Successful Recovery from Severe Fever with Thrombocytopenia Syndrome and Hemophagocytic Lymphohistiocytosis with Standard Treatment and a Calcium Channel Blocker of Nicardipine Hydrochloride

Abstract

A 67-year-old man was admitted to our hospital with a high fever. Laboratory tests revealed leukopenia, thrombocytopenia, liver dysfunction, rhabdomyolysis, and hyperferritinemia. He was diagnosed with severe fever with thrombocytopenia syndrome (SFTS) complicated by hemophagocytic lymphohistiocytosis and treated with steroid therapy, intravenous calcium channel blocker (CCB), and supportive care, without favipiravir. Serum levels of ferritin and soluble interleukin 2 receptor (sIL2R) were markedly elevated on Day 3 after admission and decreased thereafter, while an SFTS viral load of 6.8×10⁴ copies/μL was detected on Day 2, increasing to 2.9×10⁵ copies/μL on Day 6. Serum ferritin and sIL2R levels may be better indicators of mortality than the SFTS viral load, and CCBs may have a therapeutic effect.

Introduction

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging life-threatening disease caused by a novel Phlebovirus of the Bunyaviridae family (1). Secondary hemophagocytic lymphohistiocytosis (HLH) may occur with cytokine storms in severe SFTS virus infections (2).

A high viral load ≥10⁵ copies/mL at the diagnosis was reported to be associated with severe disease and a poor prognosis (2). The definitive treatment for SFTS is supportive care for HLH, including plasma exchange and corticosteroids for cytokine storms that might affect the immune system (3,4).

Favipiravir, a selective inhibitor of viral RNA-dependent RNA polymerase, may have better therapeutic outcomes and safety than ribavirin (5). Indeed, this approach has been reported to reduce the mortality rate by approximately 10% among SFTS patients in Japan (6-8). However, the present patient was unable to receive oral favipiravir because there was a high demand for favipiravir due to the coronavirus disease 2019 pandemic outbreak. Li et al. (9) retrospectively showed that calcium channel blockers can inhibit SFTS viral replication in vitro and affect the outcomes of patients with SFTS.

We herein report a case of SFTS with HLH in a patient who recovered without the use of favipiravir. His clinical course suggests that intravenous administration of a calcium channel blocker may have a favorable effect on the prognosis, and the levels of soluble interleukin 2 receptor (sIL2R) and ferritin might be useful for monitoring the progression of SFTS in cases of HLH complication.

Case Report

A 67-year-old Japanese man who climbed a mountain every day presented to our hospital with a 5-day history of fatigue and a high fever (>38°C). He smoked 20 cigarettes daily but did not have any previous health problems other than hypertension.

On admission, he appeared pale. His vital signs were as follows: Glasgow Coma Scale score, 15 (E4V5M6); respiratory rate, 20 breaths/min; arterial oxygen saturation, 98% breathing room air; pulse rate, 89 beats/min; blood pressure, 162/111 mmHg; and body temperature, 37.0°C. He had no palpable lymph nodes, signs of tick bites, eschars, skin rashes, or ecchymoses. His laboratory findings revealed leukopenia (white blood cell count, 3,578 cells/μL, and neutrophil count, 1,958 cells/μL), thrombocytopenia (platelet count, 7.8×10⁴/μL), liver dysfunction (aspartate aminotransferase, 89 U/L; alanine aminotransferase, 28 U/L; lactate dehydrogenase, 319 IU/L), rhabdomyolysis (creatine kinase, 4,904 U/L), and hyperferritinemia (860 ng/mL) (Table). Computed tomography revealed mild splenomegaly. Blood cultures were negative. Based on the clinical features and blood test results, he was provisionally diagnosed with suspected SFTS virus infection.

Table.

The Patient’s Laboratory Test Results on Admission.

Hematology
White blood cells		2,200	cells/μL		Prothrombin time		110	s
Neutrophil %		89	%		APTT		37.1	s
Lymphocyte %		5.0	%		D-dimer		3.1	μg/mL
Monocyte %		6.0	%		FDP		5.9	ng/mL
Red blood cells		572×104	/μL		TAT		10.8	ng/mL
Hemoglobin		17.8	g/dL		ADAMTS13		48%
Platelet count		7.8×104/μL
Blood biochemistry
Total protein		7.8	g/dL		LDH		319	U/L
Albumin		4.4	g/dL		BUN		19	mg/dL
Total bilirubin		1.0	mg/dL		Creatinine		0.85	mg/dL
AST		89	U/L		Sodium		132	mEq/L
ALT		28	U/L		Potassium		4.4	mEq/L
ALP		67	U/L		CRP		0.20	mg/dL
GGTP		20	U/L		Glucose		125	mg/dL
CK		4,904	U/L		Ferritin		890	ng/mL

ALP: alkaline phosphatase, ALT: alanine aminotransferase, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CK: creatine kinase, CRP: C-reactive protein, FDP: fibrinogen degradation products, GGTP: gamma glutamyl transpeptidase, LDH: lactate dehydrogenase, TAT: thrombin-antithrombin complex

On Day 3 of admission, he developed confusion (Glasgow Coma Scale score: 8, E2V2M4) with a high fever (40°C). His blood test results had further deteriorated, showing worsened cytopenia (lymphocyte count 200 cells/μL, neutrophil count, 270 cells/μL, and platelet count, 3.9×10⁴/μL) and hypertriglyceridemia (fasting triglyceride, 265 mg/dL). His serum levels of sIL2R and ferritin were markedly elevated (1,487 U/mL, and 9,487 ng/mL, respectively). He was diagnosed with secondary HLH according to the HLH diagnostic guideline of HLH-2004 protocol (10) by meeting all 5 diagnostic criteria of a high fever >38°C at peak for 8 days, splenomegaly, cytopenia affecting 2 of 3 lineages in the peripheral blood (neutropenia and thrombocytopenia), hypertriglyceridemia ≥265 mg/dL, and hyperferritinemia >500 ng/mL. His sIL-2R level was below the diagnostic criterion (>2,400 U/mL). Hemophagocytosis in biopsy samples was unable to be assessed because of bleeding coagulation disorder. The natural killer cell activity in the periphery was not examined.

Because of a high demand for favipiravir for the treatment of coronavirus disease 2019, this agent was difficult to procure. He was therefore instead treated with nicardipine hydrochloride, an intravenous calcium channel blocker, at the usual dosage for hypertension control (1.0 μg per body weight per minute). He was also treated with plasma exchange and intravenous corticosteroids (1 g methylprednisolone daily for 3 days, followed by dexamethasone palmitate), antibiotics, immunoglobulin, and granulocyte colony-stimulating factor. His clinical course is shown in Figure.

Figure.

Clinical course of the patient. AST: aspartate aminotransferase, G-CSF: granulocyte colony-stimulating factor, LDH: lactate dehydrogenase, mPSL: methylprednisolone, PLT: platelet count, sIL-2R: soluble interleukin 2 receptor

On Day 5, his serum levels of sIL2R and ferritin began to decline, and his level of consciousness began to improve. On Day 7, his serum levels of liver enzymes began to decrease, and on Day 9, his platelet count began to increase. By Day 12, his mental state had returned to normal. He was discharged on Day 15 without any complications.

The SFTS virus was detected in his serum on Day 2 using reverse transcription polymerase chain reaction (RT-PCR) (11). His SFTS viral load in the serum was 6.8×10⁴ copies/μL as quantified by TaqMan-based real-time PCR (11). On Day 6, his viral load had increased to 29×10⁴ copies/μL, despite the improvement in his clinical condition.

Discussion

The clinical symptoms of SFTS can become exacerbated during the acute phase of the disease and progress to death in a few weeks (12). Therefore, intensive treatment, including antiviral therapy and supportive treatment of complications, should be implemented as quickly as possible if SFTS virus infection is suspected. The patient was suspected of SFTS virus infection on admission and further developed HLH despite steroid therapy. He was treated thereafter with the intravenous calcium channel blocker nicardipine hydrochloride in addition to steroid therapy and supportive treatment and fully recovered without any complications. Therefore, intravenous administration of nicardipine hydrochloride might have had a beneficial effect for his recovery.

Li et al. (9) reported that intracellular calcium might affect viral infection by regulating the function of calcium-dependent cellular factors. Calcium channel blockers, including nicardipine hydrochloride, may reduce virus-induced calcium influx and influence the levels of intracellular calcium required for SFTS viral replication (9). Benidipine hydrochloride displayed the strongest inhibitory effect against SFTSV infection (>90%) at 10 μM, not nicardipine (9). However, further investigations may be valuable concerning the clinical benefits of nicardipine hydrochloride against SFTS. Indeed, in the present case, nicardipine hydrochloride at 1.0 μg per body weight per minute controlled the patient's systolic blood pressure between 100 and 130 mmHg, without any adverse events, such as hypotension. Further clinical trials are therefore needed to determine the appropriate dosage for controlling SFTS virus.

A retrospective study revealed that use of nifedipine administration improved the clinical recovery of patients with SFTS and reduced the case fatality rate by more than five-fold (9). We suspected a similar beneficial role of nicardipine in our patient.

There have been several reports on the relationship between the viral load and prognosis. High viral loads (≥10⁵ copies/mL) at the diagnosis have been reported to be associated with severe disease and a poor prognosis (2). Sun et al. (13) reported that the serum viral load was correlated with the production of multiple peripheral cytokines in patients with SFTS and that these cytokines were associated with an impaired organ function. The present patient had a high viral load of 6.8×10⁴ copies/μL on day 2, indicating a poor prognosis. Survivors, in contrast to non-survivors, reportedly experience a gradual decrease in viral load (7). However, the viral load in the present patient increased to 29×10⁴ copies/μL on day 6, suggesting a poor prognosis, despite his clinical improvement at that time. Immunosuppression of corticosteroids may increase replication of the SFTS virus, analogous to patients with severe acute respiratory syndrome, in whom the early use of steroids within one week after the onset is associated with a high viral load in the second and third weeks (14). Plasma exchange is also reported to be ineffective at lowering the SFTS viral load (13). During steroid therapy and supportive treatments, changes in the viral load may not correspond to clinical improvement.

Elevated levels of ferritin and sIL2R in the serum were among the diagnostic criteria of HLH (2). Serum ferritin and sIL2R levels have been reported to be associated with the progression of SFTS and the occurrence of complications such as liver dysfunction, coagulopathies, and disturbances of consciousness (2). An elevated ferritin level is caused by excessive activation and proliferation of T lymphocytes and macrophages (2) and is used as a biomarker for clinically suspecting SFTS (15). It also has a predictive significance for the survival of HLH; when the ferritin levels do not decline, the mortality rates are high in HLH patients (16). Serum sIL2R may be increased by hypercytokinemia (2) and may be used to monitor the disease activity of HLH patients (17,18). Therefore, the present patient's clinical course suggests that serum levels of ferritin and sIL2R may be more useful than the SFTS viral load for monitoring disease progression in patients with SFTS.

At present there is no definitive treatment for SFTS other than supportive care. Further research is therefore needed to provide a better understanding of the pathology so that the mortality can be reduced. The effectiveness of calcium channel blockers for SFTS should be evaluated in prospective randomized controlled trials.

Conclusion

We treated a man with SFTS and HLH who obtained a full recovery. Intravenous administration of calcium channel blockers might have had a therapeutic effect. His clinical course suggests that serum levels of ferritin and sIL2R may be more useful than the SFTS viral load for monitoring disease progression in patients with SFTS.

The authors state that they have no Conflict of Interest (COI).