Fever of unknown origin is diagnosed when the fever (mostly defined as an elevated body temperature ≥ 38.3°C measured by rectal or tympanic route) lasts longer than expected, i.e. 5–10 days after the onset of fever[3]. In approximately half of the cases an infectious cause is finally found; other causes are primarily inflammatory, malignant and noninflammatory diseases. A systematic review and meta-analysis included 16884 patients with FUO, the research showed that rheumatic disease is a common cause of FUO, adult-onset Still's disease(AOSD), giant cell arteritis(GCA), and systemic lupus erythematosus(SLE) were the most frequent disorders[4].In this study, AOSD, SLE, and undifferentiated connective tissue disease(UCTD) were the most frequent disorders in non-infectious inflammatory disease.
The patients with fever have other clinical symptoms, such as poor appetite, chill, cough, sore throat, headache and others, so as non-infectious inflammatory fever patients. The patients with immune fever besides the common symptoms, it also has its own unique symptoms, likely light sensitiveness, lower limb edema, Raynaud's phenomenon, and facial swelling, all of these symptoms point to connective tissue disease (CTD), including SLE, Sjogren's syndrome (SS), and other autoimmune disease (AID). Thus, clinicians need to ask the fever patients carefully about the medical history, which is conducive to the accurate diagnosis of the disease.
Platelets (PLT) are small (typically 1–3 µm in diameter) anucleate cells, derived from megakaryocytes (MKs) within the bone marrow and lung niches[5]. The majority of platelets remain quiescent during their 7- to 10-day lifespan. However, upon stimulation, platelets undergo drastic cytoskeleton-driven morphological changes, arrange homotypic aggregates via integrin coupling, and release a plethora of factors from specialized α-granules into their surrounding environment[6]. These well-defined responses are essential to primary hemostasis, allowing platelets to adhere to damaged vasculature and act as “band-aids of the blood.” However, despite their clear importance to hemostasis, the inappropriate activation of platelets can promote various pathophysiologies, including thrombosis, inflammation, diabetes, and cancer[7–9]. An elevated white blood cell (WBC) count has many potential etiologies, including malignant and nonmalignant causes. Leukocytosis is a common sign of infection, particularly bacterial, the peripheral WBC count can double within hours after certain stimuli because of the large bone marrow storage and intravascularly marginated pools of neutrophils. Stressors capable of causing an acute leukocytosis include surgery, exercise, trauma, and emotional stress. Other nonmalignant etiologies of leukocytosis include certain medications, asplenia, smoking, obesity, and chronic inflammatory conditions[10]. Rheumatic disease, especially SLE, many etiologies contribute to anemia, including autoimmune hemolytic anemia, caused by anti-RBC antibodies, anemia of chronic inflammation, and kidney disease[11].SLE and UCTD were the most frequent disorders of FUO in non-infectious inflammatory fever of this study, and the levels of PLT and neutrophils were increased, but the levels of RBC and HGB were decreased (p < 0.05).
Ferritin, initially addressed as a surrogate marker for the status of iron storage in the human body, which is derived from the Latin word “ferratus” for iron-bearing, was considered to be merely related to iron and iron level in the human body[12]. Later by the seventies, ferritin was shown to be increased in acute infectious diseases, hence aided in the explanation of increased ferritin levels in acute inflammatory conditions, the majority caused by infections[13]. Later on, elevated ferritin levels that were previously related to acute or chronic inflammatory conditions whether or not caused by an infection, were shown to play a central role in the pathogenesis of various inflammatory and autoimmune diseases[14]. The correlation between hyperferritinemia and the four major pathologies of AOSD, macrophage activation syndrome, catastrophic antiphospholipid syndrome and septic shock is a great example of the implication of ferritin, particularly as all share in common a very severe disease course with high mortality[15]. Serum ferritin is predominantly L-ferritin which is released from the liver[16], several cytokines such as IL-6 and TNF-alpha were shown to stimulate the release of ferritin into the blood stream[17], this explains high ferritin levels seen [18]. In this study, the levels of ferritin were increased in both non-infectious inflammatory fever patients and infectious patients, but the levels of ferritin were more higher in non-infectious inflammatory fever patients, the mechanism is still up in the air, it may be related to cytokines in inflammatory conditions.
Also, in this study showed that the levels of LDH and α-HBDH were both increased in the patients with non-infectious inflammatory fever. HBDH is an established marker of cell death, particularly following cardiac and/or kidney damage, and can be measured in serum[19]. HBDH primarily represents the activity of the LDH-1 and LDH-2, LDH-1 and LDH-2 are particularly expressed in myocardial tissues, red blood cells, and the kidney, and are primarily responsible for maintaining the equilibrium between acetoacetate and β-hydroxybutyrate in the biochemical pathways involved in the formation of ketone bodies[20]. Non-infectious inflammatory diseases can affect multiple systems, leads to tissues and organs necrosis or apoptosis, especially the kidneys, heart and lungs. As a result, the levels of HBDH and LDH were increased in non-infectious inflammatory fever patients.
Autoantibodies are abnormal antibodies which are generated by pathogenic B cells when targeting an individual's own tissue. Autoantibodies have been identified as a symbol of autoimmune disorders and are frequently considered a clinical marker of these disorders[21]. Study showed that AOSD, GCA, and SLE are a common cause of FUO[4], SLE is an autoimmune disease characterized by multiple organ inflammatory damage and wide spectrum of autoantibodies. The autoantibodies, especially anti-dsDNA and anti-Sm autoantibodies are highly specific to SLE, and participate in the immune complex formation and inflammatory damage on multiple end-organs such as kidney, skin, and central nervous system (CNS)[22]. Virus, such as Epstein-Barr Virus (EBV), which infects essentially all human beings at some time during their life span. EBV transmission through oral secretions results in infection of epithelial cells of the oropharynx. From the epithelial cells EBV can infect B cells, which are the major reservoir for the virus, but other cell types may also become infected[23]. As a result, EBV can shuttle between different cell types, mainly B cells and epithelial cells. Moreover, since the virus can switch between a latent and a lytic life cycle, EBV has the ability to cause chronic relapsing/reactivating infections. Chronic or recurrent EBV infection of epithelial cells has been linked to SLE and SS, whereas chronic/recurrent infection of B cells has been associated with rheumatoid arthritis (RA), multiple sclerosis (MS) and other diseases[24]. In this study, autoantibodies can be found in non-infectious inflammatory disease, especially for SLE and SS, and autoantibodies also can be found in patients with infectious fever.
The present study has several limitations. This is a single-center, retrospective study with limited enrollment. Additional studies with larger patient populations are warranted.