Unusual presentation of a severely ill patient having severe fever with thrombocytopenia syndrome: a case report

Severe fever with thrombocytopenia syndrome (SFTS) is a recently identified infectious disease endemic to China, South Korea, and Japan, with a reported fatality rate between 12% and 30% [1]. The emergence of central nervous system (CNS) manifestations during SFTS progression has been identified as a major risk factor for mortality [2].

The presence of reversible lesions that involve the splenium of the corpus callosum (SCC) has been reported in patients with a broad spectrum of diseases and conditions and is referred to as reversible splenial lesion syndrome (RESLES) [3]. The magnetic resonance imaging (MRI) features of RESLES include reversible lesions limited to the splenium of the corpus callosum (SCC) or to the SCC and frontal white matter; hyperintense signals on T2-weighted images (T2WI), fluid-attenuated inversion recovery (FLAIR) images and diffusion-weighted images (DWI); with low apparent diffusion coefficient (ADC) values and hypo- or iso-intense signals on T1-weighted imaging (T1WI) sequences with no contrast enhancement [4, 5].

The exact pathophysiology and the specific site predilection of transient SCC lesions in RESLES are not understood. It has been suggested that transient SCC lesions likely reflect rapidly resolving intramyelinic edema or the influx of inflammatory cells and macromolecules, combined with related cytotoxic edema and hypotonic hyponatremia, which result from infection [6‐8].

Here we report the case of a severely ill patient with SFTS virus-associated encephalitis/encephalopathy in whom follow-up magnetic resonance imaging (MRI) demonstrated a lesion in the SCC. This lesion eventually resolved, and our patient made a complete clinical recovery within a few weeks. Analysis of the SFTS viral load in our patient’s serum during hospitalization demonstrated a rapid decrease.

A 56-year-old Japanese man, who had been engaged in agricultural activities in a hilly rural area of Japan, presented to a local hospital in August, with a 2-day history of fever and diarrhea. Dysarthria and irritability were also evident. He had long-standing diabetes mellitus that had been well controlled with metformin. His vital signs were normal except for pyrexia (temperature of 38.5 °C).

Laboratory tests demonstrated leukopenia, thrombocytopenia, hyponatremia, and increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and creatine kinase (CK). Brain MRI revealed a hyperintense lesion in the SCC on T2- (Fig. 1a) and diffusion-weighted (DW) (Fig. 1b) image sequences. A preliminary diagnosis of cerebral infarction was made, and intravenous administration of edaravone was started. However, his clinical condition had not improved by the 3^rd day after illness onset, and he was, therefore, transferred to our hospital.

On admission, our patient’s Glasgow score (GCS) was 12 (E3, V3, M6), and he showed limb tremor and scanning speech. A tick bite wound was observed on the anterior aspect of his right ankle.

Blood tests showed leukopenia with a shift to the left, 2.8 × 10⁹/L (normal range: 4.0–9.0) with 48% bands and 1% of atypical lymphocyte.

The other laboratory tests yielded the following results: platelet count, 59 × 10⁹/L (150–450); and hemoglobin, 14.7 g/dL (12–16); C-reactive protein, 1.51 mg/dL (0–0.3); AST, 159 U/L (13–33); ALT, 59 U/L (8–42); LDH, 429 U/L (100–200); creatinine, 1.21 mg/dL (0.36–1.06); CK, 2559 U/L (62–287); serum ferritin, 1980 U/mL (122–496); and sodium levels, 129 mmol/L (135–149).

Contrast-enhanced whole-body computed tomography revealed slight enlargement of the mediastinal, axillary, and inguinal lymph nodes. On the 5^th day of illness, reverse-transcription polymerase chain reaction (RT-PCR) for SFTS virus (SFTSV) using a blood sample had a positive result, confirming that our patient had SFTSV infection (Fig. 2).

The laboratory values on that day were as follows: platelet count, 31 × 10⁹/L; fibrin/fibrinogen degradation products (FDP), 49.0 μg/mL (0–1); soluble CD25, 2402 U/mL: and increases in the AST, LDH, CK, and serum ferritin levels to 159 U/L, 429 U/L, 4016 U/L, and 24667 U/mL, respectively. A bone marrow smear showed mild hemophagocytosis (Fig. 3).

These laboratory findings fulfilled the diagnostic criteria for acute disseminated intravascular coagulation (DIC) [9] and the clinical diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) was made by the revised diagnostic criteria including fever, bicytopenia, hepatitis, high level of serum ferritin and sIL-2R, and hemophagocytosis in bone marrow [10].

Thereafter, our patient’s CNS manifestations deteriorated, and he exhibited convulsion and stupor as well as hemorrhagic manifestations, such as gingival bleeding and melena. Lumbar puncture was not performed due to DIC. However, a follow-up DW brain MRI scan on the 5^th day of illness demonstrated complete disappearance of the SCC signal enhancement (Fig. 1c).

Laboratory findings indicated gradual improvement after the 6^th day of illness. Moreover, hemorrhagic manifestations disappeared on the 9^th day of illness, and the CNS disturbance was resolved by the 16^th day. Our patient was discharged on the 24^th day after illness onset with an overall improvement in his condition. We treated our patient with symptomatic and supportive measures. Throughout the course, our patient neither required intensive care nor was treated with the administration of corticosteroids. He was treated with fluid replacement for dehydration and platelet transfusion. The clinical findings are summarized in Table 1.

The SFTS viral load in serum samples collected from our patient, on days 1, 3, 5, 7, 11, and 14 after illness onset were determined by quantitative RT-PCR (qRT-PCR), as described previously [11, 12]. On admission, there had been 2.8 × 10⁵ copies/mL, but the viral load rapidly decreased during the remaining period of hospitalization (Fig. 2).

We have reported the case of a severely ill patient with SFTSV-associated encephalitis/encephalopathy in whom an SCC lesion was detected, but showed spontaneous resolution. The presence of a reversible SCC lesion has been reported in patients with a broad spectrum of diseases and conditions, and is referred to as RESLES [3]. Infection is the most common cause of this abnormality. To the best of our knowledge, this is the first reported case of RESLES in a patient with SFTSV infection.

The common neurological symptoms of RESLES associated with encephalitis/encephalopathy may include delirium, short-term disturbance of consciousness, and seizures, but usually patients show complete recovery without neurological sequelae after a short disease course [13, 14]. Although CNS manifestations are common in patients with SFTS, signs of severe CNS disturbance, such as coma and convulsion, are thought to be major clinical indicators of poor prognosis [2]. An epidemiologic study of 538 patients with SFTS revealed that 19.1% of them developed encephalitis and 44.7% of the 19.1% died [15].

In the present case, it was not clear whether the severe CNS disturbance was due to the severe clinical course of SFTS itself or the SCC lesion that developed secondarily. Achalia et al. speculated that the prognosis of RESLES may depend on the underlying disorder and not on other factors [16]. The worsening CNS manifestations, hemorrhagic manifestations, and laboratory data in the present patient were consistent with severe SFTSV infection. HLH may also have contributed to disease severity and clinical outcome [17]. HLH results from excessive activation of the immune system, leading to uncontrolled cytokine release. Although the mechanism responsible for reversible SCC lesions is unknown, Tada et al. postulated that intra-myelinic edema or an inflammatory infiltrate might account for the transient decrease in the ADC value [4]. In the present case, we suspect that an inflammatory infiltrate caused by cytokine cascades under conditions of HLH may have been involved in the pathogenesis of the reversible SCC lesion.

SFTS patients with severe complications such as secondary HLH often receive corticosteroids, which repress immune functions. SFTS patients are somewhat immunodeficient [18] or have damaged immune systems with low levels of CD3+ and CD4+ T lymphocytes [19, 20], which may be due to a viral-associated hemophagocytic syndrome. Such immunodeficiency has an important role in disease progression, disease severity, and clinical outcome. Therefore, the administration of corticosteroids for the treatment of HLH, is controversial, because it sometimes worsens the infectious disease status including causing opportunistic infections. In fact, some lethal SFTS cases have involved patients with a history of early treatment with dexamethasone. In particular, two autopsy cases of Japanese SFTS patients, who received corticosteroids for hemophagocytosis, complicated by Aspergillus or Mucor infection were reported [21]. It is noteworthy that in the patient with Aspergillus infection, the thrombocytopenia and other organ pathologies were improving, although the aggressive pulmonary aspergillosis exacerbated the clinical course and resulted in death in the patient. Because the use of corticosteroids in severely ill SFTS patients may be possible to induce opportunistic infections, a prospective study is needed to evaluate the efficacy of corticosteroid therapy.

It appears that SFTS viral load is related to morbidity [12]. It has been reported that the SFTS viral load in acute-phase peripheral blood samples was significantly higher in patients who died than in those who survived, and that a high titer of ≥10⁸ copies/mL led to fatal outcomes [18, 22]. The mean viral load in the survivor group was 10⁵ copies/mL, which were consistent with the findings reported by Zhang et al. [18]. Thus, there is a possibility that in this case report the serum SFTS viral load elevation on admission we see, which was equivalent to that in the survivors reported by Zhang et al., contributed to the favorable outcome, even though the patient was severely ill. Therefore, a rapid decline in the viral load revealed by periodic monitoring may be useful in predicting the outcome in severely ill patients with SFTS.

The present case suggests that SFTSV infection can trigger reversible SCC lesions. Even if patients show unexpectedly severe and prolonged CNS disturbance during SFTS progression, monitoring of the serum SFTS viral load in the acute phase may reveal a rapid decline that is predictive of a favorable outcome and may enable the avoidance of the use of corticosteroids, which potentially cause opportunistic infection.