Discussion and conclusion
In September 2006, the first SFTS case occurred in Dingyuan country, Chuzhou, Anhui province [
5]. Since then, sporadic cases mainly manifested with fever and thrombocytopenia have been reported one after another in several provinces of China. In 2010, the responsible pathogen isolated from patients was named SFTSV, a novel bunyavirus. From 2010 to October 2016, more than 7000 SFTS cases have been diagnosed in China, with the average mortality of 5.3% right now, while the mortality rates of SFTS ranges from 12 to 30% at the early days of people’s recognition for this type of disease [
1,
7]. Because of nonspecific clinical features of SFTS ranging from head to toe, some patients with SFTS are misdiagnosed with other diseases such as common fever, gastrointestinal disease, human granulocytic anaplasmosis, hemorrhagic fever with renal syndrome, and leptospirosis [
1]. Based on 743 confirmed cases in previous studies, the clinical characteristics of SFTS patients are summarized in Table
2 [
1,
6,
8‐
12]. The main disease symptoms include fever (95.3%), body sores (81.1%), anorexia (75.4%), fatigue (77.7%), nausea (65.8%) and vomiting (51.5%). Other common clinical features include dizziness (47.0%), malaise (46.4%), chill (46.2%), diarrhea (44.8%), headache (43.9%), lymphadenopathy (42.8%), and cough (42.8%). In addition, joint pain and petechiae are observed in 34.1% and 23.3% patients, respectively. Furthermore, some cases present with nervous system symptoms, respiratory symptoms, and liver and spleen enlargement, respectively.
Table 2
Clinical symptoms of patients with severe fever with thrombocytopenia syndrome [
1,
6,
8‐
12]
Fever | 743 | 708 | 95.3 |
Anorexia | 574 | 433 | 75.4 |
Fatigue | 574 | 446 | 77.7 |
Nausea | 743 | 489 | 65.8 |
Vomiting | 743 | 383 | 51.5 |
Diarrhea | 743 | 333 | 44.8 |
Abdominal pain or tenderness | 446 | 127 | 28.5 |
Headache | 743 | 326 | 43.9 |
Body sores | 238 | 193 | 81.1 |
Lymphadenopathy | 731 | 313 | 42.8 |
Cough | 603 | 258 | 42.8 |
Chill | 662 | 306 | 46.2 |
Dizziness | 423 | 199 | 47.0 |
Malaise | 69 | 32 | 46.4 |
Muscular tremor | 69 | 21 | 30.4 |
Petechiae | 477 | 111 | 23.3 |
Arthralgia/joint pain | 369 | 126 | 34.1 |
Throat congestion | 196 | 44 | 22.4 |
Hematuria | 115 | 22 | 19.1 |
Apathy | 297 | 65 | 21.9 |
Confusion | 81 | 18 | 22.2 |
Coma | 297 | 36 | 12.1 |
Lethargy | 228 | 37 | 16.2 |
Convulsion | 228 | 27 | 11.8 |
Dyspnea | 284 | 51 | 18.0 |
Skin rash | 238 | 19 | 8.0 |
Chest pain | 115 | 6 | 5.2 |
Hematemesis | 343 | 33 | 9.6 |
Gingival bleeding | 180 | 15 | 8.3 |
Hematoma on puncture sites | 115 | 7 | 6.1 |
Conjunctival congestion | 261 | 21 | 8.0 |
Hyperemia of face | 115 | 9 | 7.8 |
Slurred speech | 69 | 4 | 5.8 |
Hepatomegaly | 115 | 7 | 6.1 |
Splenomegaly | 115 | 5 | 4.3 |
Abnormal laboratory findings reported in previous studies [
1,
6,
11] of SFTS cases revealed thrombocytopenia (96.0%), leukopenia (91.8%), elevated AST (95.4%), increased ALT (92.6%), elevated LDH (91.8%), low calcium (82.7%), proteinuria (78.0%), and prolonged APTT (77.2%). Serum levels of CK, creatine kinase MB fraction (CK-MB), AMY, LPS and creatinine (Cr) are high in patients with SFTS. Hematuria and fecal occult blood were also observed (Table
3). Taken together, these findings indicated that SFTSV is a pantropic virus that injures most tissues and cells; it can invade the hematological system, cardiac muscles, the liver, kidneys, and the coagulation system, inducing related symptoms and abnormal examination results [
7,
13‐
15]. Therefore, early diagnosis and treatment is beneficial for patient survival.
Table 3
Laboratory findings in patients with severe fever with thrombocytopenia syndrome [
1,
6,
11]
Thrombocytopenia | 426 | 409 | 96.0 |
Leukopenia | 427 | 392 | 91.8 |
Elevated alanine aminotransferase (ALT) | 417 | 386 | 92.6 |
Elevated Aspartate aminotransferase (AST) | 416 | 397 | 95.4 |
Elevated Lactate dehydrogenase (LDH) | 404 | 371 | 91.8 |
Proteinuria | 391 | 305 | 78.0 |
Low calcium | 353 | 292 | 82.7 |
Prolonged activated partial-thromboplastin time (APTT) | 127 | 98 | 77.2 |
Elevated Creatine kinase (CK) | 402 | 269 | 66.9 |
Elevated Creatine kinase MB fraction (CK-MB) | 144 | 93 | 64.6 |
Hematuria | 46 | 27 | 58.7 |
Low sodium | 353 | 157 | 44.5 |
Elevated serum amylase level (AMY) | 48 | 18 | 37.5 |
Elevated serum lipase level (LPS) | 48 | 7 | 14.6 |
Fecal occult blood | 105 | 34 | 32.4 |
Elevated creatinine (Cr) | 115 | 15 | 13.0 |
Herein, we described two special cases of SFTSV infection, with both patients exhibiting bone marrow plasmacytosis during the course of the disease. Although the cytology of bone marrow plasma cells mimicked multiple myeloma in case 1, BM cell immunophenotyping revealed benign, polyclonal plasma cell infiltration, compatible with reactive plasmacytosis. The Igs were polyclonal as assessed by immunofixation. In addition, the patient recovered after supportive therapy with no bone disease (lytic or osteopenic), anemia, renal insufficiency, or calcium elevation. However this patient presented with fever, lymphadenopathy and cough 8 months later and was diagnosed with angioimmunoblastic T-cell lymphoma (AITL) and died eventually. The question that whether there is relationship or not between AITL with SFTSV infection remain to be answered. In case 2, although abnormal plasma cells were found in both BM (including smear morphology and flow cytometry immunophenotyping) and peripheral blood (smear morphology) within 11 days of disease onset, diagnosis of plasma cell leukemia was ruled out because the increased Igs were polyclonal. Meanwhile, BM reexamination indicated normal cytology and immunophenotype within 24 days of disease onset, when the clinical manifestations and laboratory tests of the patient were improved, consistent with a reactive process. Reports of cytological changes, such as altered cell proliferation as well as histiocyte and phagocyte presence in the BM, in patients with SFTS are available [
6,
16]. Moreover, a study found that bone marrow cell cytology in SFTS patients display similarity to that of healthy individuals [
17]. However, reactive plasmacytosis mimicking multiple myeloma in the BM in association with SFTS is extremely rare. To our knowledge, reactive plasmacytosis characterized by transiently increased amounts of polyclonal plasma cells in the BM and peripheral blood, is an uncommon hematological event in SFTSV infection. Until now, only two other SFTS-associated reactive plasmacytosis cases have been reported in the Chinese and English literature [
18,
19]. The common clinical features of these two cases include fever, thromobocytopenia and reactive plasmacytosis which are similar to our patients. All the four cases were diagnosed as SFTS by the positive results of SFTSV RNA detection. One report described a SFTS case with reactive plasmacytosis in both BM and peripheral blood without hyperimmunoglobulinemia [
18]. The other report discussed a fatal SFTS case with reactive plasmacytosis in peripheral blood via flow cytometry without BM examination. The authors emphasized that clonality assessment of plasma cells was necessary to avoid misdiagnosis and delayed diagnosis in SFTS [
19]. However, reactive plasmacytosis in SFTSV infection might be underestimated. There are two possible reasons for this. First, it is a transient event based on the reflection of immune reactions [
20,
21]. Secondly, cell morphology in the bone marrow or blood smear is not assessed in most patients with SFTS because of the use of automated cell counters, which cannot identify plasma cells correctly [
2].
Reactive plasmacytosis is a rare event found in a variety of diseases such as infectious diseases, tumors and autoimmune disorders [
20]. Reactive plasmacytosis has been reported in several types of virus infections including Hepatitis A virus, Epstein-Barr virus, Dengue virus, Parvovirus B 19 [
21‐
24]. In this report, we describe two unusual cases of SFTSV infection presenting with reactive plasmscytosis both in peripheral blood and bone marrow. These two patients were diagnosed with SFTS, but not complicated with tumors or autoimmune diseases, therefore we consider that reactive plasmacytosis could be accompanied with SFTSV infection just as the other types of virus infections reported previously. In the process of SFTSV infection, the virus and cytokines are detectable in blood, similar to what is seen in other virus infections [
25]. Several studies reported that SFTSV infection could induce a cytokine storm, with increased levels of serum cytokines like IL-6, IL-10, MCP-1, G-CSF and IP-10, which might contribute to disease severity and outcome [
26‐
28]. Among them, IL-6 does not only participate in the differentiation of B cells into plasma cells, but also affects the generation of plasma cells as shown in knockout mice [
29,
30].
Furthermore, IL-6 plays a central role in the proliferation, differentiation, survival and immunoglobulin secretion in plasmablasts [
31]. Therefore, we propose that excessive IL-6 production may be a potential explanation for plasmacytosis in SFTS patients. Further studies exploring the mechanisms of human SFTSV infection are warranted, to determine the exact role of plasma cells in SFTS pathogenesis and expand our knowledge of SFTSV infection.
Currently, several methods are available for differentiating polyclonal plasma cells from monoclonal plasma cells, including cell morphology, serum protein electrophoresis, immunofixation by electrophoresis, and flow cytometry immunophenotyping. Recently, the widespread use of FCI makes it more simple, efficient and accurate to distinguish benign plasma cells from malignant ones. Yet, a deviation may still occur, if FCI signals are solely used for diagnosis. Therefore, it is essential to take into consideration various auxiliary examination results, when seeking a diagnosis.
In summary, although this report described a particular phenomenon that occurs in SFTSV infection, the mechanism and potential role in SFTSV in reactive plasmacytosis remain unknown. Further research should be carried out to address these questions. Interestingly, it is studied that T cell proliferation, activation and apoptosis occoured in the SFTSV infection recently [
32]. In addition, it is critical to make an early and correct diagnosis of SFTS, based on detailed epidemiological data such as onset season, occupation, residential address, working environment, and tick bite history, as well as a comprehensive analysis of clinical characteristics and laboratory findings. In the future, further education of physicians should be carried out in order to avoid misdiagnosis of SFTS and expand the knowledge of SFTSV infection. The clinicians should be aware that SFTS virus infection can be asooiciated with hematologic change such as reactive plasmacytosis.