Fever of unknown origin (FUO) – clinical cases characterized by a persistent (more than 3 weeks) increase in body temperature above 38 ° C, which is the main or even the only symptom, while the causes of the disease remain unclear, despite intensive examination (conventional and additional laboratory techniques). Fevers of unclear genesis can be caused by infectious and inflammatory processes, oncological diseases, metabolic diseases, hereditary pathology, systemic connective tissue diseases. The diagnostic task is to identify the cause of the increase in body temperature and establish an accurate diagnosis. For this purpose, an extended and comprehensive examination of the patient is carried out.
ICD 10
R50 Fever of unknown origin
General information
Thermoregulation of the body is carried out reflexively and is an indicator of the general state of health. The occurrence of fever (> 37.2 ° C with axillary measurement and > 37.8 ° C with oral and rectal) is associated with a response, protective and adaptive reaction of the body to the disease. Fever is one of the earliest symptoms of many (not only infectious) diseases, when there are no other clinical manifestations of the disease. This causes difficulties in diagnosing this condition. To establish the causes of fever of unclear genesis, a more extensive diagnostic examination is required. The beginning of treatment, including trial, before establishing the true causes of FUO is prescribed strictly individually and is determined by a specific clinical case.
Causes
Fever lasting less than 1 week, as a rule, accompanies various infections. A fever lasting more than 1 week is most likely caused by some serious illness. In 90% of cases, fever is caused by various infections, malignant neoplasms and systemic lesions of connective tissue. The cause of fever of unclear genesis may be an atypical form of a common disease, in some cases the cause of the temperature increase remains unclear.
The basis of fever of unclear genesis may be the following conditions:
- infectious and inflammatory diseases (generalized, local) – 30-50% of all cases (endocarditis, pyelonephritis, osteomyelitis, abscesses, tuberculosis, viral and parasitic infections, etc.);
- oncological diseases – 20-30% (lymphoma, myxoma, hypernephroma, leukemia, metastatic lung cancer, stomach, etc.);
- systemic inflammation of connective tissue – 10 -20% (allergic vasculitis, rheumatism, rheumatoid arthritis, Crohn’s disease, systemic lupus erythematosus, etc.);
- other diseases – 10-20% (hereditary diseases and metabolic diseases, psychogenic and periodic fevers);
- undiagnosed diseases accompanied by fever – about 10% (malignant tumors, as well as cases when the fever passes spontaneously or after the use of antipyretic or antibacterial agents).
The mechanism of increasing body temperature in diseases accompanied by fever is as follows: exogenous pyrogens (of bacterial and non–bacterial nature) affect the thermoregulation center in the hypothalamus through endogenous (leukocyte, secondary) pyrogene – a low-molecular protein produced in the body. Endogenous pyrogen has an effect on the heat-sensitive neurons of the hypothalamus, leading to a sharp increase in heat production in the muscles, which is manifested by chills and a decrease in heat transfer due to narrowing of the skin vessels. It has also been experimentally proven that various tumors (lymphoproliferative tumors, liver tumors, kidney tumors) can produce endogenous pyrogen themselves. Thermoregulation disorders can sometimes be observed with damage to the central nervous system: hemorrhages, hypothalamic syndrome, organic brain lesions.
Classification
There are several variants of the course of fever of unclear genesis:
- classic (previously known and new diseases (Lyme disease, chronic fatigue syndrome);
- nosocomial (fever appears in patients admitted to the hospital and receiving intensive therapy, 2 or more days after hospitalization);
- neutropenic (the number of neutrophils < 500 per 1 ml or their decrease is predicted in 1-2 days with bacterial infections, candidiasis, herpes).
HIV-associated (HIV infection in combination with toxoplasmosis, cytomegalovirus, histoplasmosis, mycobacteriosis, cryptococcosis).
According to the level of increase, body temperature is distinguished:
- subfebrile (from 37 to 37.9 ° C),
- febrile (from 38 to 38.9 ° C),
- pyretic (high, from 39 to 40.9 ° C),
- hyperpyretic (excessive, from 41 ° C and above).
The duration of the fever may be:
- acute – up to 15 days,
- subacute – 16-45 days,
- chronic – more than 45 days.
By the nature of changes in the temperature curve over time , fevers are distinguished:
- constant – for several days there is a high (~ 39 ° C) body temperature with daily fluctuations within 1 ° C (typhus, croup pneumonia, etc.);
- laxative – during the day the temperature ranges from 1 to 2 ° C, but does not reach normal values (with purulent diseases);
- intermittent – with alternating periods (1-3 days) of normal and very high body temperature (malaria);
- hectic – there are significant (more than 3°C) daily or at intervals of several hours changes in temperature with sharp changes (septic conditions);
- return – the period of temperature increase (up to 39-40 °C) is replaced by a period of subfebrile or normal temperature (recurrent typhus);
- undulating – manifested in a gradual (from day to day) increase and a similar gradual decrease in temperature (lymphogranulomatosis, brucellosis);
- incorrect – there are no patterns of daily temperature fluctuations (rheumatism, pneumonia, flu, oncological diseases);
- perverted – morning temperature readings above evening (tuberculosis, viral infections, sepsis).
Symptoms
The main (sometimes the only) clinical symptom of fever of unknown origin is a rise in body temperature. For a long time, fever may be asymptomatic or accompanied by chills, excessive sweating, heart pain, suffocation.
Diagnostics
It is necessary to strictly observe the following criteria in the diagnosis of fever of unknown origin:
- the patient’s body temperature is 38 ° C and above;
- fever (or periodic temperature rises) are observed for 3 weeks or more;
- the diagnosis has not been determined after the examinations conducted by generally accepted methods.
Patients with fever of unknown origin are difficult to diagnose. Diagnosis of the causes of fever includes:
- blood and urine test, coagulogram;
- biochemical blood tests (sugar, ALT, AST, CRP, sialic acids, total protein and protein fractions);
- aspirin test;
- three-hour thermometry;
- Mantoux reaction;
- lung radiography (detection of tuberculosis, sarcoidosis, lymphoma, lymphogranulomatosis);
- ECG;
- Echocardiography (exclusion of myxoma, endocarditis);
- Ultrasound of the abdominal cavity and kidneys;
- MRI or CT scan of the brain;
- consultation of a gynecologist, neurologist, ENT doctor.
To identify the true causes of fever, additional studies are used simultaneously with conventional laboratory tests. For this purpose , the following are assigned:
- microbiological examination of urine, blood, smear from the nasopharynx (allows to identify the causative agent of infection), blood test for intrauterine infections;
- isolation of viral culture from body secretions, its DNA, viral antibody titers (allows to diagnose cytomegalovirus, toxoplasmosis, herpes, Epstein-Barr virus);
- detection of antibodies to HIV (enzyme–linked immunosorbent complex method, Western blot test);
- examination of a thick blood smear under a microscope (to exclude malaria);
- blood testing for antinuclear factor, LE cells (to exclude systemic lupus erythematosus);
- bone marrow puncture (to exclude leukemia, lymphoma);
- computed tomography of abdominal organs (exclusion of tumor processes in the kidneys and pelvis);
- skeletal scintigraphy (detection of metastases) and densitometry (determination of bone density) in osteomyelitis, malignancies;
- examination of the gastrointestinal tract by radiation diagnostics, endoscopy and biopsy (for inflammatory processes, tumors in the intestine);
- conducting serological reactions, including indirect hemagglutination reactions with the intestinal group (with salmonellosis, brucellosis, Lyme disease, typhoid);
- collection of data on allergic reactions to medications (in case of suspected drug disease);
- study of family history in terms of the presence of hereditary diseases (for example, familial Mediterranean fever).
To make a correct diagnosis of fever, anamnesis collection and laboratory tests can be repeated, which at the first stage could be erroneous or incorrectly evaluated.
Treatment
In the event that the patient’s condition with fever is stable, in most cases it is necessary to refrain from treatment. Sometimes the issue of conducting trial treatment for a patient with fever is discussed (with tuberculostatic drugs if tuberculosis is suspected, with heparin if deep vein thrombophlebitis is suspected, pulmonary embolism; with antibiotics anchored in bone tissue if osteomyelitis is suspected). The appointment of glucocorticoid hormones as a trial treatment is justified in the case when the effect of their use can help in diagnosis (in case of suspected subacute thyroiditis, Still’s disease, rheumatic polymyalgia).
It is extremely important in the treatment of patients with fever to have information about possible earlier intake of medications. The reaction to taking medications in 3-5% of cases may be manifested by an increase in body temperature, and it may be the only or main clinical symptom of hypersensitivity to medications. Drug fever may not appear immediately, but after a certain period of time after taking the drug, and does not differ in any way from fevers of another genesis. If there is a suspicion of drug fever, it is necessary to cancel this drug and monitor the patient. If the fever disappears within a few days, the cause is considered to be clarified, and if the elevated body temperature persists (within 1 week after the withdrawal of the medication), the medicinal nature of the fever is not confirmed.
There are various groups of drugs that can cause drug fever:
- antimicrobials (most antibiotics: penicillins, tetracyclines, cephalosporins, nitrofurans, etc., sulfonamides);
- anti-inflammatory drugs (ibuprofen, acetylsalicylic acid);
- medicines used for gastrointestinal diseases (cimetidine, metoclopramide, laxatives, which include phenolphthalein);
- cardiovascular medications (heparin, alpha-methyldopa, hydralazine, quinidine, captopril, procainamide, hydrochlorothiazide);
- drugs acting on the central nervous system (phenobarbital, carbamazepine, haloperidol, chlorpromazine thioridazine);
- cytostatic drugs (bleomycin, procarbazine, asparaginase);
- other medications (antihistamines, iodides, allopurinol, levamizole, amphotericin B).