Fever, acute adult

Fever is a regulated rise in body temperature to 38.0 degrees Celsius or more caused by an upward shift of the hypothalamic set point. Acute fever here means fever lasting up to 14 days in an adult. Most acute fevers are self limiting viral infections, but a minority represent sepsis, meningitis, malaria, endocarditis, abdominal sepsis or another condition where hours matter.

Definition. Fever is a single core temperature of 38.3 degrees Celsius or more, or 38.0 degrees Celsius sustained over 1 hour. Hyperpyrexia is a temperature over 41.5 degrees Celsius.

Older adults. The baseline is lower, so a single oral temperature over 37.8 degrees Celsius, repeated readings over 37.2 degrees Celsius, or a rise of 1.1 degrees Celsius over baseline counts as fever.

Normal temperature. Oral mean is about 36.8 degrees Celsius, with diurnal variation of about 0.5 degrees Celsius and a late afternoon peak. Rectal and core readings are higher than oral. Axillary and tympanic readings are less reliable.

Mechanisms. Exogenous pyrogens (endotoxin, bacterial and viral products) and endogenous pyrogens (interleukin 1, interleukin 6, tumour necrosis factor, interferons) act on the preoptic hypothalamus through prostaglandin E2. Heat is conserved by vasoconstriction and shivering until the new set point is reached. Defervescence follows with sweating and vasodilation.

Chills and rigors. A chill is a sensation of cold during the rising phase of fever. A rigor is sustained, violent shivering with teeth chattering and shaking of the whole body, lasting 15 to 30 minutes, during a rapid rise in temperature.

Rigors accompany bacteraemia, malaria, cholangitis, pyelonephritis, abscess, endocarditis, and reactions to drugs, blood products and amphotericin. They raise the likelihood of bacteraemia but are neither sensitive nor specific.

Fever pattern.

• Continuous: little daily variation.
• Remittent: daily variation without return to normal.
• Intermittent: return to normal each day. Quotidian, tertian (every 48 hours) and quartan (every 72 hours) describe the interval between spikes.
• Relapsing: days of fever alternating with fever free days.
• Hectic: wide swings.
• Biphasic: a break then a return.
• Patterns are suggestive only, and antipyretics blur them.

Fever versus hyperthermia. Hyperthermia is a rise in temperature from uncontrolled heat gain or failed heat loss with an unchanged set point. It does not respond to antipyretics and needs cooling and specific treatment, not antibiotics. Causes include heat stroke, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, anticholinergic toxicity, and stimulant and salicylate poisoning.

Host categories that change risk. Immunocompetent, older adult, pregnant, HIV positive, neutropenic, asplenic, injecting drug user, recent traveller, postoperative and hospitalised patients.

History.

• Onset, maximum temperature and how measured, pattern, chills, rigors, sweats, other symptoms, antipyretic use, response.
• Focal symptoms by system: headache, neck stiffness, photophobia, confusion; sore throat, ear pain, sinus pain; cough, sputum, pleuritic pain, breathlessness; abdominal pain, vomiting, diarrhoea, jaundice; dysuria, flank pain, discharge, testicular pain; back pain, joint pain, muscle pain, calf pain; rash, wound, boil, bite; eye pain.
• Contacts: household or workplace illness, children with rash, tuberculosis, meningococcal disease.
• Travel in the past 12 months (malaria areas, dengue, typhoid, viral haemorrhagic fever regions), malaria chemoprophylaxis adherence, vaccination status (typhoid, yellow fever, hepatitis A and B, meningococcal, pneumococcal, influenza, COVID-19).
• Exposures: mosquitoes, ticks, fleas, lice, animals (cattle, goats, dogs, bats, rodents), unpasteurised milk, undercooked meat, fresh water, floodwater, caves, bushmeat, sick persons.
• Sexual history, injecting drug use, tattoos, transfusion.
• Surgery, dental work, catheters, prostheses, valves, recent hospital stay, immunosuppression, diabetes, splenectomy, cancer, pregnancy.
• Drugs: recent new drugs (drug fever), antibiotic exposure, vaccine.

Examination.

• Complete vital signs: temperature with site, pulse (relative bradycardia in typhoid, leptospirosis, Q fever and some viral infections), respiratory rate, blood pressure, oxygen saturation, capillary refill, mental state. Calculate qSOFA (respiratory rate 22 or more, systolic pressure 100 mmHg or less, altered mentation; 2 or more is high risk) and a national early warning score.
• Skin: petechiae, purpura, maculopapular or vesicular rash, rose spots, eschar, erythema migrans, cellulitis, abscess, injection sites, Janeway lesions, Osler nodes, splinter haemorrhages.
• Eyes and mucous membranes: conjunctival suffusion (leptospirosis), jaundice, Roth spots, oral ulcers, thrush, pharyngeal exudate, peritonsillar swelling, trismus.
• Neck stiffness, Kernig and Brudzinski signs (insensitive), photophobia, focal neurology, fundi.
• Lymph nodes, sinuses, ears, dentition.
• Chest: crackles, consolidation, effusion. Heart: new murmur.
• Abdomen: right upper quadrant tenderness, splenomegaly, hepatomegaly, suprapubic and loin tenderness, rebound, bowel sounds. Rectal and prostate examination in men with fever and urinary symptoms. Pelvic examination when indicated.
• Spine percussion, joints, calf swelling, line sites, wounds, pressure areas, genitalia.

Red flags.

• Systolic pressure under 90 mmHg or a fall over 40 mmHg, respiratory rate 22 or more, oxygen saturation under 92%, altered mentation, lactate over 2 mmol/L, oliguria.
• Petechial or purpuric rash, neck stiffness, photophobia, severe headache, seizure.
• Neutropenia, splenectomy or hyposplenism, immunosuppression, chemotherapy, uncontrolled HIV.
• Pregnancy, age over 65, diabetes with poor control, injecting drug use, prosthetic valve or joint, indwelling devices.
• Returned within 3 months from a malaria endemic area (fever in a traveller is malaria until proved otherwise), inability to drink, prostration, jaundice with fever.
• Haemorrhagic features, bleeding gums, haematemesis (viral haemorrhagic fever, dengue, leptospirosis, severe malaria).
• Drooling, stridor, trismus, muffled voice (epiglottitis, deep neck infection).
• New murmur with fever, severe localised pain (necrotising fasciitis, abscess), rigors with jaundice (cholangitis).
• Temperature over 41.0 degrees Celsius or under 36.0 degrees Celsius in sepsis.

Viral. Influenza, COVID-19, other respiratory viruses (respiratory syncytial virus, adenovirus, rhinovirus), infectious mononucleosis (Epstein-Barr virus), cytomegalovirus, acute HIV infection, hepatitis A, B and E, dengue, chikungunya, Zika, yellow fever, Rift Valley fever, Crimean-Congo haemorrhagic fever, Ebola and Marburg viruses, Lassa fever, measles, varicella, rubella, parvovirus B19, enteroviruses, herpes simplex, mumps.

Bacterial: respiratory and ENT. Streptococcal pharyngitis, tonsillitis and peritonsillar abscess, sinusitis, otitis media, mastoiditis, epiglottitis, deep neck space infection, pneumonia (pneumococcal, atypical, Legionella), empyema, acute bronchitis, pertussis, diphtheria.

Bacterial: abdominal and genitourinary. Gastroenteritis (Salmonella, Shigella, Campylobacter), typhoid and paratyphoid fever, cholangitis, cholecystitis, liver abscess, appendicitis, diverticulitis, intra-abdominal abscess, spontaneous bacterial peritonitis, pyelonephritis, prostatitis, epididymo-orchitis, pelvic inflammatory disease, tubo-ovarian abscess, chorioamnionitis, septic abortion.

Bacterial: systemic and neurological. Bacteraemia and sepsis, meningitis (meningococcal, pneumococcal, listerial), meningococcaemia, brain abscess, infective endocarditis, toxic shock syndrome, leptospirosis, brucellosis, rickettsial infections (scrub typhus, tick bite fever, murine typhus), relapsing fever, Q fever, tularaemia, plague, anthrax, melioidosis, secondary syphilis, gonococcaemia, Lyme disease, acute tuberculosis (miliary).

Bacterial: skin, bone and joint. Cellulitis, necrotising fasciitis, abscess, pyomyositis, septic arthritis, osteomyelitis, vertebral osteomyelitis, spinal epidural abscess, infected prosthesis, line related infection.

Parasitic and fungal. Malaria (Plasmodium falciparum, vivax, ovale, malariae, knowlesi), amoebic liver abscess, early African trypanosomiasis, acute schistosomiasis (Katayama syndrome), visceral leishmaniasis, trichinosis, babesiosis, toxoplasmosis, histoplasmosis, cryptococcosis in immunosuppressed patients.

Noninfectious.

• Drug fever (beta lactams, sulphonamides, phenytoin, carbamazepine, allopurinol, antimalarials, methyldopa, heparin).
• Venous thromboembolism, myocardial infarction, pericarditis, aortic dissection, pancreatitis, hepatitis (alcoholic), haematoma and tissue injury, burns, crush injury, rhabdomyolysis, postoperative atelectasis.
• Inflammatory: gout and pseudogout, adult onset Still disease, giant cell arteritis, systemic lupus erythematosus flare, vasculitis, serum sickness, transfusion reaction, Jarisch-Herxheimer reaction.
• Malignant: lymphoma, leukaemia, renal cell carcinoma, tumour lysis.
• Endocrine and others: thyroid storm, subacute thyroiditis, adrenal crisis, phaeochromocytoma crisis, sickle cell crisis, thrombotic thrombocytopenic purpura, alcohol withdrawal and delirium tremens, seizure, intracranial haemorrhage with central fever.
• Hyperthermia: heat stroke, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, anticholinergic toxicity, stimulant and salicylate poisoning.

1. Stratify risk immediately. Calculate qSOFA and a national early warning score, and apply the systemic inflammatory response criteria (temperature over 38.0 or under 36.0 degrees Celsius, heart rate over 90, respiratory rate over 20, white count over 12 or under 4 x 10^9/L). Measure lactate. Lactate over 2 mmol/L indicates hypoperfusion; 4 mmol/L or more with hypotension indicates septic shock physiology.
2. Bedside tests for everyone: blood glucose, oxygen saturation, urine dipstick, pregnancy test in women of reproductive age.
3. Malaria: any febrile patient who has been in an endemic area in the past year (especially past 3 months) needs a rapid diagnostic test and thick and thin blood films. A single negative film does not exclude malaria; repeat films at 12 and 24 hours.
4. Laboratory: full blood count with differential (leucopenia and thrombocytopenia suggest viral infection, dengue, malaria, typhoid or sepsis), C reactive protein (over 100 mg/L raises the likelihood of bacterial infection), procalcitonin (over 0.5 microgram/L suggests bacterial infection; falling levels support stopping antibiotics), urea, creatinine and electrolytes, liver function tests (cholestasis in cholangitis, high transaminases in hepatitis, dengue, leptospirosis), coagulation and fibrinogen, creatine kinase, lactate, and arterial or venous blood gas when sick.
5. Blood cultures: two or more sets from separate sites (aerobic and anaerobic, 10 mL a bottle) before antibiotics in any patient with suspected sepsis, rigors, a prosthesis, a murmur or no focus. Antibiotics are not delayed more than 45 minutes in sepsis for cultures.
6. Source testing: urine culture, throat swab or rapid antigen test (Centor criteria of fever, absent cough, tender anterior cervical nodes and tonsillar exudate; a score of 3 or 4 supports testing and treatment), respiratory viral polymerase chain reaction for influenza and COVID-19, chest radiograph, sputum culture, stool culture or multiplex polymerase chain reaction, HIV fourth generation antigen and antibody test (with RNA polymerase chain reaction if seroconversion is suspected), syphilis serology, hepatitis serology, infectious mononucleosis testing, urine Legionella and pneumococcal antigen in severe pneumonia.
7. Tropical and zoonotic tests by exposure: dengue NS1 antigen (days 1 to 5) and IgM (after day 5), typhoid blood culture (positive in 40% to 80%; bone marrow culture is more sensitive), leptospirosis polymerase chain reaction and IgM, brucella blood culture and serology, rickettsial serology or polymerase chain reaction, arbovirus and haemorrhagic fever testing after isolation. The Widal test is unreliable and should not direct treatment.
8. Lumbar puncture for suspected meningitis. CT before puncture only if immunocompromised, known central nervous system disease, new seizure within 1 week, papilloedema, depressed consciousness or focal deficit; do not delay antibiotics or dexamethasone for imaging.
9. Imaging by source: abdominal ultrasound or CT for biliary, hepatic, renal or abdominal sepsis; transthoracic then transoesophageal echocardiography and the modified Duke criteria when endocarditis is possible; MRI of the spine for fever with back pain; CT of sinuses or neck for deep infection.
10. Noninfectious causes: ECG and troponin, D dimer with imaging for thromboembolism, lipase, thyroid function, drug history, and toxicology when hyperthermia is likely.

Limits. A normal white cell count does not exclude bacterial infection. Culture sensitivity is reduced by prior antibiotics. Procalcitonin rises in trauma, surgery and some non bacterial states and may be falsely low early. C reactive protein lags by 6 to 12 hours. Rapid malaria tests can miss low parasitaemia and deleted HRP2 strains. Meningeal signs are insensitive.

Immediate (suspected sepsis or red flags). Within the first hour: oxygen to keep saturation 94% to 98%, intravenous access, blood cultures, lactate, and the first dose of broad spectrum antibiotics (within 1 hour for shock or high probability of sepsis, and within 3 hours when sepsis is possible). Give a balanced crystalloid 30 mL/kg for hypotension or lactate 4 mmol/L or more.

Start noradrenaline to keep mean arterial pressure at 65 mmHg or more if hypotension persists. Control the source (drain abscess, relieve obstruction, remove infected devices). Isolate patients with suspected viral haemorrhagic fever, tuberculosis, meningococcal disease or measles, and use full protective equipment.

Empirical antibiotics by suspected source (adjust to local resistance and allergy).

• Unknown source, community acquired sepsis: ceftriaxone 2 g intravenously once daily. Add metronidazole 500 mg intravenously every 8 hours for intra-abdominal or pelvic sepsis. Add gentamicin 5 mg/kg intravenously once daily (maximum usually 480 mg, dosing weight adjusted, levels monitored, avoided in acute kidney injury and pregnancy unless essential) for urosepsis or severe disease. Add vancomycin 25 to 30 mg/kg intravenously as a loading dose then 15 to 20 mg/kg every 8 to 12 hours (levels monitored) or flucloxacillin 2 g intravenously every 6 hours for skin, line or bone sources.
• Hospital acquired or severe intra-abdominal sepsis: piperacillin-tazobactam 4.5 g intravenously every 6 hours. Extended spectrum beta lactamase risk, severe sepsis or prior resistant isolates: meropenem 1 g intravenously every 8 hours.
• Meningitis: ceftriaxone 2 g intravenously every 12 hours plus dexamethasone 10 mg intravenously every 6 hours for 4 days, started before or with the first antibiotic dose. Add amoxicillin 2 g intravenously every 4 hours if over 50 years of age, pregnant or immunosuppressed (Listeria). Add vancomycin where pneumococcal resistance is common.
• Pharyngitis (group A streptococcus): phenoxymethylpenicillin 500 mg orally four times daily for 10 days, or benzathine benzylpenicillin 1.2 million units intramuscularly once.
• Pyelonephritis: ceftriaxone 1 to 2 g intravenously once daily, or ciprofloxacin 500 mg orally twice daily for 7 days when the isolate is susceptible and no fluoroquinolone resistance risk exists.
• Community acquired pneumonia: amoxicillin 1 g orally every 8 hours for 5 days for mild disease; for moderate to severe disease add clarithromycin 500 mg twice daily or doxycycline 200 mg then 100 mg twice daily.
• Febrile neutropenia (neutrophils under 0.5 x 10^9/L): piperacillin-tazobactam 4.5 g intravenously every 6 hours within 1 hour of triage.
• Enteric fever: ceftriaxone 2 g intravenously daily for 7 to 14 days, or azithromycin 1 g orally on day 1 then 500 mg daily for 6 days for uncomplicated disease. Fluoroquinolone resistance is common and results direct treatment.

Specific infections.

• Severe malaria: artesunate 2.4 mg/kg intravenously at 0, 12 and 24 hours then once daily until oral therapy is possible (minimum 24 hours), followed by a full 3 day oral artemisinin combination course. Uncomplicated falciparum malaria: artemether-lumefantrine 4 tablets (80 mg/480 mg total, for patients of 35 kg or more) at 0, 8, 24, 36, 48 and 60 hours with fatty food. Monitor glucose (hypoglycaemia), parasite density and renal function. For Plasmodium vivax and ovale add primaquine 0.5 mg/kg orally daily for 14 days after testing for glucose 6 phosphate dehydrogenase deficiency.
• Influenza: oseltamivir 75 mg orally twice daily for 5 days in severe disease or risk groups, begun within 48 hours (reduce to 30 mg twice daily when creatinine clearance is 31 to 60 mL/min, and 30 mg once daily at 10 to 30 mL/min).
• Rickettsial infections, leptospirosis (mild) and Q fever: doxycycline 100 mg orally or intravenously twice daily for 7 days (14 days for Q fever). Severe leptospirosis: benzylpenicillin 1.5 million units intravenously every 6 hours or ceftriaxone 1 g intravenously daily for 7 days.
• Brucellosis: doxycycline 100 mg orally twice daily with rifampicin 600 to 900 mg orally daily for 6 weeks.
• Dengue: no antiviral. Oral fluids for warning signs absent; intravenous isotonic crystalloid 5 to 7 mL/kg/hour for 1 to 2 hours then reduced to 3 to 5 mL/kg/hour and 2 to 3 mL/kg/hour as haematocrit and perfusion permit; shock needs 10 to 20 mL/kg over 15 to 30 minutes. Paracetamol only; avoid aspirin and NSAIDs.
• Close contacts of meningococcal disease: ciprofloxacin 500 mg orally once, or rifampicin 600 mg orally twice daily for 2 days, or ceftriaxone 250 mg intramuscularly once in pregnancy.

Symptom control.

• Paracetamol 1 g orally or intravenously every 6 hours (maximum 4 g daily; 3 g in frail patients or under 50 kg; 15 mg/kg a dose under 50 kg). Ibuprofen 400 mg orally every 8 hours with food (maximum 2.4 g daily). Antipyretics improve comfort but do not change outcome in sepsis; avoid NSAIDs in dengue, renal impairment, volume depletion and bleeding.
• Fluids, rest, light clothing, tepid sponging. Rigors from blood product, drug or amphotericin reactions: stop the infusion, paracetamol, hydrocortisone 100 mg intravenously, and pethidine 25 mg intravenously for severe rigors.
• Hyperpyrexia or hyperthermia: active cooling (cold water immersion or evaporative cooling with fans, ice packs to axillae and groin) to under 39 degrees Celsius, benzodiazepine for agitation, and treat the cause. Antipyretics are ineffective. Malignant hyperthermia: dantrolene 2.5 mg/kg intravenously repeated to a total of 10 mg/kg. Neuroleptic malignant syndrome: stop the antipsychotic, cooling, benzodiazepines, dantrolene or bromocriptine.

Monitoring. Observations every 1 to 4 hours in sepsis. Review at 48 to 72 hours with culture results; narrow or stop antibiotics when a focus or a viral cause is found. Repeat lactate within 2 to 4 hours if raised.

Referral and escalation. Critical care for shock, respiratory failure or organ dysfunction. Infectious diseases for malaria, suspected haemorrhagic fever, endocarditis, bone and joint infection, HIV and returned travellers. Surgery for abscess, necrotising infection and peritonitis. Notify public health for notifiable diseases.

Admission. Any red flag, qSOFA 2 or more, early warning score of 5 or more, malaria in a non immune patient or any severe feature, suspected meningitis, immunosuppression, neutropenia, inability to take oral fluids or drugs, pregnancy with fever, or unreliable follow up.

Discharge and safety netting. Patients with stable vital signs, a self limiting illness, no red flags and reliable follow up may go home with oral fluids, paracetamol, and advice to return within hours for rash, drowsiness, severe headache, persistent vomiting, breathlessness, reduced urine, confusion, or fever beyond 48 to 72 hours.

Special groups. Pregnancy: severe malaria, listeriosis, pyelonephritis, chorioamnionitis and influenza are dangerous; avoid doxycycline and fluoroquinolones when possible; high fever in the first trimester carries a risk to the foetus. Older adults: fever is blunted, presentations are atypical (delirium, falls), and urinary and respiratory sources dominate. HIV: consider tuberculosis, bacteraemia (Salmonella), cryptococcosis and Pneumocystis.

Asplenia: overwhelming sepsis with encapsulated organisms; give ceftriaxone 2 g intravenously immediately. Returning travellers: exclude malaria first, then typhoid, dengue, rickettsiosis and haemorrhagic fever; ask about quarantine exposures. Injecting drug users: endocarditis and spinal abscess.