fever of unknown origin



Overview

Definition

Unexplained fever is a group of illnesses in which the fever lasts for at least 3 weeks, the temperature exceeds 38.3°C several times, and the diagnosis cannot be confirmed after at least 1 week of intensive history taking, physical examination, and laboratory tests [1-2].

Classification

Based on the underlying etiology, unexplained fever can be classified into four main categories: classic, hospitalized, immunodeficiency, and HIV (Human Immunodeficiency Virus) related [1,3].

Classic

Fever lasting for more than 3 weeks, with temperature exceeding 38.3°C several times, and the patient has been evaluated at least 3 times in the hospital or examined in the outpatient clinic for more than 1 week without confirmation of the diagnosis.

The most common causes of classic unexplained fever are infectious diseases, autoimmune diseases, and malignant neoplastic diseases.

Hospitalized

Refers to a patient who has been hospitalized for at least 24 hours with fever without obvious signs of infection prior to admission, and the cause of the fever has not been diagnosed for at least 3 days.

It is common in conditions such as thrombophlebitis, pulmonary embolism, and drug fever.

Immunodeficiency

Immunodeficiency is defined as the presence of neutrophil deficiency (<0.5 x 109 cells/L) or other immunodeficiencies in patients with recurrent fevers that remain undiagnosed for more than 3 days.

Infections are commonly caused by pathogens with low virulence, such as Pseudomonas albicans and Aspergillus.

HIV-associated

A recurrent fever lasting 4 weeks in an outpatient with definite HIV infection, or lasting more than 3 days in a hospitalized HIV patient.

Etiology

Causes

The etiology of unexplained fever is diverse and can probably be categorized into the following three main groups [4].

Infectious factors

Infectious factors leading to unexplained fever are predominantly bacterial infectious diseases, such as tuberculosis, localized abscesses (e.g., liver abscess, pelvic abscess), and infective endocarditis [5-6].

Unexplained fever due to viral infections is second to bacterial infections, commonly such as EBV, cytomegalovirus, and human immunodeficiency virus [7-8].

Some unexplained fevers are associated with parasitic and fungal infections such as malaria and pulmonary aspergillosis [8].

Disease factors

Autoimmune diseases

Unexplained fever due to autoimmune diseases accounts for about 20% to 30% or so, commonly such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, adult Steele’s disease [9].

Hematologic diseases

Lymphoma is one of the most common hematologic diseases causing prolonged unexplained fever, which is often characterized by prolonged fever as the main and first manifestation, and some patients may have periodic fever [10].

Malignant tumors

The proportion of unexplained fever due to malignant tumors has decreased due to the development of imaging techniques such as CT and MRI [11].

Malignant tumors themselves can cause fever, such as lung cancer and renal cancer, which is related to endogenous thermogenic factors produced by the tumor cells themselves (e.g., tumor necrosis factor, interleukin-1), and absorbed heat caused by relative ischemia and hypoxia in tumor tissues [10].

Other diseases

Some patients may have adverse reactions after taking drugs, which belong to a kind of hypersensitivity reaction of the body, and drug fever can occur, common drugs such as antibiotic drugs (ceftriaxone), anti-tuberculosis drugs (rifampicin), etc [10].

Hypothalamic (mesencephalic) syndrome can also lead to prolonged unexplained fever, which may be caused by inflammation, trauma, and tumors [10].

Other factors

In addition to the above causative factors, there are still about 10% of unexplained fevers for which the cause can never be identified [1,4].

Predisposing factors

Bacterial (e.g., Mycobacterium tuberculosis), viral (e.g., EBV, human immunodeficiency virus), fungal (e.g., Aspergillus), or parasitic (e.g., Plasmodium vivax) infections may induce infection-associated unexplained fever.

Some medications (e.g., ceftriaxone, rifampicin) may also induce drug fever with unexplained fever.

Symptoms

All patients with unexplained fever have fever as the main symptom, but different causes and pathogenesis result in different clinical manifestations [1,6].

Main symptoms

Fever lasting more than 3 weeks.

Multiple temperature measurements during this period exceeded 38.3°C.

Other symptoms

Patients may present skin rashes such as macular rash, papules, butterfly-shaped erythema on the face, hepatosplenomegaly, enlarged lymph nodes, hemorrhage and other symptoms.

Some patients may have symptoms of infection such as cough, sputum, diarrhea, abdominal pain, urinary urgency, urinary pain, and also joint swelling and limb swelling and pain.

Complications

Water and electrolyte balance disorders

Prolonged unexplained fever leads to dehydration, and patients may suffer from water and electrolyte balance disorders, with symptoms such as nausea, dizziness, blurred vision, and weakness of limbs.

Convulsions of high fever

Some patients with unexplained fever may develop hyperthermic convulsions, which are usually generalized and usually last no more than 10 minutes, and they wake up soon after the attack.

Heart failure

Prolonged unexplained fever and high body temperature can lead to persistent tachycardia, which may be complicated by heart failure, resulting in dyspnea, coughing, hemoptysis, and panic.

Consultation

Department of Medicine

Department of Infectious Diseases

It is recommended to consult the Department of Infectious Diseases when symptoms such as unexplained fever, rash, cough, sputum, abdominal pain, diarrhea, and painful urination occur.

Rheumatology and Immunology

If you have unexplained fever, accompanied by symptoms such as butterfly-shaped erythema on the face, swollen and painful joints, and swollen and painful limbs, we suggest you consult the Department of Rheumatology and Immunology in a timely manner.

Emergency Department

If you have symptoms such as high or ultra-high fever (temperature >39.1℃), dizziness, blurred vision, convulsions, dyspnea, hemoptysis, or panic, we recommend you to consult the Emergency Department promptly.

Preparation

Preparation for consultation: registration, preparation of documents, common problems

Tips for the Emergency Department

It is recommended to wear loose clothing to the clinic to facilitate the physical examination.

If you have a combined rash, avoid using cosmetics before the visit to avoid masking the condition.

Record the development and characteristics of your condition for your doctor’s reference.

Preparation List

Symptom list

Particular attention should be paid to the time of onset of symptoms, special manifestations, etc.

Is there fever? What is the highest temperature? When did it start? Does the fever go away on its own?

Is there a rash such as macules, papules, or erythema of the face? When did it start?

Are there any symptoms such as enlarged liver and spleen, swollen lymph nodes, bleeding, etc.?

Are there any symptoms such as cough, sputum, diarrhea, urinary urgency, painful urination?

Are there any symptoms such as joint swelling and pain, limb swelling and pain, abdominal pain, etc.?

Are there any symptoms such as nausea, dizziness, blurred vision, weakness of limbs?

Are there any symptoms such as convulsions, dyspnea, hemoptysis, or panic?

List of medical history

Is there any history of infection by pathogenic microorganisms such as Mycobacterium tuberculosis, EBV, human immunodeficiency virus, Aspergillus, Plasmodium, etc.?

Any history of medications such as ceftriaxone, rifampicin, etc.?

Any history or family history of autoimmune diseases (e.g., systemic lupus erythematosus), hematologic diseases (e.g., lymphoma), malignant tumors (e.g., lung cancer), etc.?

Checklist

Test results of the last six months, which can be brought to the doctor’s office

Laboratory tests: blood routine, urine routine, fecal routine, blood biochemistry, calcitoninogen, C-reactive protein, autoantibody test, tumor marker test, thyroid function test, bacterial culture, etc.

Imaging examination: ultrasonography, X-ray, CT examination, MRI examination, etc.

Other tests: fiberoptic endoscopy, puncture test, biopsy, etc.

List of medications used

Medications used in the last 3 months, if available in a box or package, bring it to the doctor’s office

Non-steroidal anti-inflammatory drugs: ibuprofen, acetaminophen, etc.

Sugars, salts, and acid-base balance regulators: calcium gluconate, sodium bicarbonate, etc.

Glucocorticoids: prednisone, methylprednisolone, etc.

Anti-infective drugs: cefuroxime, acyclovir, fluconazole, etc.

Anti-tumor drugs: paclitaxel, cytarabine, etc.

Improve the condition of anti-rheumatic drugs: methotrexate, leflunomide, azathioprine and so on.

Diagnosis

Diagnostic basis

Unexplained fever has more causes, there is no clear diagnostic criteria, mainly based on the history, clinical manifestations, laboratory tests, imaging tests and other diagnostic [1-4].

Medical history

The following is not necessary for the diagnosis of the disease, but can provide some reference for the diagnosis of the disease if the following conditions are present [12].

History of previous infections with pathogenic microorganisms such as Mycobacterium tuberculosis, EBV, human immunodeficiency virus, Aspergillus, and Plasmodium.

Had taken drugs such as ceftriaxone and rifampicin.

Has a history or family history of autoimmune diseases (e.g., systemic lupus erythematosus), hematologic diseases (e.g., lymphoma), and malignant tumors (e.g., lung cancer).

Clinical manifestations

Fever lasts for more than 3 weeks, with multiple measurements of temperature exceeding 38.3℃.

Patients may present with skin rashes such as macular rash and pteronyssinus erythematosus, liver and spleen enlargement, enlarged lymph nodes, cough, sputum, abdominal pain, dysuria, arthralgia, and swelling and pain of limbs.

Some patients may have nausea, dizziness, blurred vision, convulsions, dyspnea, hemoptysis, and panic.

Laboratory Tests

Blood tests

Blood tests may be performed to determine if there are any abnormal changes in the white blood cell count or lymphocyte count.

When the white blood cell count, neutrophil, lymphocyte count and other indexes are elevated, it often suggests the existence of infection, which has a certain significance in the diagnosis and treatment of unexplained fever [1,12].

When there are abnormal elevation of lymph count, white blood cell count, etc., it is of great significance to clarify whether there is complication of lymphoma, leukemia and other hematologic diseases.

Urine routine

Urine routine is mainly used to clarify the condition of leukocyte and bacterial counts in urine, and the presence or absence of proteinuria.

If the result of urine routine suggests that the white blood cell and bacterial counts are significantly higher, it often suggests the combination of urinary tract infection, which is helpful for the diagnosis of unexplained fever and the judgment of the degree of infection.

If the urine routine shows proteinuria and hematuria, it suggests that there may be impaired renal function, which may help to diagnose the cause of the disease, etc. [9].

Stool routine

Fecal routine is mainly used to detect whether there are leukocytes, pus cells and other components in the feces, which is used to clarify whether there is a combination of gastrointestinal infections.

If the count of leukocytes and pus cells in the feces is significantly increased, the patient may have digestive system infection, which will help the doctor to diagnose the disease and guide the treatment. If the fecal occult blood test is positive, it is necessary to consider the possibility that the patient may have peptic ulcers or intestinal tumors.

Blood biochemistry

Blood biochemistry includes liver function, kidney function, etc., mainly used to determine the patient’s liver and kidney function.

If the blood creatinine and urea nitrogen are elevated, it suggests that the kidney function is impaired; if the transaminase is significantly elevated, it suggests that the liver function is impaired, which is important for assisting in the diagnosis of the disease and judging the severity of the disease.

Calcitonin

Calcitonin is a commonly used acute-phase reactive protein that can be used to determine the presence of pathogenic microbial infections.

If calcitoninogen is significantly elevated, it suggests the presence of bacterial infection; if calcitoninogen is normal or mildly elevated, it generally suggests viral infection or aseptic inflammation, which is of great significance in assisting doctors to clarify the etiology of the disease and determine the severity of the disease [13].

C-reactive protein

C-reactive protein can clarify the presence of inflammation.

If C-reactive protein is elevated, it often suggests the presence of inflammatory reaction, which is of some significance to the diagnosis of the disease.

Autoantibody test

Autoantibody tests are used to assess whether a patient has abnormal levels of autoantibodies.

If the results of autoantibodies (e.g., antinuclear antibody profile, rheumatoid factor or anti-cyclic citrullinated peptide antibodies, anti-neutrophil cytoplasmic antibodies, etc.) are positive or have abnormally elevated titers, it can assist in the diagnosis of unexplained fever and guide treatment [1,9].

Tumor markers

Tumor markers can reflect the existence and biological characteristics of tumors in the body to a certain extent, and are mainly used to determine whether the patient has a combination of neoplastic diseases [14].

If tumor markers (e.g., alpha-fetoprotein/AFP, glycoprotein/CA-199) are significantly elevated, they can play an important role in helping to clarify the etiology of unexplained fever.

Thyroid Function Test

Thyroid function tests can be used to determine whether a patient’s thyroid function is abnormal.

If there is an elevation of free thyroxine and a decrease in thyrotropin, hyperthyroidism may be present, which is important in the differential diagnosis of unexplained fever [13].

Bacterial culture

Bacterial culture of sputum, urine and feces of the patient can be used to find out the presence of infection at the respective site.

If the results of sputum bacterial culture, urine or feces bacterial culture are abnormal, it is of great significance in clarifying the etiology and treatment of unexplained fever [1-2].

Imaging

Ultrasonography

Ultrasonography is mainly used to clarify whether there are occupying lesions, or cystic pus cavities in the patient’s organs such as the liver, kidneys, spleen, ovaries, pelvis, breast and thyroid, as well as whether there is any change in the structure of the joints.

If the ultrasound of the liver shows hyper- or hypoechoic, central liquefied areas, it suggests the possibility of liver tumors; if there are manifestations such as hypoechoic masses in the renal parenchyma, there may be the possibility of renal tumors, which may assist in clarifying the diagnosis of unexplained fever and guiding treatment [6].

If ultrasound shows fluid in the joint cavity, abnormal thickness and morphology of articular cartilage, it is of auxiliary significance in the diagnosis and differentiation of unexplained fever.

X-ray examination

X-ray examination is often used to initially assess whether the patient has lung infection or neoplastic disease, as well as limb bone and joint peripheral tissue infection.

If the X-ray examination shows patchy or streak shadow in the lungs, it suggests the possibility of lung infection; if there is partial or complete obstruction of bronchial lumen and lobar atelectasis, it suggests the possibility of lung tumor disease, which is of certain significance in the diagnosis of the disease and assessment of the condition.

CT examination

CT examination can be used to clarify whether the patient has lung infection or neoplastic disease.

When CT examination suggests the presence of large patchy shadows and striated shadows in the lungs, it suggests the possibility of lung infection; if there are manifestations such as partial or complete obstruction of the tracheal lumen, vacuolar sign, cluster sign, etc., it has an important guiding role in the diagnosis and differentiation of unexplained fever [15].

MRI examination

MRI examination can be used to clarify the presence of lesions in the central nervous system, bone marrow, muscles and other parts of the body.

If the patient’s central nervous system, bone marrow, muscles and other obvious occupation, hemorrhage, edema and other manifestations, suggesting the existence of the corresponding parts of the possibility of neoplastic disease, can help clarify the diagnosis of unexplained fever.

Other examinations

Fiberoptic endoscopy

Fiberoptic endoscopy is mainly used for the examination of the digestive tract, trachea and bronchus, urinary tract, uterine cavity and other internal body cavities, as well as obtaining the suspected diseased tissues in the corresponding parts.

For example, if the fiberoptic endoscopy examination reveals the occupancy of the lungs, stomach and intestines, it suggests the possible existence of neoplastic diseases in the lungs, stomach and intestines, and plays an important role in the diagnosis of the cause of the disease, differential diagnosis and treatment.

Puncture examination

Including body cavity fluid (e.g., peritoneal fluid, pericardial fluid) puncture examination, bone marrow puncture examination, and so on.

If tumor cells appear in abdominal fluid, it suggests the presence of malignant tumors in abdominal organs; if pericardial fluid is bloody, it is usually pericardial metastatic cancer, which can assist in definitive diagnosis and guide treatment.

Biopsy

Biopsy, including biopsy of lymph nodes or other lesions, is mainly used to clarify the diagnosis of patients with unexplained fever.

For example, the biopsy of lymph nodes shows the destruction of lymph node structure and the presence of R-S cells and mutated cells, which is important for the diagnosis and guidance of the cause of unexplained fever.

Differential diagnosis

Urticaria

Similarities: Both may present with rash, fever, abdominal pain, diarrhea, and dyspnea.

Differences: patients with urticaria usually have a clear history of exposure to allergenic substances before the onset of urticaria, fever can be relieved when the skin symptoms subside, and the rash is often characterized by an indeterminate number of wind bumps, accompanied by obvious itching. Laboratory tests show markedly elevated immunoglobulin E, usually without elevated white blood cell counts, and imaging studies usually show no abnormal changes in the lungs or abdominal organs [16].

Kidney stones

Similarities: Both may present with abdominal pain, urgency, dysuria, nausea, and dizziness.

Differences: Patients with kidney stones often have pain in the lumbar region or spinal ribcage, etc. The pain is severe and intolerable, and symptoms such as nausea, vomiting, and dizziness are often present during an attack. Laboratory tests usually show microscopic hematuria, and urine bacterial culture is usually negative. Calcitoninogen is usually not elevated in patients with uninfected kidney stones. Ultrasound and abdominal X-rays usually show significant kidney stones.

Treatment

Aim of treatment: Relieve the patient’s uncomfortable symptoms, clarify the cause of the disease in time, and carry out targeted treatment.

Treatment principle: The treatment of unexplained fever needs to be individualized. General treatment is mainly used to relieve fever and other symptoms, and should take non-steroidal anti-inflammatory drugs, glucocorticosteroids, anti-infective drugs, anti-tumor drugs and other medications, as well as radiotherapy, surgery and other treatments according to the cause of the disease.

General treatment

For patients with high fever whose body temperature exceeds 39.1℃, or those whose fever lasts too long, antipyretic treatment can be carried out through physical cooling, such as ice packs, warm water baths, ice caps, etc., to alleviate the discomfort of the patient so as to avoid causing serious complications.

Medication

Non-steroidal anti-inflammatory drugs

Common medications include ibuprofen and acetaminophen.

NSAIDs play the role of antipyretic and anti-inflammatory by inhibiting the enzyme cyclooxygenase, and can be used for antipyretic treatment of patients with unexplained fever.

Adverse effects of this class of drugs include gastrointestinal reactions such as nausea, vomiting, and gastrointestinal bleeding, skin reactions such as rash and photosensitization, and hepatic and renal impairment [17].

Sugars, salts and acid-base balance regulators

Common drugs such as calcium gluconate, sodium bicarbonate, etc.

They can regulate water and electrolyte balance disorders in febrile patients.

Intravenous administration too quickly or in large doses may lead to adverse reactions such as vomiting, nausea, and cardiac arrhythmias.

Glucocorticoids

Commonly used drugs such as prednisone and methylprednisolone.

They have powerful anti-inflammatory and immunosuppressive effects and are suitable for the treatment of patients with unexplained fever due to autoimmune diseases.

Patients with long-term application of glucocorticosteroids may experience side effects such as infection, osteoporosis, drug-induced diabetes mellitus, and in severe cases, aseptic necrosis of the femoral head [6,17].

Anti-infective drugs

Commonly used drugs such as cefuroxime, acyclovir, fluconazole.

They are commonly used in the treatment of patients with unexplained fever due to bacterial, viral, fungal and other infections.

Cefuroxime and other cephalosporin antibiotics, adverse reactions include rash, mild abnormalities in liver function, decreased hemoglobin, etc. A small number of patients may experience serious adverse reactions such as toxic epidermal exfoliative necrosis.

Nucleoside analog antiviral drugs such as acyclovir, which is a broad-spectrum antiviral drug, can have common adverse reactions such as nausea, vomiting, diarrhea, etc., and a small number of patients can have drowsiness, delirium, tremor, etc., which can mostly be relieved after stopping the drug [17].

Fluconazole and other antifungal drugs can appear nausea, vomiting, abdominal pain, skin rash, transient liver function abnormalities, headache and other adverse reactions.

Anti-tumor drugs

Commonly used drugs such as paclitaxel and cytarabine.

By affecting protein synthesis, interfering with mitosis, nucleic acid synthesis and other effects, killing or inhibiting the growth of tumor cells and play an anti-tumor effect.

This kind of drugs can appear allergic reaction, bone marrow inhibition, neurotoxicity (such as limb numbness, sensory abnormalities) and other adverse reactions.

Anti-rheumatic drugs to improve the condition

Commonly used drugs such as methotrexate, leflunomide, azathioprine and so on.

By inhibiting intracellular dihydrofolate reductase, they play the role of improving and delaying the progress of the disease, and are suitable for the treatment of autoimmune diseases such as systemic lupus erythematosus.

Common adverse effects of this class of drugs include diarrhea, nausea, ulcerative stomatitis, dermatitis, alopecia, liver damage and interstitial inflammation of the lungs, etc., and it should be used with caution in patients with hepatic and renal insufficiency [17].

Radiotherapy

Radiotherapy includes radical radiotherapy, palliative radiotherapy, adjuvant radiotherapy and other forms of radiotherapy, which can eliminate or eradicate the primary foci and metastatic foci of tumors, inhibit tumor flare-ups, delay tumor proliferation, and thus relieve symptoms.

It is mainly applied to the treatment of unexplained fever caused by lung cancer, kidney cancer and other malignant tumors [11].

Surgical treatment

For unexplained fever caused by malignant tumors, some patients can be treated by surgical resection and other means, which can delay the progression of the disease and improve the fever symptoms.

In patients with autoimmune diseases such as rheumatoid arthritis, when joint deformities and functional limitations occur, surgical treatment can be used to correct the deformities and improve joint function [6].

Prognosis

Cure

The etiology of unexplained fever is diverse, and the clinical manifestations are also different, so the prognosis varies greatly between different diseases.

Most unexplained fever caused by infectious diseases, drug fever, etc. can be effectively controlled through treatment targeting the cause and other treatments, and most patients will not recur.

Most autoimmune diseases, blood diseases, malignant tumors, etc., patients often need to take long-term medication, and some of the diseases (e.g., systemic lupus erythematosus with renal involvement, metastatic lung cancer, etc.) are more aggressive, which seriously affects the quality of life of patients.

Prognostic factors

The prognosis of unexplained fever is influenced by a number of factors, and the following factors may lead to a poor prognosis.

Recurrent respiratory and gastrointestinal infections.

Combination of severe water and electrolyte balance disorders, or complications such as heart failure.

Lack of timely and standardized symptomatic and causative treatment.

Daily

Daily management

Dietary management

Daily diet should emphasize balanced nutrition, drink more water, consume more high quality protein such as eggs, milk, etc., and vitamin-rich foods such as carrots and animal liver.

Avoid eating raw and cold food to avoid digestive tract infection; avoid drinking alcoholic beverages and wine; avoid eating spicy food such as chili peppers and mace.

Patients with autoimmune diseases can appropriately reduce the consumption of photosensitive foods such as cilantro and lemon.

Life management

Pay attention to personal hygiene, clean and disinfect the living environment regularly, open windows more often for ventilation, and actively prevent infection.

Patients with autoimmune diseases should pay attention to sun protection when going out and wear sun hats, sun-protective clothing or umbrellas, etc., so as not to let the light affect their condition.

Patients with unexplained fever are not recommended to do strenuous exercise, so as not to aggravate the condition by sweating a lot, exertion, etc. Patients with high fever need to rest in bed.

Psychological support

The course of unexplained fever is usually long and easy to recur, patients may have anxiety, depression and other negative emotions.

In case of emotional instability and psychological depression, relatives and friends can increase the company and provide psychological intervention if necessary.

Disease monitoring

Monitor and record body temperature daily.

Observe whether there is any infection, such as cough, sputum, diarrhea, abdominal pain, painful urination.

Observe whether there is any change in the degree of illness, such as increase in cough and bowel movement, change in the extent of rash, change in heart rate and consciousness, etc. If there is any blurring of consciousness and markedly accelerated heart rate, it is necessary to consult a doctor promptly.

If there are intolerable adverse drug reactions (e.g. nausea, diarrhea, skin rash, numbness of limbs, etc.), timely follow-up is required.

Follow-up

Since the duration of unexplained fever is long and the disease is easily recurring, regular checkups can help relieve the symptoms, identify the cause of the disease, and provide timely and targeted treatment.

Regular checkups should be conducted according to the doctor’s instructions, and the cycle of checkups is usually one to two months.

Tests that may be needed during the review include routine blood test, routine urine test, blood biochemistry, calcitoninogen, X-ray examination or CT examination, and so on.

Prevention

The causes of unexplained fever are complex and varied, and it is generally difficult to prevent them effectively. However, you can help reduce the risk of developing the disease by, for example, following a healthy lifestyle or behavior.

Pay strict attention to personal hygiene and promote frequent hand washing.

Adjust dietary habits, consume more fresh vegetables and fruits, and high quality protein such as milk and meat.

Maintain a regular routine and avoid staying up late. Engage in regular and moderate physical exercise, such as jogging and swimming.

Avoid taking medications that may induce unexplained fever, such as ceftriaxone and rifampicin.

Undergo regular medical checkups and seek prompt medical attention if there are any uncomfortable symptoms.