I. Overview
Long-term unexplained fever is a fever that lasts for more than two weeks, with a temperature of 38℃ or higher, and is not clearly diagnosed within a week of the patient’s admission after observation of the condition and multiple examinations. The fever type includes flaccid fever and irregular fever, etc. Other fever types include indolent fever, intermittent fever, undulating fever, etc., which vary according to the disease.
II. Mechanism of occurrence
Normal human body temperature is controlled by the cerebral cortex and the hypothalamus thermoregulatory center. Through neurological and humoral factors, the process of heat production and heat dissipation is regulated to keep the body temperature relatively constant. When endogenous pyrogen acts on the thermoregulatory center, the level of heat production and heat dissipation increases, but its peripheral thermoregulatory mechanisms, including skin vasoconstriction or dilation, hypersweat, muscle tension, etc., remain normal and the fever appears is called endogenous fever. When exogenous pyrogen, including bacteria and their endotoxins, viruses, fungi and other microorganisms, tumors, necrotic substances, immune reactions and other activation of the mononuclear macrophage system, the production of IL-1, TNF and other pyrogen for the hypothalamic thermoregulatory nerve cells, the release of arachidonic acid, prompt prostaglandin synthesis, resulting in exogenous fever.
Common causes
There are various clinical classifications of unexplained long-term febrile diseases, which are broadly classified into two categories: infectious and non-infectious according to the etiological category.
Infectious fever: Acute, chronic systemic and focal infections caused by various pathogenic microorganisms can cause fever, while bacterial and fungal infections are one of the most common causes of long-term fever, while tuberculosis infection of internal and external organs of the lungs is a common cause of infectious long-term fever. Other infections such as helminths, helminths, protozoa, etc., have different infection sites and degrees, and have different fever characteristics.
2. Non-infectious fever: including malignant tumors, connective tissue diseases, hematological system diseases, aseptic tissue necrosis, endocrine system diseases, central nervous system diseases, physical factors and plant nervous disorders can cause long-term fever.
IV. Accompanying symptoms
1.Prolonged fever with chills: see sepsis, infectious cholangitis, hemolytic disease, malaria, etc.
2. Long-term fever with arthralgia: mostly seen in systemic lupus erythematosus, dermatomyositis, rheumatic fever, vasculitis and other connective tissue diseases.
3. Long-term fever with rash: seen in typhoid fever, Lyme disease, systemic lupus erythematosus, dermatomyositis, rheumatic fever, adult Still disease, serum sickness, etc.
4.Prolonged fever with headache, coma or convulsions: seen in central nervous system infections, including encephalitis B, epidemic encephalomyelitis, and lupus brain, cerebral leukoencephalopathy, etc.
5. Long-term fever with cough, chest pain or shortness of breath: mostly seen in bronchitis, pneumonia, tuberculosis and other infectious diseases of the lung, but lupus lung, systemic vasculitis and other rheumatic diseases should also be considered.
6.Prolonged fever with enlarged liver, spleen and lymph nodes: seen in hematological diseases (leukemia, lymphoma, malignant histiocytosis, etc.), infectious diseases (infectious mononucleosis, brucellosis, etc.), malignant tumors and rheumatic diseases (SLE, adult Still disease, etc.).
7.Prolonged fever with hemorrhagic phenomenon: seen in sepsis, epidemic hemorrhagic fever, leptospirosis, acute leukemia, etc.
8, long-term fever with myalgia or muscle weakness: consider polymyositis, mixed connective tissue disease, rheumatic polymyalgia, hyperthyroidism myopathy, etc.
V. Differentiation points
(A) Infection-related fever
Infections are mainly tuberculosis, rheumatic fever, sepsis, infective endocarditis, etc. They are characterized by fever accompanied by chills and chills, increased white blood cell count and neutrophils, positive results of pathogenic and serological tests, and effective antibiotic treatment.
1, typhoid fever: the onset is slow, the fever rises in a trapezoidal pattern, and the high fever persists after 4-6 days, accompanied by indifferent expression, relatively slow pulse, abdominal distension, diarrhea and other symptoms. In some patients, a rose rash is seen on the skin of the chest, abdomen and back on day 7-10, and the liver and spleen may be mildly enlarged. Blood leukocytes are reduced, eosinophils are reduced or absent, blood and bone marrow cultures are positive, and fecal and urine cultures can be collected in the third week. The diagnosis can be confirmed if the titer increases during the course of the disease.
2, tuberculosis: insidious onset, slow progression, mostly afternoon low fever, night sweats, fatigue, cough, hemoptysis, chest pain, weight loss and menstrual disorders, etc. One of the main symptoms can be a prolonged fever, fever type is chills fever type or irregular type, body temperature can be high to 39 ºC or more, but also can be slightly feverish. X-rays are important for early diagnosis, determining the site, nature and extent of the lesion and deciding on a treatment plan. A positive tuberculin test is a sign of tuberculosis infection, but the diagnostic significance is relative. The detection of tuberculosis bacilli in sputum is the most reliable method to diagnose pulmonary tuberculosis. direct smear antacid staining method is commonly used, 24-hour concentrated sputum collection, fluorescence microscopy and fiberoptic bronchoscopy brushing and lavage can improve the detection rate, and biopsy at the lesion has a confirmatory value for bronchial endothelial tuberculosis. PCR-TB-DNA testing is a new way to diagnose.
3, sepsis: sepsis is a systemic symptom caused by pathogenic or conditionally pathogenic bacteria invading the blood and multiplying, and in severe cases, infectious shock and migratory lesions occur, and even multiple organ function involvement or failure, with a high mortality rate. Clinical manifestations may include chills, high fever, mostly tachyphylaxis, joint pain, rash, hepatosplenomegaly, etc. The peripheral blood leukocyte count is significantly increased and the nucleus is left shifted. Blood culture and bone marrow culture are the basis for diagnosis.
(2) Tumor-related fever: Fever in tumor patients is mostly seen in solid tumors and hematologic tumors, such as leukemia, malignant lymphoma, malignant histiocytosis, etc. The fever is usually not accompanied by chills, often accompanied by progressive wasting, anemia, and ineffective antibacterial treatment.
Malignant lymphoma: Progressive painless lymph node enlargement is the most typical, and liver and spleen are also often enlarged. 30%-50% of malignant lymphoma have persistent fever of unknown origin or periodic fever as the main symptoms, followed by weight loss, night sweats, anemia and skin itching. As the disease progresses, tissues other than lymph nodes, such as liver, spleen and bone marrow, may be involved and produce corresponding symptoms. Laboratory tests may include neutrophilia and eosinophilia of varying degrees, increased blood sedimentation and increased granulocyte alkaline phosphatase. Bone marrow aspiration may reveal typical Reed-Sternberg cells or similar cells with a single nucleus. Lymph node biopsy can confirm the diagnosis of the disease.
2. Acute leukemia: rapid onset, fatigue, malaise, fever, anemia, bleeding and bone pain. Symptoms may also be mild, but progressively worsen. There is often sternal pressure, lymph nodes, liver and spleen enlargement. There may be signs of leukemic cell infiltration in the skin, testes or other areas. Fever is one of the most common symptoms and may be caused by infection. Initially, there may be only a low fever; if the infection cannot be controlled, a high fever may develop, or it may manifest as a prolonged fever. Different types of leukemia can be distinguished according to peripheral blood film and bone marrow examination.
3. Malignant histiocytosis: Most of them have an acute onset, and high fever is often the earliest symptom. The fever pattern can be irregular fever, flaccid fever, retention fever and intermittent fever. Clinical manifestations include fever, exhaustion, wasting, anemia, hepatosplenomegaly and hemorrhagic tendency, and in a few cases, jaundice, lymph node enlargement and even impaired consciousness. Most of the peripheral blood tests show complete cytopenia, and occasionally abnormal tissue cells can be seen. Bone marrow imaging is an important basis for the diagnosis of the disease, which may show varying numbers of abnormal histiocytes. Since bone marrow involvement is not diffuse, multi-site aspiration may be performed if necessary.
(iii) Fever associated with connective tissue disease: SLE, polyarteritis nodosa, polymyositis, Wegener’s granulomatosis, adult Still’s disease, etc. The fever is characterized by a predilection for women of childbearing age, multi-system involvement, frequent presence of autoantibodies in the serum, and ineffectiveness of anti-even treatment, while non-steroidal anti-inflammatory drugs and glucocorticoids are effective.
1. SLE: Fever is a common symptom of SLE. About 80% of patients have fever during the course of the disease, mostly high fever, and the temperature can be sustained at 39`C, or intermittent fever, and a few patients have hypothermia. Fever is often self-limiting and can be rapidly reduced by glucocorticoids, but SLE patients are prone to co-infection and should be routinely checked for infection when fever develops. It is often accompanied by photosensitivity, pteroid erythema, alopecia, Raynaud’s phenomenon, dermal vasculitis, oral ulcers, polyarticular pain, superficial lymph node enlargement; important organ damage includes nephritis, pericarditis, interstitial pneumonia, central nervous involvement, hematologic abnormalities, and gastrointestinal symptoms. Laboratory tests are characterized by positive serum autoantibodies, about 95% positive anti-nuclear antibodies, anti-ds-DNA antibodies with potency related to disease activity, and anti-Sm antibodies as SLE marker antibodies; in addition, there is often increased globulin, hypoproteinemia, increased sedimentation, and decreased serum complement.
2. Polyarteritis nodosa: an inflammatory disease of unknown cause involving mainly small and medium-sized muscular arteries. The clinical manifestations are diverse, with acute or cryptic onset. It is often accompanied by fever, which can be persistent or intermittent, and the temperature can be as high as 39°C or higher, or it can be low fever. Arthralgia, myositis and muscle pain can be more prominent, manifesting as diffuse myalgia or muscle tenderness in the lower extremities, with reticular cyanosis, single or multiple neuropathy. Hypertension is present in half of the cases, with renal involvement in more than 80%. Abdominal pain and nausea and vomiting are common. Cardiac involvement manifests as pericarditis, myocarditis and rhythm disturbances, and coronary arteritis may lead to myocardial infarction.
3, adult Steele’s disease: the prominent clinical manifestation is fever, which is seen in almost all patients (98% a 100%). The initial onset of the disease is mostly unexplained fever (5% of unexplained fever). The fever is usually sudden and high, with one peak a day and occasionally two peaks. The fever is predominantly high, with the body temperature more than 39℃, usually peaking in the late afternoon or evening, and the body temperature lasts for 3-4 hours before sweating on its own without treatment and dropping to normal in the morning. Some patients start with low to moderate fever and develop high fever after 2-4 weeks. Some patients have irregular body temperature and can develop high fever at any time of the day. The fever pattern is mostly flaccid fever, but it can also be irregular fever and fever with fever. Each episode lasts from 1 week to several weeks, and a few last for several months. The fever is often accompanied by a polymorphic congested rash, arthralgia, sore throat, enlarged lymph nodes, liver and spleen, pleurisy or pericarditis, etc. The rash appears or recedes with the rise or fall of body temperature. Laboratory tests are negative for rheumatoid factor and antinuclear antibodies. Blood leukocytes are elevated, neutrophils are elevated, and acute phase reactants (CRP, ESR) and serum ferritin are significant. Lymph node biopsy shows reactive hyperplasia, and bone marrow cytology shows infected bone marrow picture.
4, rheumatic fever: generally 2-3 weeks before the onset of the disease can have a short-term history of pharyngitis, tonsillitis and other fever, 2-5 weeks after the appearance of typical clinical symptoms. Fever is generally not too high and irregular fever pattern, a few patients can see short-term high fever, but most of the long-term persistent low-grade fever, lasting about 3-4 weeks. The onset of rheumatic fever is usually rapid, with hyperhidrosis, anemia, weight loss, and wandering polyarthritis, often in large joints, with redness, swelling, and heat. Heart inflammation is another important clinical manifestation, which may include palpitations, shortness of breath, and in severe cases, heart failure. Erythema annulare and subcutaneous nodules occur mostly in children and are less common clinically, and chorea is seen only in children. Laboratory tests may include increased ESR, CRP, increased ASO, and positive pharyngeal swab culture.
5. Wegener’s granulomatosis: Systemic symptoms may include fever, malaise, weight loss, arthralgia, etc. Fever is common and is sometimes caused by bacterial infection of the sinuses. The typical triad of symptoms refers to upper respiratory, pulmonary and renal lesions. Respiratory symptoms include sinusitis, nasal septal perforation, cough, hemoptysis, dyspnea, and respiratory failure. Renal pathology presents with proteinuria, hematuria, and in severe cases, hypertension and nephrotic syndrome, eventually leading to uremia. Laboratory tests show increased sedimentation, neutrophilia, positive RF, increased serum immunoglobulins, and anti-neutrophil cytoplasmic antibodies (c-ANCA) in the serum, which are specific. Pathological biopsy showed granulomatous inflammatory changes.
6.Rheumatic polymyalgia: It is a middle-aged and old-aged lesion, which is common after 50 years old. Myalgia is mostly symmetrical, more pronounced in the proximal muscles of the upper extremities, and is often accompanied by localized pressure pain. Patients almost always have anemia and accelerated sedimentation, generally with a sedimentation rate greater than 50 mm/h, increased CRP, decreased leukocytes and platelets, occasionally positive ANA and RF, and normal complement.
7. Aortitis: It is a chronic progressive inflammation of the aorta and its branches causing stenosis or occlusion of different parts of the blood vessels, and a few patients develop arterial dilatation or aneurysm. It can be acute, with fever, myalgia, arthralgia, weight loss, etc. Some patients have an insidious onset, and symptoms do not appear until the vessels are narrowed or occluded. In the acute inflammatory phase, there is mild anemia, increased leukocytes, increased sedimentation, CRP, and elevated gammaglobulin.
8, polymyositis / dermatomyositis : is a systemic disease, patients may have morning stiffness, fatigue, loss of appetite, weight loss, fever (low to moderate fever, or even hyperthermia), joint pain, Raynaud’s phenomenon, diffuse pulmonary fibrosis, with the development of malignant tumors or other connective tissue diseases. Muscular symptoms usually involve the proximal limb girdle muscles and anterior cervical flexors of the extremities first. They present with symmetric muscle swelling, pain, tenderness, and progressive muscle weakness. Involvement of the esophagus, pharynx, larynx, and thoracic muscles may produce hoarseness, dysphagia, and even dyspnea. Mauve edema of the upper eyelids (Heliotrope’s sign) is a characteristic feature of the disease. Elevated serum muscle enzymes and elevated creatine kinase (CK) and its isoenzymes are often associated with disease activity and are helpful in the diagnosis. Some patients have positive anti-nuclear, anti-PM-1 and anti-Jo-1 antibodies. Electromyography has myogenic damage. Muscle biopsy is an important basis.
9, rheumatoid arthritis: insidious onset, before the emergence of obvious joint symptoms are weakness, general malaise, fever, poor circulation and other symptoms. Proximal interphalangeal joints, metacarpophalangeal joints, wrist joints, toes, knees, ankles, elbows and other joints are commonly involved, joint swelling, pain, pressure and stiffness, mostly symmetrical, persistent, but sometimes light and sometimes heavy. The rheumatoid subcutaneous nodules, pleurisy, interstitial pneumonia or pleural effusion, superficial lymph node enlargement and other extra-articular manifestations may appear. 70% of the patients are positive for IgM type RF, and C-reactive protein and blood sedimentation are indicators of inflammatory response, which are closely related to RA disease. C-reactive protein and blood sedimentation are indicators of inflammatory response and are closely related to RA disease. Hand X-ray is often used as an important indicator of RA disease staging.
10, serum sickness: mainly rash, fever, arthralgia, lymph node enlargement, etc. The rash is mainly urticaria-like rash, purpura-like rash or measles-like rash, which often occurs first at the injection site. The fever is more gradual, up to 38-39℃, accompanied by swelling of lymph nodes of varying degrees, soft and slightly painful. Some patients have swelling of the face, eyelids and extremities, and very few may have edema of the larynx. In some patients, fever is accompanied by abdominal pain, nausea and vomiting. About 2 days after the rash appears, there may also be joint pain and swelling, often involving multiple joints, symmetrical.
11.Erythema nodosum: It is a non-infectious inflammatory disease, mostly seen in young women, characterized by painful erythema nodosum, which is a hypersensitivity reaction of blood vessels in subcutaneous tissue. In the early stage, there are often fever, chills, peripheral discomfort and polyarticular pain.