A 56-Year-Old Male Farmer From China With Severe Fever With Thrombocytopenia Syndrome and Pulmonary Aspergillosis: A Case Report and Review of Literature

Introduction

Dabie bandavirus is a tick-borne virus that can cause severe fever with thrombocytopenia in humans. In 2010, the Chinese Center for Disease Control and Prevention named this disease severe fever with thrombocytopenia syndrome (SFTS) [1]. It is an acute infectious disease that has shown an epidemic trend in parts of Asia, including China, South Korea, and Japan, in recent years [2–4]. The diagnosis is confirmed by detecting viral RNA in blood via real-time RT-PCR, or by identifying viral sequences through metagenomic next-generation sequencing (mNGS). Serologically, recent infection is confirmed by the presence of SFTS virus (SFTSV)-specific IgM antibodies or a ≥4-fold increase in IgG antibody titers between acute and convalescent sera using enzyme-linked immunosorbent assay (ELISA) or immunofluorescence assay [1,5]. The main clinical features are fever, thrombocytopenia (platelet count <100×109/L), leukopenia (white blood cell count <4.0×109/L), and multiple organ dysfunction [5]. The mortality rate for severe cases is high, making it a significant public health challenge [1]. During the course of SFTS, patients are highly susceptible to various opportunistic infections due to severe immunosuppression caused by the viral infection. A retrospective study found that in respiratory infections, the most commonly detected pathogen was Aspergillus fumigatus, followed by Aspergillus flavus, Candida albicans, and Klebsiella pneumonia [6].

Invasive pulmonary aspergillosis (IPA) is one of the most dangerous complications of SFTS. SFTS complicated by IPA (SAPA) not only significantly increases the difficulty of treatment but is also closely associated with a higher mortality rate [7,8]. In a study of 96 SFTS patients, 35 (36.5%) developed SAPA [7]. The SAPA group had a significantly longer mean hospital stay (16.5±12.1 days vs 8.0±3.1 days; P<0.001), a higher intensive care unit (ICU) admission rate (40.0% vs 3.3%; P<0.001), and a higher mortality rate (34.3% vs 3.3%; P<0.001) compared with the non-SAPA group [7]. Current management of SFTS is primarily supportive, as no specific antiviral therapy has been definitively proven effective in controlled trials [5]. Although several agents, including ribavirin, favipiravir, and calcium channel antagonists, have shown potential antiviral effects in vitro or in preliminary studies, their clinical efficacy remains to be validated in large-scale controlled trials [9–11].

For patients who develop SAPA, timely antifungal therapy is critical. According to the expert consensus on severe SFTS, voriconazole or isavuconazole monotherapy is recommended as initial treatment for IPA, with combination therapy (voriconazole plus an echinocandin) for severe cases [5,12,13]. In this paper, we describe a case of SAPA diagnosed in our hospital and review the relevant literature to summarize the clinical characteristics and management of this condition, aiming to enhance clinicians’ awareness and provide insights for early diagnosis and treatment.

Case Report

A previously healthy 56-year-old male farmer from Anhui Province was admitted to our hospital 8 days after the onset of symptoms. He had no history of smoking, chronic obstructive pulmonary disease (COPD), or other lung conditions. His presenting symptoms included recurrent high-grade fever (peaking at 40°C) for 8 days, diarrhea (2–3 episodes daily) for 3 days, and generalized myalgia, dizziness, and fatigue over the preceding 2 days. Two days prior to admission, laboratory testing revealed leukopenia (white blood cell count 2.95×109/L) and thrombocytopenia (platelet count 94×109/L). On hospital day 1, complete blood count showed worsening thrombocytopenia (platelet count 77.00×109/L, measured using an automated hematology analyzer [Mindray BC-7500 series]), along with elevated hepatic and muscle enzymes (aspartate aminotransferase 221.20 IU/L, alanine aminotransferase 77.60 IU/L, creatine kinase 666.00 IU/L). Inflammatory markers were mildly elevated (procalcitonin 0.54 ng/mL; C-reactive protein [CRP] 8.92 mg/L). Initial tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A, and influenza B, as well as blood cultures, were all negative. No significant abnormalities were identified on chest computed tomography (CT) (Figure 1A) or electrocardiogram. Empirical antibiotic therapy with doxycycline and moxifloxacin was initiated, alongside supportive care including hepatoprotective agents, fluid replacement, and potassium and albumin supplementation. On hospital day 3, mNGS of blood (Adicon, China) detected Aspergillus species (160 sequences) and Aspergillus fumigatus (97 sequences). Concurrently, mNGS of sputum identified Dabie bandavirus (55 sequences), Streptococcus pneumoniae (1 355 577 sequences), and Aspergillus fumigatus (181 196 sequences). The patient also began to exhibit mild respiratory symptoms, such as cough with sputum, at this time, but conventional sputum smears and cultures remained negative. Given the combined microbiological and clinical evidence, a diagnosis of SAPA was suspected. Consequently, targeted antiviral therapy with favipiravir and antifungal therapy with voriconazole were added. On hospital day 7, serological testing using ELISA confirmed the SFTS diagnosis, with both SFTSV-specific IgM and IgG antibodies testing positive. A follow-up chest CT on day 10 revealed new bilateral pulmonary infiltrates, featuring cavitation and interstitial changes, alongside new bilateral pleural effusion and atelectasis (Figure 1B). The serum galactomannan index was elevated at a signal-to-cut-off ratio (S/CO) of 1.407, and the CRP level was also elevated. However, the serum (1,3)-β-D-glucan (G) test and sputum smears/cultures returned negative results. By day 13, the patient’s diarrhea had resolved and platelet count normalized; however, he remained febrile and began producing tenacious, dark brown sputum. On day 15, while the serum galactomannan level further increased to 1.627 S/CO despite a therapeutic voriconazole trough level (10.92 μg/mL), the CRP level showed a decrease. Due to the rising galactomannan level suggesting poorly controlled IPA, caspofungin was added to the antifungal regimen. Given the persistent fever and complicated pulmonary infiltrates, empirical antibacterial coverage with imipenem/cilastatin was also initiated on day 15 due to concern for bacterial co-infection. However, a repeat CT scan on day 16 showed a reduction in the extent of lower lobe lesions, though cavitation and interstitial changes persisted (Figure 1C). On hospital day 21, the patient developed a superinfection with SARS-CoV-2. Bronchoalveolar lavage fluid mNGS confirmed a high viral load (SARS-CoV-2 sequence count 3 303 101), alongside persistent Aspergillus fumigatus (7383 sequences) and newly detected Pseudomonas aeruginosa (1287 sequences). Although concurrent sputum smears and bacterial/fungal cultures of bronchoalveolar lavage fluid were negative, the mNGS results provided definitive microbiological evidence of the co-infection. Atilotrelvir/ritonavir was added for antiviral therapy, and the imipenem/cilastatin was continued for the treatment of Pseudomonas aeruginosa. Following this intervention, the patient’s fever subsided, and respiratory symptoms improved significantly. The patient was successfully discharged on hospital day 24 while afebrile. During a subsequent telephone follow-up, the patient completed a 3-month course of oral voriconazole as an outpatient, resulting in resolution of the lesions. The detailed treatment timeline and trends in key laboratory parameters are summarized in Table 1 and Figure 2, respectively.

A literature review of SAPA cases was conducted by searching the Wanfang Database, the China National Knowledge Infrastructure databases, the Chinese Scientific Journal Database, and PubMed databases for records up to October 2025, using the keywords “severe fever with thrombocytopenia syndrome” and “Aspergillus”. Thirteen cases of SAPA were ultimately identified [14–26]. The inclusion criteria were case reports that provided a clear diagnosis of SFTS combined with IPA and detailed descriptions of the clinical management and outcomes. Exclusion criteria included review articles and epidemiological studies lacking detailed individual case information. Among them, there were 9 male and 4 female patients, with an average age of 64 years. Underlying conditions, including hypertension, diabetes, hyperlipidemia, or atrial fibrillation, were present in 7 patients, while only 1 patient had a pre-existing pulmonary condition (COPD). A history of tick exposure was reported in 11 cases. The initial clinical presentation predominantly consisted of influenza-like symptoms, such as fever, chills, fatigue, and myalgia, and some patients also experienced diarrhea, headache, and lethargy. Multiple organ damage was universally observed, including hepatic (92.31%), myocardial (69.23%), and renal (61.54%) injury, followed by pancreatitis (23.08%) and central nervous system involvement (15.38%). The treatment regimen was primarily based on a combination of antifungals (mainly voriconazole), antivirals (ribavirin or favipiravir), and antibacterials, with some patients additionally receiving corticosteroids and/or human immunoglobulin. Four patients (4/13) required combination antifungal therapy. Four of 13 (30.77%) patients died (Table 2).

Discussion

This case offers several insights for clinicians managing SFTS patients, particularly regarding the risk of secondary aspergillosis. It serves as a reminder that SAPA can occur in previously healthy individuals without traditional risk factors for invasive aspergillosis, underscoring the importance of clinical vigilance even in seemingly low-risk patients. The case also highlights the value of rapid diagnostic tools such as mNGS in enabling early targeted therapy, especially when conventional microbiological tests remain negative. Additionally, the narrow therapeutic window for SAPA intervention and the potential for disease progression despite prompt treatment underscore the need for further research into risk stratification and the optimal timing of antifungal therapy.

Our literature review of 13 confirmed SAPA cases, including the present one, reveals that 4 out of 12 patients (33.33%) without pre-existing pulmonary diseases died [17,18,21,23]. Among these fatal cases, one was particularly severe, involving disseminated infection with intracranial aspergillosis [17]. Notably, one surviving patient with intracranial aspergillosis required prolonged hospitalization lasting 5 months [22]. This underscores a critical clinical challenge: the rapid and often fatal progression of secondary aspergillosis in SFTS patients, which can extend beyond the lungs to involve other organs and, even in survivors, may result in protracted and resource-intensive care. This complication is associated with a drastic worsening of prognosis, characterized by prolonged hospitalization, high ICU admission rates, and elevated mortality [2,7].

The severe impact of SAPA on clinical outcomes was quantified in a referenced study [7]. It reported that, compared with patients without this complication, those with SAPA had a significantly prolonged mean hospital stay (16.5 days vs 8.0 days) and a drastically higher ICU admission rate (40.0% vs 3.3%) [7]. Most critically, the presence of SAPA was linked to a markedly elevated mortality of 34.3%, a more than tenfold increase compared with the 3.3% mortality observed in the non-SAPA group. These data clearly indicate that SAPA, as one of the most severe complications of SFTS, is a major factor leading to patient deterioration, increased consumption of medical resources, and ultimately, death.

In our patient, Aspergillus fumigatus was detected simultaneously in both blood and sputum via mNGS on hospital day 3, coinciding with the onset of mild cough and sputum production but preceding significant radiographic abnormalities, prompting immediate initiation of voriconazole therapy, and the patient ultimately recovered. Our review of 13 reported cases revealed that a single patient with a pulmonary comorbidity (COPD) was diagnosed via blood NGS on the second day of admission and received prompt voriconazole, resulting in a favorable outcome [14]. The remaining 12 patients without pre-existing pulmonary disease all developed IPA following SFTSV infection. Similarly, our patient had no prior history of pulmonary disease. Thus, a timely and proactive approach to diagnosis and treatment for SFTS patients with suspected SAPA is strongly warranted.

SAPA may follow a recognizable clinical timeline. Patients initially present with typical SFTS symptoms including fever, fatigue, myalgia, and diarrhea, with pulmonary imaging often inconspicuous for fungal infection. This pattern is exemplified by our patient and is consistent with other reports, where initial SFTS symptoms are followed by respiratory deterioration at 1–2 weeks of illness [16–22,24,26], underscoring the importance of clinical vigilance for secondary fungal infection during this critical window. The critical deterioration usually occurs 1–2 weeks into the illness, marked by rapid-onset, refractory bronchospasm and severe respiratory failure [8,27]. This pattern defines a narrow therapeutic window, as highlighted by Bae et al, who reported that 56% of ICU-admitted SFTS patients developed IPA within a median of 8 days [8].

The pathogenesis of SAPA likely involves a permissive host state created by SFTSV infection. A critical factor in this process may be the profound impairment of both innate and adaptive immunity resulting from early leukopenia (particularly lymphopenia), direct viral effects, and cytokine storms, which can establish favorable conditions for fungal invasion and dissemination [28,29]. While IPA is classically acquired via inhalation of spores, the detection of Aspergillus fumigatus sequences by mNGS in the peripheral blood of SFTS patients during the early stages, including in our case and other reports [14,23,24], introduces an alternate hypothesis. Coupled with studies detecting Aspergillus in tick vectors [30], this raises the possibility of direct inoculation through a tick-bite wound leading to early fungemia. It is important to note that these bloodborne sequences could also represent contamination or transient, non-pathogenic DNA. Therefore, whether pulmonary aspergillosis is acquired through inhalation of spores or results from direct hematogenous dissemination via a tick-bite wound requires further investigation.

Ultimately, SFTSV-induced immunosuppression appears to be the central enabling factor for progression to invasive disease, regardless of the initial port of entry. Our case vividly exemplifies this high-risk trajectory within the narrow window. The patient had an initially mild, “common-type” SFTS course that responded to antivirals (favipiravir) with viral clearance. However, this apparent recovery was abruptly complicated by IPA and later SARS-CoV-2 co-infection. This clinical course raises the possibility that severe fungal complications can arise even in initially milder cases, which may involve a critical interplay between direct fungal inoculation and SFTSV-induced immune dysregulation [31,32].

The core value of our report lies in demonstrating a pathway to overcoming the diagnostic delay that often defines SAPA. Traditional microbiological methods have limited speed and sensitivity in such acute settings. It is important to note that all conventional sputum and blood cultures in our case returned negative, precluding standard antimicrobial susceptibility testing and underscoring the diagnostic challenge in such acute presentations. It is worth noting that while a high load of Streptococcus pneumoniae sequences was detected in the initial sputum mNGS, the patient was already receiving moxifloxacin, which is effective against this pathogen. The progression of pulmonary lesions despite antibacterial coverage, combined with the development of cavitation, strongly supported Aspergillus as the primary cause of the clinical deterioration. Here, the application of mNGS on peripheral blood was decisive. It provided a rapid, unbiased pathogen identification within 48 hours of clinical suspicion, directly leading to the immediate initiation of targeted antifungal therapy. This aligns with growing evidence regarding mNGS’s utility in managing complex infections [33,34] and is supported by other case reports detecting Aspergillus sequences in SFTS patient blood [14,23,24]. Notably, 8 of the 13 previously reported SAPA cases (61.5%) utilized mNGS to establish the etiological diagnosis [14,17,18,20–24], highlighting the growing role of this technology in complex infectious scenarios. Our experience, consistent with this literature, strengthens the argument for considering mNGS as a critical tool in the early diagnostic workup of deteriorating SFTS patients, especially when atypical or refractory respiratory symptoms emerge.

For patients with SFTS who develop SAPA, timely antifungal therapy is critical. According to expert consensus, voriconazole or isavuconazole monotherapy is recommended as initial treatment for IPA, with combination therapy for severe cases [5,12,13]. Treatment approaches across the reviewed cases were broadly similar, typically involving combinations of antibacterial agents with or without antifungal and antiviral therapy. Voriconazole was the primary antifungal in most patients, consistent with guideline recommendations. Of note, 6 patients received 2 or more antifungal agents during their treatment course [17,18,20,22,24,26], reflecting the complexity and severity of fungal infection in some cases. Our patient initially received voriconazole, with subsequent addition of caspofungin as combination therapy. However, despite this intensified regimen, pulmonary lesion control remained suboptimal, possibly attributable to concurrent bacterial co-infection (with Pseudomonas aeruginosa) and SARS-CoV-2 infection. Regarding antiviral therapy, although no agent has been definitively proven to be effective for SFTS in controlled trials, favipiravir was administered in our case based on a clinical trial evaluating its efficacy and safety in SFTS patients [10].

Furthermore, particular attention must be paid to the judicious management of modifiable risk factors, especially the use of corticosteroids. The literature cautions that corticosteroid use may increase the risk of secondary infections like IPA [32], and in our review of 13 cases, only 4 patients explicitly received corticosteroids during treatment [19,20,22,25]. In our case management, this informed a cautious approach toward corticosteroid use. The decision to prioritize specific antifungal and antiviral therapy over broad immunosuppression, guided by rapid mNGS results, likely contributed to the favorable outcome.

Despite early intervention initiated on day 3 after Aspergillus fumigatus was detected via mNGS in both blood and sputum, pulmonary lesions in our patient still progressed. This observation highlights the aggressive nature of SAPA and suggests that even prompt targeted therapy may not always suffice to halt disease progression. Given this challenge, identifying high-risk patients who might benefit from more proactive strategies becomes particularly important. Previous studies have identified various risk factors for IPA development in this population, including uncontrolled diabetes, central nervous system symptoms, platelet count <40×109/L [35], and more specific immunological markers (CD4 T cell count <68 cells/mm3 combined with a CD8 T cell count <111 cells/mm3, as well as interleukin 6 >99 pg/mL combined with interleukin 10 >111 pg/mL) [31]. Early identification of high-risk individuals based on these factors may facilitate timely prophylactic intervention. A study suggests that early antifungal prophylaxis in high-risk SFTS patients can significantly reduce SAPA incidence and mortality [7]. Consequently, future studies are needed to determine how best to stratify risk in this population and to evaluate the potential of targeted, risk-stratified prophylactic strategies in the highest-risk SFTS patients, while carefully balancing any such benefit against the overarching concern of promoting antimicrobial resistance.

Conclusions

In conclusion, this case, along with a literature review, highlights that SAPA represents a major challenge in SFTS management. However, its poor prognosis may be alterable through early intervention. The integration of rapid diagnostic technologies like mNGS into the clinical pathway can critically compress the time to diagnosis, enabling timely and targeted therapy.