Fever is a very common clinical symptom, and we encounter patients with fever almost every day in internal medicine and infection medicine. Its etiology is numerous and involves various clinical departments. Despite the advanced diagnostic techniques of modern medicine, the differential diagnosis of fever of unknown origin (FUO) is a very difficult problem for clinical workers. Fever is a very complex clinical phenomenon, and it is far from being possible to solve all problems in one discussion.
The average normal body temperature of a healthy person is 37,0°C, with a fluctuating range of 36,2 to 37,2°C. It is lowest at 6:00 am and highest from 4 to 6:00 pm. Generally, a fever is considered to be when the oral temperature is higher than 37,3℃, the anal temperature is higher than 37,6℃, or when the body temperature changes by more than 1,2℃ in a day.
Mechanism of fever
It has been confirmed that the body’s thermoregulatory center is in the hypothalamus. The anterior hypothalamus and the preoptic area are densely populated with thermoreceptors and a few cold receptors, and both thermogenic and thermal responses can be induced by stimulating this area (the anterior hypothalamus is not a thermal center); the posterior hypothalamus is probably the site where neural “intelligence” is integrated and processed (not a thermogenic center).
The body’s thermoregulatory center regulates both thermogenesis and heat dissipation through neural and humoral factors to maintain the dynamic balance of body temperature. The main sites of heat production are the skeletal muscles and the liver during quiet time, and even more so during exercise or illness with fever; the main site of heat dissipation is the skin, where about 90% of heat is lost through radiation, conduction, convection and evaporation. If these areas are dysfunctional due to various factors, fever can result. For example, hyperthyroidism, strenuous exercise, convulsions or persistent epilepsy can lead to excessive heat production, while extensive skin lesions and congestive heart failure can lead to impaired heat dissipation. In addition to these conditions, most fevers in humans may be related to the action of thermogenic agents on the thermoregulatory center. Pyrogen is a general term for a group of substances that can cause abnormal increases in body temperature in animals with a constant temperature, and can cause fever in small amounts. Exogenous pyrogens (e.g. viruses, mycoplasma, chlamydia, rickettsia, spirochetes, bacteria and their toxins, fungi, protozoa, antigen-antibody complexes, pyrogenic steroids (e.g. urinary testosterone), uric acid crystals, etc.) are mostly unable to cross the blood-brain barrier and mainly pass through host cells (mainly macromonocytes and macrophages) The so-called endogenous pyrogens (e.g. IL-1, IL-6, IFN-α, IFN-β, TNF, etc.) produced by the host cells (mainly macromonocytes and macrophages) act on the thermoregulatory centers and cause fever. However, there are exceptions: LPS can act directly on the hypothalamus as well as prompt the host cells to synthesize various endogenous pyrogens. Thus, the etiology of fever is very complex and diverse. The purpose of fever is to increase the inflammatory response, inhibit bacterial growth, and create a pathophysiological environment that is not conducive to the development of infection or other disease. Fever can be one of the common manifestations of many classes of clinical disease and is a common challenge in the diagnosis of infectious diseases.
The causes of unexplained fever are clinically classified into 4 categories from a diagnostic point of view: namely, infections, malignant diseases, connective tissue diseases and inflammatory vascular diseases and other diseases.
Causes of infection in FUO
Fever within 2 weeks is called acute fever, acute fever patients with short fever duration, mostly accompanied by obvious concomitant symptoms, etiology diagnosis is generally not difficult. Fever of unknown origin (FUO) is a group of diseases that persist for more than 3 weeks, with body temperature exceeding 38,3℃ several times, and cannot be diagnosed after at least 1 week of intensive examination. This is an important group of diseases that have become a challenging problem in medical practice because of their complex etiology and often lack of characteristic clinical manifestations and laboratory findings.
(i) Bacterially induced (limited) inflammation
1, abscess 2, diverticulitis 3, endocarditis 4, biliary tract infection 5, implant infection 6, infected aortic aneurysm 7, duct infection 8, osteomyelitis 9, genitourinary infection 10, dental and ear, nose and throat infections.
(ii) Other (systemic) bacterial infections 1, spirochetal disease 2, brucellosis 3, cat-scratch disease 4, nosocomial 5, Whipple’s disease 6, mycobacteriosis 7, tuberculosis 8, atypical mycobacteriosis 9, parrot fever 10, Q fever 11, salmonellosis 12, Yersinia pestis
(C) viral infections 1, EBV infection 2, HIV infection 3, cytomegalovirus infection.
(D) fungal infections 1, Aspergillosis 2, candidiasis 3, histoplasmosis 4, cryptococcosis 5, Pneumocystis carinii infection.
(E) parasitic infections 1, amebiasis 2, malaria 3, toxoplasmosis 4, visceral leishmaniasis (black fever).
II. Etiology of malignant diseases in FUO
(A) Hematologic tumors 1, lymphoma 2, leukemia 3, myelodysplastic syndrome.
(B) Solid tumors 1, lung cancer 2, liver cancer 3, colon cancer 4, renal cell carcinoma 5, pleural mesothelioma.
(C) Connective tissue and inflammatory vascular diseases
1, Felty (Felty syndrome) 2, hypersensitivity vasculitis 3, ankylosing spondylitis 4, leukoarthrosis 5, polyarteritis nodosa 6, recurrent polychondritis 7, giant cell vasculitis/rheumatic polymyalgia 8, dermatomyositis 9, Schnitzler’s syndrome (pityriasis-vascular inflammation) 10, systemic lupus erythematosus 11, adult systemic Still’s disease 12, Takayasu vasculitis 13, Wegener’s granulomatosis.
IV. Other causes in FUO
1, Angioimmunoblastoma lymphadenopathy 2, Drug fever 3, Castleman syndrome 4, Lymph node inflammatory pseudotumor 5, Exogenous allergic alveolitis (hypersensitivity pneumonia) 6, Familial Mediterranean fever 7, Hyper IgD syndrome 8, Idiopathic granulomatosis (including granulomatous hepatitis) 9, Crohn’s disease 10, Necrotizing lymphadenitis 11, Occult hematoma 12, Mesenteric lipofuscinosis13, retroperitoneal fibrosis14, recurrent pulmonary embolism15, nodular disease16, subacute thyroiditis17, vegetative hyperthermia8, pseudofever, self-induced fever19, atrial mucinous neoplasm20, periodic neutropenia can be one of the common manifestations of many classes of diseases in clinical practice and a common dilemma in the diagnosis of infectious diseases.
I. Diagnostic procedures for fever of unknown origin.
1, careful history taking 2, detailed and repeated physical examination 3, confirmation of fever and fever pattern 4, discontinuation of unnecessary substances
5, the basic items of diagnostic examination (laboratory, instrumentation) 6, purposeful additional examination 7, observation of changes in the condition.
Second, the overall differential diagnosis of fever of unknown origin should grasp the two main points: among the above-mentioned causes of fever, three are more common: infection, tumor and connective tissue disease, of which infectious diseases account for about 1/3, or even up to 60% or more, but nearly 10% of patients ultimately cannot be clearly identified as the cause. Overall, for patients with fever of unknown origin, the following two points should be noted in the consideration of their diagnosis.
1, even in difficult patients, non-characteristic manifestations of common diseases are still more common than rare diseases to pay attention to grasp the non-characteristic manifestations of some common diseases. For example, a patient with endocarditis can have no heart murmur, a patient with liver abscess can have no hepatic swelling, a patient with biliary tract infection may have no jaundice, Murphy’s sign can be negative, etc. For example, Shen XX, male, 26 years old, from Jiangxi, was a student at a university in Shanghai. In 1993, he had a sudden onset of hyperthermia with a temperature of 39-40℃ on his way back to Shanghai after winter vacation, and he came to our emergency room 2 days later with abnormal personality and behavior and delirium. There was no headache, abdominal pain, diarrhea, nausea, vomiting, no cough, sputum, and no urination for more than 10 hours. Examination: T39, 8℃, delirium, irrelevant answers, uncooperative examination, hysterical manifestations, no rash all over the body, deep pressure pain in the middle and upper abdomen, no muscle guarding and rebound pain, bladder fullness, no special positive signs found. Blood picture WBC 6,8×109/L, N0,80. what disease is considered? After admission WBC decreased to 2, 8×109/L, N0, 62, E0/L. Blood and urine amylase were elevated, Fertilizer reaction O1:160, A1:320, bone marrow culture was Salmonella paratyphi A. Confirmation of diagnosis: A paratyphoid fever, with pancreatitis.
2, to pay attention to the discovery of “localization” clues, according to which the initial classification of suspicious diagnosis.
For new patients, the first thing we are eager to understand is where the patient’s lesions are located. Both infectious and non-infectious diseases often have their common sites of involvement, i.e., characteristic “localization” manifestations (e.g., headache, abdominal pain, jaundice, rash, enlarged liver, spleen or lymph nodes, and respiratory and gastrointestinal symptoms), which can help determine whether the lesion is localized (e.g., pulmonary, hepatic, biliary, intra-abdominal or intracranial) focal infections or solid tumors, etc.) or systemic lesions (e.g. sepsis, hematologic disorders, connective tissue diseases or endocrine system diseases, etc.), and to make a preliminary classification of the suspected diagnosis, which can speed up the process of diagnosis. For example, we have treated many patients with infective endocarditis who were unable to make a clear diagnosis for a long time before admission, and then found a significant heart murmur on admission, and the diagnosis was basically clear within half an hour. (The source of this information is the lecture by Associate Professor Ni Wu of the Department of Infection of Changzheng Hospital)
Diagnostic steps of fever
First step of history taking and physical examination I. Principles to be grasped in history taking and physical examination 1. When asking about a symptom or examining a part of the patient’s body, we should know: “What do I hope to find? What clues might be there that will help me clarify the diagnosis?” For example, there is a febrile patient with recurrent transient chills and chills followed by hyperthermia. Initial impression: bacteremia and possible local foci of infection. Therefore, during physical examination, we should focus on finding “localized” signs that suggest the presence of infection foci (such as gum redness, pus overflow, skin boils; heart murmur, lung breath sound changes and rales, abdominal pressure pain, etc.) 2. When a patient’s diagnosis is not clear, we must repeat the history, repeat the physical examination, and even repeat some important laboratory tests. New findings can often add important differential diagnostic information that has not been obtained before. This is based on two main reasons: (1) the history and examination at the beginning of the admission are sometimes inevitably missed This may be caused by two factors: on the one hand, the doctor may forget to ask questions, and on the other hand, the patient may consider some clues less important or forgotten, or even have something to hide. For example, some unmarried women may intentionally conceal their sexual history, which may cause difficulties in differentiating appendicitis from ectopic pregnancy. (2) The development of the disease has its own time pattern, and some signs and symptoms are gradually revealed.
The specific steps of physical examination
(1) The onset of disease is generally more rapid in infectious diseases, especially bacterial and viral infections (except typhoid and tuberculosis), while the onset of non-infectious diseases is relatively slow. However, the rapidity of onset is not an important basis for differential diagnosis. For example, among the non-infectious diseases, malignant group, lymphoma, phagocytic syndrome and other hematologic diseases can manifest as an acute onset and a dangerous condition. (ii) Fever type Many diseases often have their special fever type of fever: often persisting at about 40°C, with a 1-day temperature difference <1°C. Common in typhoid fever, typhus, lobar pneumonia, etc.; flaccid fever: also often high fever, 1 day temperature difference of 1 to 2 ℃ or more. Common in rheumatic fever, sepsis, septicemia, liver abscess, severe tuberculosis, etc.; intermittent fever: 1 day temperature difference is large, fluctuating between normal and high fever, showing a recurrent process. Commonly seen in malaria, pyelonephritis, lymphoma, brucellosis, etc.; undulating fever: seen in brucellosis; wasting fever: greater fluctuation in fever, between 4 and 5°C, from hyperthermia down to below normal. Commonly seen in sepsis; saddle fever: seen in dengue fever; regressive fever: sudden rise in body temperature to more than 39℃, lasting for several days and then suddenly dropping to normal, with the hyperthermic and antifebrile periods lasting several days each. It is common in regression fever, Hodgkin's disease, etc.; Irregular fever: It is common in rheumatic fever, infective endocarditis, influenza, amebic liver abscess, tuberculosis, malignancy, etc. According to statistics, although the fever type is helpful for disease diagnosis, due to the existence of individualized differences and the application of antibacterial drugs, antipyretic and analgesic drugs or glucocorticoids, the level, fever type and interval of fever are irrelevant to the diagnosis in most cases. In typhoid fever, for example, there are few cases of so-called "rising temperature steps, high fever retention, and slow decline", and most of them show flaccid fever or irregular fever, especially those who apply antibiotics early, which have a greater impact on the fever pattern.
Therefore, we should understand that: ① dynamic observation of the change of fever pattern may be more helpful for diagnosis. ②There are often important diagnostic clues hidden in the temperature list and medical order record sheet ③Emphasis: Do not abuse antipyretic drugs (c) Fever and fever duration 1. Acute fever: The natural fever duration is within 2 weeks. The vast majority are infectious fever, virus is the main pathogen, non-infected only a minority. 2, long-term low-grade fever (chronic microfever): refers to the body temperature in 37,5 ℃ ~ 38,4, lasting more than 4 weeks. Its common causes are as follows: tuberculosis, post-streptococcal infection state, chronic urinary tract infection, chronic focal infection (dental infectious peri-abscess, sinusitis, biliary tract infection, prostatitis, chronic pelvic inflammatory disease, etc.), chronic viral hepatitis, CMV infection, syphilis and other non-infectious hyperthyroidism, connective tissue disease, cirrhosis, peptic ulcer, enteritis of unknown cause, hematological disease, malignancy, mesencephalic syndrome, primary If a person with prolonged hypothermia such as premenstrual hypothermia, pregnancy hypothermia, summer microthermia, neurological microthermia, post-infection hypothermia, etc. is accompanied by increased blood sedimentation, it cannot be explained by functional disease and should be considered as tuberculosis, tumor or connective tissue disease.
(D) Accompanying symptoms and signs
1.Chills
Chills are most common in certain bacterial infections and malaria, and are one of the most common signs used to diagnose these diseases. Blood cultures drawn during chills and chills often have a high positive rate. Chills are rare in tuberculosis, typhoid fever, rickettsial disease and viral infections, and are generally not seen in rheumatic fever.
In addition, chills caused by infectious diseases should be distinguished from infusion reactions: the latter begins soon after infusion, without a history of recurrent episodes before infusion, and its shivering is more intense, without obvious signs of systemic toxemia such as malaise, nausea, depression; after stopping rehydration and giving glucocorticoids and other treatments, chills can be terminated within 10 to 15 minutes.
2.Facial appearance
Attention should be paid to the characteristic facial features of some diseases: such as typhoid face, drunken appearance (renal syndrome hemorrhagic fever), butterfly-shaped erythema (systemic lupus erythematosus), pallor around the mouth.
(scarlet fever), etc. Further, herpes of the mouth and lips can be seen in lobar pneumonia, intermittent malaria, epidemic meningitis, etc., while it is generally not seen in lobar pneumonia, caseous pneumonia, falciparum malaria and tuberculous meningitis, which can be helpful in diagnosis.
3, rash many diseases that can cause fever have their characteristic rash, such as typhoid fever rose rash, measles barbwire, renal syndrome hemorrhagic fever scratch-like bleeding spots and so on, these common more typical rash has been familiar to everyone, here do not repeat. The rashes that are rare or easily missed during physical examination can often play an important role in the diagnosis of some difficult cases if they are detected in time. The characteristic rash of certain febrile diseases.
4. Generalized lymph node enlargement can be seen in certain systemic infections, such as infectious mononucleosis, tuberculosis, rabbit fever, toxoplasmosis, HIV infection, as well as leukemia, malignant lymphoma, connective tissue disease, etc., while restricted lymph node enlargement is commonly seen in restricted infections, as well as in malignant lymphoma and metastasis of malignant tumors. Therefore, especially when patients have localized lymph node enlargement, attention should be paid to check whether there are lesions near the drainage area. For example, Tsutsugamushi disease often presents with localized lymph node swelling and pain in the drainage area of crusted ulcers. Swollen lymph nodes with pressure and spontaneous pain are usually inflammatory (including aseptic inflammation, such as hemorrhagic necrotizing lymphadenitis), but malignant lymphoma or metastatic cancer may also have spontaneous pain or pressure when they enlarge too rapidly. It should be noted that more typical patients with malignant lymphoma may have generalized lymph node enlargement with periodic fever, but 16%-30% of patients have fever as the first symptom, and about 70% have enlarged lymph nodes in the neck. Moreover, the degree of superficial lymph node enlargement is not necessarily proportional to the level of fever. (In one case earlier this year, there was only a soy-sized lymph node in the neck, which was slightly hard. The biopsy report was lymphoma)
5. Other concomitant symptoms and signs such as respiratory symptoms, neurological symptoms, cardiovascular system symptoms, bleeding symptoms and jaundice, hepatosplenomegaly and other manifestations have important reference value for diagnosis. The corresponding diagnosis can be made according to their different characteristics. For patients with fever suspected of connective tissue disease, special attention should be paid to understanding the manifestations of their skin, joints, muscles and other parts.
Diagnostic steps of fever
Step 2 – Targeted ancillary examinations and laboratory tests
About 25% of the cases of fever of unknown origin can be clearly diagnosed by non-invasive laboratory tests, but nearly half of them need to be clarified by invasive tests such as various types of biopsies or surgical explorations. These tests are numerous and should be used as targeted as possible under the premise of preliminary determination of diagnostic direction to avoid wasteful examination items routine tests: blood, urine, fecal routine, chest X-ray, ultrasound, blood sedimentation, etc. Infectious diseases:pathogen culture of blood, middle urine, feces, bone marrow and sputum; condensation set test, heterophilic agglutination reaction, fertilizer reaction, exophthalmia test, tuberculin test, etc.; neutrophil alkaline phosphatase score, C-reactive protein; pharyngeal swab, sputum, urine and fecal smear for fungus; sputum and fecal smear for parasitic eggs; imaging examination of infectious foci and other connective tissue diseases:autoantibodies, rheumatoid factor, lupus cells, etc.; protein electrophoresis, immunoglobulin quantification; skin muscle or kidney tissue biopsy; electromyography and other malignant tumors: CT, MRI, isotope scan and other imaging examinations; endoscopy such as bronchoscopy, gastroscopy, enteroscopy; bone marrow, lymph nodes and corresponding tissue puncture biopsy or surgical exploration; Ben – week protein, etc. The following points should be noted when using the above examination methods: 1. The changes in eosinophil count should be noted during blood tests. fever with mild increase in eosinophils can be seen in scarlet fever, Hodgkin’s disease, polyarteritis nodosa and drug fever, etc., while a significant increase is common in parasitic or allergic diseases, and eosinophil deficiency is strong evidence of typhoid or paratyphoid fever. 2. Liver disease or anemia can cause an increase in blood sedimentation, the diagnosis of the suggestive is not strong. However, the blood sedimentation in the early stages of typhoid fever is usually not accelerated, which helps to differentiate it from sepsis. The speed of blood sedimentation is also a common indicator to determine whether tuberculosis is active.
C-reactive protein (CRP) is a non-specific acute phase protein that is elevated to varying degrees in a variety of diseases, but is most characteristic of bacterial infections and tissue damage. It is useful in identifying bacterial and viral infections. Bacterial infections often have varying degrees of CRP elevation, while viral infections have CRP levels below normal, with good stability compared to peripheral blood and blood sedimentation.
4, sometimes bone marrow aspiration should be multi-site, multiple reviews can cause fever in many hematologic diseases, such as lymphoma, malignant group, phagocytic syndrome, etc., in the early stage of the disease process is often only local bone marrow invasion, based on a single site, a bone aspiration results, often lead to missed diagnosis. For example, in such diseases we see, more than 2 to 3 bone punctures are often required to make a definitive diagnosis. There was a case of a 14-year-old with long-term intermittent fever who had 12 bone punctures in the course of nearly 1 year, and the last one was done in the sternal stalk before the diagnosis of malignant group was confirmed.
5, blood culture specimen collection requirements febrile patients, should be as far as possible before the application of antibiotic therapy, in the chills, chills in the period of multiple blood collection for aerobic and anaerobic bacteria culture, when the positive rate is higher (the volume of blood collection should be more than 8ml). For patients who have already received antimicrobial therapy, blood culture or blood clot culture can be taken 48 to 72 hours after drug withdrawal if necessary, which can increase the positive rate. In cases of suspected infective endocarditis, arterial blood culture can increase the detection rate.
Diagnostic steps for fever
Step 3 Diagnostic treatment If the patient is still unable to find the cause of fever after various tests, or if the relevant tests cannot be performed due to conditions, appropriate treatment can be given according to the highly suspected disease if necessary. However, the suspected disease should not be confirmed or excluded solely on the basis of treatment results. In particular, the use of glucocorticoids for so-called diagnostic treatment in febrile patients without clear indications should be avoided unprincipled or without strict observation. In terms of diagnostic value, a negative response to a potent treatment generally has a greater significance than a positive one. If the fever is not effective after regular treatment with chloroquine, malaria is very unlikely; in patients with proposed tuberculosis who do not regress or whose fever pattern does not change after 2-3 weeks of treatment with rifampin and isoniazid, tuberculosis is less likely. In the diagnostic treatment of febrile patients, the most commonly used drugs are antibacterial drugs. When choosing antimicrobial drugs for diagnostic treatment, we should try to use drugs that are effective against the suspected causative organism and consider the possibility of anaerobic bacterial infection. Examples of commonly used potent antibacterial drugs: Staphylococcus aureus, Staphylococcus epidermidis and other G + cocci – vancomycin; Pseudomonas aeruginosa – amikacin, ceftazidime, imipramine (Tylenol); mycoplasma, chlamydia, etc. – erythromycin, azithromycin, etc. -Erythromycin, Azithromycin, etc.; Tularensis (rabbit fever) – Streptomycin, Gentamycin.
Diagnostic ideas of FUO in the elderly
I. Special features of FUO in the elderly: 1. The disease causing the fever is often heavy, with the possibility of serious complications. 2. The symptoms are atypical, often lacking symptoms of the diseased organ in addition to fever. 3. The body temperature is not high and “hypothermia” is common. 4. The presence of underlying diseases can easily conceal the direct cause of fever. 6. The frequent use of drugs can affect the clinical manifestations of the disease or the appearance of drug fever.
2. Notes on the diagnosis of fever in the elderly: 1. The elderly have more hypothermia, so pay attention to the repeated measurement of body temperature, and it is better to measure the anal temperature more accurately. 2. The elderly often cannot accurately describe the occurrence of the disease and the symptoms at that time, so in addition to asking the patient himself, also pay attention to the patient’s relatives or his close people to understand the condition. The patient’s physical examination should pay attention to possible pathogens invading the portal. For example, endocarditis is more common in the elderly, and changes in heart murmurs may occur should be noted with repeated cardiac auscultation. Giant cellulitis is common and temporal artery biopsy is important.4. In terms of ancillary tests: around the possible causes of fever, non-invasive tests such as ultrasound, CT, MRI, and nuclear scan should be considered first. Try to avoid doing big invasive examinations.
Third, common causes of fever in the elderly are infectious diseases most common: among them endocarditis, abscess, tuberculosis are the most common. Next are tumors: malignant lymphoma is the most common, followed by solid tumors. Again, connective tissue and inflammatory vascular diseases: among such diseases, giant cell arteritis and nodular arteritis are most common.
From the above common causes of fever in the elderly, the causes of FUO in the elderly are different from those in young people. Among the causes of FUO in young people, connective tissue and inflammatory vascular disease are more common than in the elderly. In contrast, malignant neoplasms are more common in the elderly. Infections are the most common cause of fever in both the elderly and the young; however, the spectrum of infectious diseases is not as exhaustive as the diagnostic ideas of drug fever:The diagnosis of drug fever is an exclusive diagnosis. For each patient with unexplained fever that occurs during drug treatment, the possibility of drug fever should be considered.1. Systematic questioning of medication history: First of all, each drug used should be clarified, and the diagnosis of drug fever should not be abandoned as long as there is a temporal association between fever and drug use. For example, no fever before the use of a certain drug, but only after the use of a certain drug began to appear fever, can provide an important basis for diagnosis. 2, exclusion method to discontinue drugs that may cause fever: in the simultaneous use of multiple drugs, in order to identify the drugs that cause fever, the best method is to take the exclusion method one by one, if the patient’s situation allows, generally first the suspected drugs or according to experience that the most likely to cause fever If the patient’s condition allows, the suspected drug or the drug that is empirically considered to be most likely to cause fever is usually discontinued. After discontinuing each drug, observe for 3 days to see if the temperature drops. 3. Re-exposure test: In special cases, a re-exposure test with a drug known to cause fever can be considered to determine the final diagnosis. (Patients with serious underlying diseases or those with too strong initial reactions to drugs should not do exposure tests).