Severe Fever with Thrombocytopenia Syndrome Complicated by Mixed Pulmonary Aspergillus and Mucorales Infection and Isavuconazole-Associated Liver Injury: A Case Report

Abstract

Background

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral disease characterized by severe immune dysregulation and high mortality, predisposing patients to opportunistic infections.

Case Presentation

We report a 76-year-old male patient diagnosed with SFTS complicated by chronic hepatitis B with low-level viral replication, liver injury, and myocardial injury. After initial treatment with intravenous immunoglobulin, hepatoprotective therapy, and antiviral therapy, the patient stabilized. During hospitalization, he developed pulmonary infection. Sputum culture was positive for Aspergillus fumigatus and serum galactomannan (GM) test was positive. Initial treatment with voriconazole led to radiological improvement in the right lung lesion; however, progression of the left lung lesion was observed. Bronchoalveolar lavage fluid metagenomic next-generation sequencing (mNGS) identified Rhizopus microsporus, leading to the diagnosis of invasive pulmonary Aspergillus–Mucorales coinfection. Oral isavuconazole combined with nebulized amphotericin B was administered, resulting in significant clinical and radiological improvement. Approximately one month after isavuconazole therapy, the patient developed jaundice and coagulation dysfunction. After exclusion of hepatitis B virus reactivation and other potential causes, isavuconazole-associated drug-induced liver injury was considered probable based on the clinical course and a RUCAM score of 8.

Conclusion

SFTS patients are highly susceptible to invasive fungal infections due to immune dysregulation, thrombocytopenia, and endothelial injury. Clinicians should consider mucormycosis in patients with poor response to voriconazole and progressive pulmonary lesions, and early bronchoscopy with mNGS is recommended. Although isavuconazole is considered relatively safe, liver function monitoring is essential, especially in patients with underlying liver disease.

Introduction

Severe fever with thrombocytopenia syndrome (SFTS) is an acute tick-borne infectious disease caused by infection with the severe fever with thrombocytopenia syndrome virus (SFTSV). It is primarily transmitted through tick bites and is clinically characterized by fever, thrombocytopenia, leukopenia, and multiple organ dysfunction. The case fatality rate ranges from 10% to 30%.¹ SFTS is mainly endemic in East Asian countries, including China, Japan, and South Korea, with the highest number of reported cases in China, predominantly in rural mountainous and hilly regions.² Recent studies have shown that, in addition to direct viral injury, SFTSV infection can induce profound immune dysregulation, including lymphocyte depletion, impaired cellular immunity, macrophage dysfunction, and excessive inflammatory responses. These immune abnormalities may increase susceptibility to opportunistic infections, particularly invasive pulmonary aspergillosis (IPA).³ However, reports of SFTS complicated by mixed Aspergillus and Mucorales infections are extremely rare, and both diagnosis and treatment remain highly challenging. Isavuconazole is a newer-generation broad-spectrum triazole antifungal agent with potent activity against Aspergillus species and Mucorales. It has been approved for the treatment of invasive aspergillosis and invasive mucormycosis and has become an important therapeutic option for patients with invasive mold infections, especially those who are intolerant of or have an inadequate response to conventional antifungal therapies.^4,5 Compared with voriconazole, isavuconazole exhibits more predictable pharmacokinetic characteristics, fewer drug–drug interactions, and improved tolerability, with a lower frequency of hepatobiliary adverse events.⁴ Therefore, isavuconazole is increasingly used in patients requiring prolonged antifungal treatment or with complex clinical conditions. However, despite its favorable safety profile, clinically significant isavuconazole-associated liver injury, including cholestatic and mixed-pattern injury, has been reported.⁶ In patients with hepatitis B virus infection, SFTS-related systemic inflammatory response, and polypharmacy, hepatic injury may still be induced or exacerbated. Here, we report a case of SFTS complicated by invasive pulmonary aspergillosis and mucormycosis coinfection, together with isavuconazole-associated drug-induced liver injury, to enhance clinicians’ awareness of such complex clinical scenarios.

Case Presentation

A 76-year-old male presented with a 5-day history of fever, fatigue, and anorexia on May 27, 2025. The patient had been engaged in agricultural work prior to disease onset and had no significant past medical history. Initial laboratory investigations revealed a platelet count of 19 × 10⁹/L and a white blood cell count of 3.2 × 10⁹/L. Liver function tests showed elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of 433 U/L and 837 U/L, respectively, while the creatine kinase (CK) level was 3437 U/L. The serum albumin level was 28.6 g/L. SFTSV RNA was positive. Serological testing showed positive hepatitis B surface antigen (HBsAg) and negative HIV antibody, and the HBV DNA level was 60.5 IU/mL. The patient was diagnosed with SFTS, chronic hepatitis B with low-level viral replication, liver injury, and myocardial injury. Subsequently, the patient developed persistent high fever and worsening thrombocytopenia, with the platelet count decreasing to 12 × 10⁹/L. Liver enzymes and coagulation parameters progressively worsened. After immunoglobulin (25 g/day for 5 days), entecavir, and supportive therapy, the patient’s clinical condition stabilized, and the liver function and complete blood count gradually returned to near-normal levels. Recombinant granulocyte colony-stimulating factor (rhG-CSF) was not administered during hospitalization.

During hospitalization, cough and sputum production developed. Sputum culture identified Aspergillus fumigatus, and GM test was positive. Chest CT showed bilateral pulmonary lesions (Figure 1A and B). Voriconazole antifungal therapy was administered for over two months. Follow-up chest CT showed absorption of right lung lesions but progressive consolidation in left lung lesions. Broad-spectrum antibiotic therapy with meropenem, ceftriaxone, and levofloxacin failed to reverse left lung lesion progression (Figure 1C and D). Breakthrough mucormycosis was suspected during voriconazole therapy due to progressive lesions. Bronchoscopy revealed a necrotic, friable endobronchial mass (Figure 2A and B). mNGS detected Rhizopus microsporus (a Mucorales fungus), Acinetobacter baumannii, Stenotrophomonas maltophilia, and Staphylococcus haemolyticus. A diagnosis of invasive pulmonary Aspergillus–Mucorales coinfection was established. Treatment with oral isavuconazole combined with nebulized amphotericin B was initiated, resulting in significant clinical improvement and radiological regression after 2 weeks. Nebulized amphotericin B was subsequently discontinued, and isavuconazole was continued as the sole antifungal agent.

Figure 1.

Chest computed tomography (CT) images of the patient. (A and B) Chest CT taken on June 24, 2025: Multiple nodular and patchy shadows in both lungs, bilateral pleural thickening, and bilateral pleural effusion. (C and D) Chest CT taken on September 29, 2025: The lesion in the right lung has shown absorption, while the lesion in the left upper lung has significantly progressed with an increased area of consolidation; there is a small amount of pleural effusion on the left side. (E and F) Chest CT taken on January 7, 2026: The left lung lesion shows significant absorption, and the left pleural effusion has further decreased.

Figure 2.

Bronchoscopy images of the patient. (A and B) Bronchoscopy performed on September 25, 2025: A long cord-like lesion was observed in the upper lobe bronchus of the left lung, covered with gray-black sputum, and prone to bleeding upon palpation.

After approximately 1 month of isavuconazole therapy, the patient developed jaundice and coagulation abnormalities. Laboratory tests showed an ALT level of 902 U/L, an AST level of 712 U/L, and a total bilirubin level of 217 μmol/L, accompanied by prolonged prothrombin time (PT) and an elevated international normalized ratio (INR). The HBV DNA level remained low at 35.2 IU/mL, with no evidence of hepatitis B virus reactivation. After exclusion of hepatitis B virus reactivation and other potential causes, isavuconazole-associated drug-induced liver injury was considered the most likely cause of the marked hepatic deterioration. Isavuconazole was discontinued, and the patient received comprehensive hepatoprotective treatment, including artificial liver support therapy, glutathione, ursodeoxycholic acid, and other supportive measures. Liver function gradually recovered after these interventions. Due to lack of alternatives, isavuconazole was cautiously reintroduced under strict monitoring without recurrence of severe hepatotoxicity, and pulmonary lesions ultimately resolved after two months (Figure 1E and F). The clinical course, treatment timeline, and outcomes are summarized in Table 1.

Table 1.

Clinical Timeline, Treatment Course, and Outcomes of the Patient

Time	Clinical Events	Treatment
Admission	SFTS with liver and myocardial injury	IVIG and supportive care
Early hospitalization	Thrombocytopenia and coagulopathy	Supportive treatment
Pulmonary infection	Aspergillus fumigatus detected	Voriconazole
Disease progression	Progressive pulmonary lesion	Broad-spectrum antibiotics
Bronchoscopic confirmation	BALF mNGS detected Rhizopus microsporus	Isavuconazole (1 month) plus nebulized amphotericin B (2 weeks)
Liver injury	Jaundice and liver dysfunction	Temporary antifungal interruption
Follow-up	Pulmonary improvement	Isavuconazole rechallenge

Abbreviations: SFTS, severe fever with thrombocytopenia syndrome; BALF, bronchoalveolar lavage fluid; mNGS, metagenomic next-generation sequencing; IVIG, intravenous immunoglobulin.

Discussion and Conclusion

Recent studies have demonstrated that, in addition to direct viral damage, immune dysfunction induced by SFTSV is a major contributor to secondary opportunistic infections in patients with SFTS.⁷ SFTS is primarily characterized by cell-mediated immune impairment. SFTSV infection may lead to T-cell exhaustion and lymphopenia, cytokine imbalance, and dysfunction of macrophages and dendritic cells, all of which markedly impair host antifungal immunity.⁸ It has been reported that CD4+ and CD8+ T-cell counts are significantly reduced in patients with severe SFTS, and these reductions are closely associated with disease severity and mortality risk.⁹ Platelets not only participate in the hemostatic process but also play a critical role in anti-infective immunity. A decrease in platelet count further impairs the bactericidal capacity of neutrophils and macrophages, while disruption of the endothelial barrier increases the risk of pathogen invasion.^10,11 The risk of secondary fungal or bacterial infections increases significantly in SFTS patients with platelet counts <50 × 10⁹/L.¹² These immune alterations likely contributed to the development of invasive fungal coinfection in the present case. IVIG was administered during the acute phase of SFTS (25 g/day for 5 days) as an immunomodulatory therapy. However, invasive pulmonary Aspergillus and Mucorales infections subsequently developed, suggesting that SFTSV-associated immune dysfunction may persist despite supportive immunotherapy. In addition, hypoalbuminemia (albumin 28.6 g/L) was observed during the acute phase. Reduced serum albumin levels may potentially influence the pharmacokinetic characteristics of highly protein-bound drugs; however, therapeutic drug monitoring of isavuconazole was unavailable in this case.

Invasive pulmonary aspergillosis (IPA) is one of the most common secondary fungal infections in SFTS. Studies indicate that the incidence of IPA in SFTS patients is approximately 30%, with significantly increased mortality rates observed in patients co-infected with Aspergillus species.¹³ In this case, right lung lesions improved after voriconazole treatment, whereas left lung lesions continued to progress and showed poor response to broad-spectrum antibacterial therapy. Ultimately, Rhizopus microsporus was identified in bronchoalveolar lavage fluid using metagenomic next-generation sequencing (mNGS), consistent with breakthrough mucormycosis. Recent studies suggest that prolonged exposure to broad-spectrum antibiotics may disrupt intestinal and respiratory microbiota homeostasis through the gut–lung axis.^14,15 This may have contributed to the development of breakthrough mucormycosis in this patient. In addition, persistent immunosuppression following SFTSV infection may further promote invasive growth of Mucorales. Although breakthrough mucormycosis has been widely reported in COVID-19-associated fungal infections, it remains relatively rare in SFTS.¹⁶ In this case, early sputum culture only detected Aspergillus fumigatus, while subsequent NGS analysis of lavage fluid identified Rhizopus microsporus, highlighting the limited sensitivity of conventional sputum culture for deep pulmonary Aspergillus infections. For SFTS patients, particularly those with severe thrombocytopenia, progressive pulmonary lesions, or poor response to voriconazole therapy, breakthrough mycotic infections should be suspected; mNGS aids in early etiological diagnosis.

This patient had a pre-existing chronic hepatitis B background and had experienced SFTSV infection, multiple infections, and prolonged anti-infective therapy, leading to a progressive decline in hepatic reserve function. After approximately one month of isavuconazole treatment, the patient developed significant jaundice, elevated transaminase levels, coagulation disorders, with total bilirubin rising to 217.0 μmol/L and PT and APTT markedly prolonged, indicating severe liver injury accompanied by pronounced coagulation abnormalities and a trend toward progression to liver failure. The patient’s HBV-DNA levels remained consistently low, with no evidence of viral reactivation or other definitive factors of liver injury such as biliary obstruction. Although the patient had previously received voriconazole and broad-spectrum antibiotics, these agents had been discontinued before the onset of the marked hepatic deterioration. In addition, nebulized amphotericin B had been discontinued, and isavuconazole was the only ongoing antifungal agent at the time of hepatic deterioration. Following discontinuation of isavuconazole and initiation of supportive therapies including artificial liver support, liver function and coagulation parameters gradually improved. To further evaluate the causal relationship between isavuconazole and liver injury, this study employed the RUCAM scoring system for assessment.¹⁷ The RUCAM score was 8, indicating a probable causal relationship between isavuconazole and liver injury. This assessment was supported by the temporal association, improvement after drug discontinuation, exclusion of alternative etiologies, and previously reported hepatotoxicity of isavuconazole. Notably, the patient’s liver function gradually recovered after discontinuation of isavuconazole and initiation of artificial liver support therapy. Given the need for continued antifungal treatment and the limited therapeutic alternatives, isavuconazole was subsequently reintroduced under close monitoring of liver function and coagulation parameters. No recurrence of significant liver injury or further severe deterioration of liver function was observed, while the pulmonary lesions were largely resolved. Although the absence of recurrent liver injury upon rechallenge does not completely exclude an association with isavuconazole, This case illustrates the potential role of cautious rechallenge in highly selected patients when continued antifungal therapy is necessary, therapeutic alternatives are limited, and the potential benefits are judged to outweigh the risks, provided that close monitoring is implemented.

Funding Statement

This work was supported by Anhui Chest Hospital Project (AHXK2025Z1004) and Beijing Huikang Renai Foundation Project (BHCFRF-20250520-28).

Data Sharing Statement

The clinical data supporting the findings of this case report are available from the corresponding author Niu Hua upon reasonable request.

Ethical Approval

This was a retrospective case report involving only the collection and analysis of clinical data and medical images. The study did not interfere with the patient’s treatment and did not pose additional risks to the patient. The requirement for ethics approval was waived.

Consent for Publication

Written informed consent was obtained from the patient for publication of this case.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas: took part in drafting, revising or critically reviewing the article, gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests in this work.