Diagnostic methods for the etiology of prolonged fever (I)
Infectious disease is an important cause of prolonged fever of unknown origin
Fever of unknown origin (FUO or FOU) is defined as a fever lasting for more than 2-3 weeks with a body temperature ≥38 5℃, which cannot be clearly diagnosed after detailed medical history, physical examination and routine laboratory tests.
Infection is still the most common and important cause of FUO. According to the clinical analysis of 110 cases of unexplained prolonged fever in our department in recent years, infectious diseases accounted for 52.7% of the causes of FUO, including 47 cases of bacterial infections including typhoid fever, infective endocarditis, sepsis and abdominal abscesses, while tuberculosis accounted for 46.6% of infectious diseases, with extra-pulmonary tuberculosis being the majority (accounting for 2/3 of tuberculosis); followed by CMV virus and other previously uncommon pathogens such as Burkitt’s spirochetes. In addition, CMV and other previously uncommon pathogens such as Burkholderia pseudomallei and HIV, amoebas and fungi can also manifest as FUO, which is noteworthy.
In recent years, there has been an increase in tuberculosis, especially in the elderly, and the clinical presentation is varied and atypical. Tuberculosis, especially extrapulmonary tuberculosis such as deep lymph node tuberculosis, hepatic tuberculosis, splenic tuberculosis, genitourinary tuberculosis, hematogenous disseminated tuberculosis and spinal tuberculosis have complex clinical manifestations and account for a significant proportion of long-term unexplained fever, which should be taken seriously. Detailed medical history and thorough physical examination may provide certain clues, and it is crucial to catch the suspicious positive clues and follow them to the end for a definite diagnosis. Tuberculosis usually starts slowly with prolonged low-grade fever, which starts in the late afternoon or evening, and the next morning the body temperature can be reduced to normal; it may be accompanied by malaise, night sweats and wasting. It may be accompanied by malaise, night sweats and weight loss, or no obvious discomfort, but the temperature is unstable, often appearing after activity. Some patients may have intermittent high fever, or high fever when the disease progresses, in the form of retention fever or flaccid fever. Despite the high fever, the patient’s general condition is relatively good, unlike the general wasting and extreme weakness of patients with bacterial infections or malignant lesions with fever. Patients may have normal peripheral blood leukocyte counts, elevated gamma-globulin ratios, often increased sedimentation, and a strong positive tuberculin (PPD) test. However, a negative PPD test does not exclude tuberculosis, especially hematogenous tuberculosis. Li Longyun et al. summarized the clinicopathological discussion of 124 febrile cases from 1953 to 1997 in the Chinese Journal of Internal Medicine and reported that 4 of the 7 cases with hematogenous disseminated pulmonary tuberculosis confirmed by autopsy had normal chest radiographs before death, and liver biopsy before death was often helpful for diagnosis. In this group of 14 patients with tuberculosis, only 1 case had a diagnosis consistent with autopsy, and the remaining 13 cases were misdiagnosed, which is noteworthy. Pulmonary tuberculosis and cervical lymphatic tuberculosis are generally not difficult to diagnose, and the diagnosis can be confirmed by X-ray chest X-ray, sputum examination for antacid bacilli and lymph node biopsy. Patients often complain of low back pain or hip pain, which is aggravated by activity and not relieved by lying down, and the positive and negative lateral views of the lower thoracolumbar spine can reveal wedge-shaped changes in the vertebrae. Hepatosplenic tuberculosis is difficult to diagnose and usually requires pathological confirmation, and experimental anti-TB treatment is difficult to achieve short-term results. In clinical cases of unexplained prolonged fever with progressive hepatosplenomegaly, persistent pain and pressure in the liver area, the possibility of hepatotuberculosis should be suspected, and liver aspiration biopsy should be performed if accompanied by anemia, increased globulin, increased alkaline phosphatase and increased sedimentation. If the patient is in good general condition and negative for hepatitis B markers, early dissection should be performed to confirm the diagnosis of hepatic occupations that cannot be confirmed by percutaneous liver aspiration and/or laparoscopy. The main manifestation of splenic tuberculosis is FUO and splenomegaly, and those with fever and left upper abdominal discomfort should undergo abdominal ultrasound or CT scan, which can sometimes reveal intrapleural occupying lesions. In conclusion, FUO with intra-abdominal masses should be investigated by early dissection. It is worth noting that tuberculosis can also have metaplastic manifestations, including wandering polyarthritis or arthralgia and erythema of nodules and fever in the lower extremities, and salicylic acid preparations are ineffective. Non-responsive tuberculosis is common in patients with severe immunosuppression and should be taken seriously with high fever, bone marrow suppression or leukemia-like reactions. Early biopsy of the liver, spleen and lymph nodes should be performed in suspected patients.
Typhoid fever, infective endocarditis, subphrenic abscess or liver abscess are also common causes of FUO. In patients with prolonged fever and normal or low white blood cell count, especially in summer and autumn, fever, splenomegaly with abnormal liver function and diarrhea and abdominal distension, blood culture should be performed several times, and the diagnosis of typhoid fever can be confirmed if S. typhi is isolated from blood, bone marrow or stool. During the course of the disease, the agglutination potency of “O” and “H” antibodies to Fester’s reaction should be dynamically observed, and a 4-fold or higher increase in the recovery period is useful for diagnosis. The diagnosis of typical infective endocarditis is not difficult. However, the diagnosis is more difficult for those who do not have underlying heart disease and do not have obvious heart murmurs. The possibility of this disease should be alerted to repeated short-term use of antibiotics, repeated fever, and remission of fever after medication. In particular, careful auscultation of the heart murmur and the dynamic changes of the murmur should be performed, and attention should be paid to the presence of unexplained progressive anemia, splenomegaly, microscopic hematuria and bruises and other embolic phenomena. Blood cultures should be drawn several times before the application of antibacterial drugs. Timely trans-surface two-dimensional echocardiography is diagnostic for detecting the location, size, number and morphology of superfluous organisms. If necessary, two-dimensional echocardiography via esophagus can detect 1-1 mm superfluous organisms, and it is not affected by mechanical valve echo, and its positive rate of detecting superfluous organisms reaches 90%-95%, which is significantly better than two-dimensional echocardiography via body surface. Intra-abdominal abscesses are a common cause of FUO, especially liver abscesses and subdiaphragmatic abscesses. Liver abscesses can be misdiagnosed if they are deep, hepatomegaly is not obvious, and local signs are mild or absent, but FUO is the main presentation. Patients often have increased serum alkaline phosphatase, abnormal liver enzymes and increased bilirubin, and pressure pain in the liver area can still be found on close examination. Patients with bacterial liver abscess have severe toxemia, mostly manifesting as chills, flaccid hyperthermia, distension and pain in the liver area, and are prone to toxic shock, with elevated peripheral blood leukocyte count and neutrophils. The diagnosis of liver abscess is 90%-97% by abdominal CT scan, and the diagnosis can be confirmed by diagnostic puncture with pus under the guidance of ultrasound or CT scan. In addition, the disease can be secondary to sepsis, and blood cultures can isolate Staphylococcus aureus or Escherichia coli and other gram-negative bacilli. Amebic liver abscesses are mostly solitary abscesses with mild toxemia, which can be diagnosed by aspiration of chocolate colored pus and ELISA for serum amebic antibodies. Subdiaphragmatic abscesses are often secondary to perforated ulcer disease or appendicitis or after laparotomy. Patients have toxemia symptoms such as high fever, pain in the lower chest or upper abdomen, and may have pleural effusion or lower lobe lung atelectasis.
Viral diseases are usually self-limiting, EBV and cytomegalovirus infections can be the cause of FUO, and the diagnosis is mainly based on the isolation of the virus, or serological detection of the corresponding antigen or specific IgM antibodies.
In addition, in patients with long-term use of broad-spectrum antibiotics or immunosuppressants, if the fever is chronic and unexplained, deep fungal disease should be excluded, and in case of combined mucocutaneous candidiasis, the heart and lungs should be examined, and sputum, urine or blood specimens should be collected for fungal culture according to the relevant clinical symptoms to facilitate the diagnosis.
Hematologic diseases that can cause fever
Fever awaiting investigation is a common and difficult clinical problem. Some hematologic diseases can cause fever and should be taken seriously.
1.Hemolytic anemia
Hemolytic anemia can cause low or moderate fever, but rarely high fever. The mechanism may be related to the destruction of red blood cells and the primary cause of hemolysis (e.g., connective tissue disorders). Common febrile hemolytic anemias include thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, other intravascular hemolysis, and autoimmune hemolytic anemia. The fever caused by hemolytic anemia is combined with anemia and hemolysis, and the body temperature gradually returns to normal as the hemolysis is controlled. Malaria-induced hemolytic anemia can cause high fever (39℃ or more), chills, and profuse sweating.
2.Malignant histiocytic hyperplasia (malignant group)
The disease is mostly accompanied by high fever, which can be continuous or irregular. Antibiotic control is ineffective, and some cases respond to adrenocorticosteroids. The mechanism of hyperthermia in the malignant group is not known. These fevers have manifestations of malignant group, such as large liver and spleen lymph nodes, jaundice, emaciation, ascites, hematocrit, and the presence of malignant group cells in the bone marrow.
3. Reactive phagocytic syndrome
The disease causes fever similar to that of malignant group. However, it is essentially a benign disease. Generally, with appropriate supportive treatment, the disease is self-limiting, and the fever can disappear with the improvement of blood picture; if the infection is caused by reactive phagocytosis, the fever is often related to the infection. Control the infection, then control the fever.
4.Lymphoma
Lymphoma can cause hyperthermia and irregular fever. It also does not respond to antibiotics. Adrenal corticosteroids and chemotherapy are effective. Such fever combined with lymphoma manifestations, such as superficial or deep lymph node enlargement, widening of the mediastinum, large liver and spleen or gastrointestinal infiltration manifestations, skin infiltration manifestations, can be detected by pathology lymphoma cells. In some patients who develop lymphoma leukemia, lymphoma cells can be found in the peripheral blood and bone marrow.
5.Acute non-lymphoblastic leukemia type M7
This type of leukemia is mainly malignant proliferation of primitive and naive megakaryocytes, which can be combined with acute myelofibrosis, accompanied by high fever, ineffective with antibiotics, and a large number of primitive naive megakaryocytes and fibrous tissue in the peripheral blood and bone marrow. In patients in complete remission, the body temperature may be normal.