression, head injury and neurosurgery should be elicited.

▪
Meningitis is an inflammation of the subarachnoid space and meninges (membranes covering the brain and spinal cord) most often secondary to an infection. It classically presents with headache, vomiting, neck stiffness and fever. Depending on the duration of onset, meningitis can be classed as acute, subacute or chronic. Acute meningitis develops over hours to days; chronic meningitis over weeks or longer, and may last for months to years; subacute meningitis is in between the two, usually over weeks.
▪
Acute meningitis is most often bacterial, with the frequency of pathogens differing according to age group and immune status. Some forms of acute bacterial meningitis (meningococcal disease) can present with a typical purpuric non-blanching rash and may be associated with severe sepsis and shock. Viral meningitis is usually less severe and self-limiting and often begins with symptoms of a viral infection, such as fever, malaise, headache and muscle aches.
▪
Head injury increases the risk of meningitis by damaging the protective layer of meninges and allowing respiratory or skin flora into the protected subarachnoid space. Neurosurgery predisposes to infection with the above and also hospital-acquired pathogens.
▪
Chronic meningitis presents with the same symptoms as acute, only over a more prolonged period. Associated features should be sought for the more common causes of chronic meningitis, including tuberculosis, cryptococcus and Lyme disease.
▪
Encephalitis is inflammation of the brain tissue resulting in an altered level of consciousness, headache and fever. Additional symptoms may be present, depending on the site of infection, and they include seizures, tremors, stroke, hallucinations and abnormal behaviours. Encephalitis is usually viral in aetiology, but may also be bacterial (e.g. syphilis) or parasitic (e.g. toxoplasmosis).
▪
Intracranial abscesses are bacterial infections of the central nervous system (CNS); they include brain abscess, subdural or extradural empyema, classified according to their anatomic location. These abscesses occur secondary to seeding from a primary site, either from a contiguous one such as in otitis media, sinusitis, mastoiditis or dental infection; secondary to haematogenous spread from a remote site such as endocarditis; after a head injury or neurosurgery and, rarely, following meningitis.

Not all patients with nervous system symptoms and fever have a primary nervous system infection. Some systemic infections can cause neurological symptoms, such as severe or cerebral malaria, neurologic signs in severe typhoid fever and meningeal signs in HIV seroconversion illness.

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