Central nervous system Aspergillus fumigatus infection with subarachnoid haemorrhage secondary to hemophagocytic lymphohistiocytosis: a rare case report

Abstract

Background

Secondary central nervous system (CNS) Aspergillus fumigatus infection leading to subarachnoid hemorrhage following the onset of hemophagocytic lymphohistiocytosis (HLH) represents an extremely rare case. We provide a detailed account of the disease course, including laboratory results and brain imaging.

Case presentation

A 23-year-old male patient presented with fever and was subsequently diagnosed with HLH after comprehensive examinations. His symptoms were significantly alleviated following treatment with liposomal doxorubicin, etoposide, and methylprednisolone. Three months later, the patient returned with headaches. After completing brain MRI and cerebrospinal fluid next generation sequencing (NGS), he was diagnosed with CNS Aspergillus fumigatus infection. Antifungal treatments including caspofungin, voriconazole, and amphotericin B were administered sequentially. Various indicators were dynamically monitored throughout the course, including cerebrospinal fluid NGS. Four months after the diagnosis of CNS Aspergillus fumigatus infection, the patient suddenly developed subarachnoid hemorrhage, and deceased one month later.

Conclusions

Patients with HLH on immunosuppressive therapy may be at increased risk of invasive fungal infections, including CNS Aspergillus fumigatus, and close follow-up is necessary. Early completion of cerebrospinal fluid NGS in patients suspected of having concurrent CNS Aspergillus fumigatus infection has positive significance for diagnosis and treatment. Aggressive treatment also plays a significant role in prolonging life expectancy.

Background

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressive inflammatory disorder. HLH can be classified as primary or secondary. Primary HLH is mostly caused by genetic mutations that affect the cytotoxicity of T lymphocytes and NK cells, and is most common in children. Secondary HLH can occur in infections, malignancies, autoimmune or metabolic diseases [1]. Occasionally, idiopathic HLH may occur for unknown reasons. HLH is frequently misdiagnosed or overlooked in clinical practice, posing significant challenges in its early diagnosis and effective treatment [2]. Aspergillus species, a kind of filamentous fungi ubiquitous in nature, found immunocompromised groups the most vulnerable, functioning both as opportunistic pathogens and potentially lethal infectious agents. While pulmonary infections are the most common sites of Aspergillus infection, central nervous system (CNS) Aspergillus remains uncommon, constituting only 1% of all cases [3]. CNS Aspergillus fumigatus infections are characterized by atypical symptoms, rapid progression, diagnostic difficulties, and poor outcomes. Moreover, CNS Aspergillus fumigatus infections may be complicated by cerebrovascular accidents during the course [4–5]. We presents a case from Hainan Hospital of Chinese PLA General Hospital, where a patient diagnosed with HLH subsequently developed CNS Aspergillus fumigatus infections, culminating in subarachnoid hemorrhage and death from brain herniation.

Case presentation

Fever and HLH

A 23-year-old male was admitted to Hainan Hospital of Chinese PLA General Hospital in late July 2023 due to fever. The patient had been in good health prior to this episode. Neurological examination revealed no abnormal signs. Laboratory results indicated decreased white blood cells, neutrophils, hemoglobin, platelets and fibrinogen, with elevated serum ferritin, triglycerides, D-dimer, aspartate aminotransferase, lactate dehydrogenase, total bilirubin, creatinine, urea nitrogen, procalcitonin, interleukin-6, and C-reactive protein (Table 1). Other tests including thyroid function, autoantibodies, tumor markers, respiratory virus, TORCHS, cryptococcal capsular antigen, G test, GM test, tuberculosis, arbovirus nucleic acid test and blood cultures were all negative. No abnormalities showed on brain MRI (Fig. 1A), PET-CT, and lung CT. Abdominal CT indicated splenomegaly. Based on the laboratory and imaging findings, HLH was considered. Further bone marrow biopsy showing NK cell activity: 15.73%, sCD25: 18,197 U/ml. Bone marrow smear revealed 1% phagocytic cells. The patient was diagnosed with HLH (Hscore: 265). The treatment regimen chosen was liposomal doxorubicin (25mg/m², day 1), etoposide (100mg/m², first day of every week) and methylprednisolone (15 mg/kg/d day 1–3, 0.75 mg/kg/d day 4–7, 0.25 mg/kg/d day 8–10, 0.1 mg/kg/d day 11–14). The treatment programme is repeated every 2 weeks, and resulted in significant symptom alleviation and normalization of body temperature, laboratory tests improved on subsequent examinations as well (Table 1).

Table 1 Main laboratory indicators during the patient’s hospitalisation

Fig. 1

Dynamic changes in imaging results for the patient. (A) Normal brain MRI. (B) Enhanced brain MRI suggests dilatation of the lateral and fourth ventricles, with enhancement seen in the fourth ventricle. (C) Coronal view of brain MRI suggests marked bilateral lateral ventricular dilatation. (D) T2 sequences of brain MRI suggests dilatation of the lateral and tertiary ventricles. (E) Normal brain MRA. (F) Normal brain MRV. (G) Brain CT indicate subarachnoid hemorrhage, compression and swelling. (H) Brain CT suggests swelling with significant compression of the lateral ventricles compared to previous scans. (I) Brain CT showed further progression of subarachnoid hemorrhage and significant brain swelling compared to previous scans

Headache and CNS infection

In mid-November 2023, the patient was readmitted to hospital with fever, headache, and blurred vision. Brain MRI showed abnormal signals in the ventricles and ventricular dilation (Fig. 1B, C, D). Brain MRA and MRV demonstrated no significant abnormalities (Fig. 1E, F). The lumbar puncture were performed and indicated significantly elevated intracranial pressure, increased cerebrospinal fluid white blood cells and protein levels, while glucose and chloride were within normal ranges (Table 1). No bacteria, fungi, or acid-fast bacilli were detected in the cerebrospinal fluid smear. Next generation sequencing (NGS) for cerebrospinal fluid suggested an Aspergillus fumigatus sequence count of 1038. Consequently, the patient was diagnosed with CNS Aspergillus fumigatus infection. Treatment included a combination of caspofungin (100 mg/d) and voriconazole (6 mg/kg, 1/12 h day 1; 4 mg/kg, 1/12 h from day 2) for antifungal therapy, along with mannitol for reduction of intracranial pressure. After treatment, the patient’s body temperature normalized, although the headache persisted but was less severe. We dynamically monitored cerebrospinal fluid results including NGS during the hospital stay (Fig. 2).

Fig. 2

Dynamic changes in cerebrospinal fluid test indicators for the patient

Due to the persistent headache symptoms and no significant reduction in Aspergillus fumigatus sequence counts observed in dynamic cerebrospinal fluid NGS, we initiated amphotericin B (0.1 mg/kg/d day 1, increased by 5 mg every other day starting on day 2 to dose of 1 mg/kg/d) for intensified antifungal treatment in early December. Following the treatment, the patient’s headache symptoms were significantly alleviated. Cerebrospinal fluid NGS examination in late December indicated a substantial decrease in Aspergillus fumigatus sequence counts compared to previous results. Over the subsequent eight weeks, the patient’s condition remained stable, with notable clinical symptom relief. Unfortunately, due to significant renal impairment, amphotericin B was discontinued in February 2024.

Coma and subarachnoid haemorrhage

On March 10, the patient exhibited a decline in consciousness level. Brain CT showed minimal changes compared to previous scans. On March 13, the patient experienced a sudden decrease in pulse oximetry and entered a comatose state. A follow-up brain CT scan indicated subarachnoid hemorrhage, brain compression, and significant brain swelling (Fig. 1G, H). Another follow-up brain CT scan in early April showed further progression of subarachnoid hemorrhage and significant brain swelling compared to previous scans (Fig. 1I). Ultimately, the patient died from brain herniation in mid-April.

Discussion and conclusions

HLH is a rapidly progressive inflammatory disease, usually caused by the activation of lymphocytes and histiocytes due to various etiologies, leading to a multi-organ hyperinflammatory response syndrome induced by the secretion of a large number of cytokines [1]. Clinically, secondary HLH is more frequent, with common causes including infections, malignancies, and autoimmune diseases, but a considerable number of patients still have an unclear etiology [6]. The diagnosis of HLH requires meeting 5 out of the following 8 criteria: (1) Fever persisting for > 7 days, body temperature > 38.5℃; (2) Splenomegaly; (3) Cytopenia involving two or three lineages in the peripheral blood, hemoglobin < 90 g/L, absolute neutrophil count < 1.0 × 10⁹/L, platelets < 100 × 10⁹/L; (4) Hypertriglyceridemia and/or hypofibrinogenemia: triglycerides > 3mmol/L, fibrinogen < 1.5 g/L; (5) Bone marrow biopsy or biopsy of the spleen, lymph nodes, skin showing hemophagocytic cells without evidence of malignancy; (6) Decreased NK cell activity or complete absence; (7) Serum ferritin ≥ 500 µg/L; (8) sCD25 ≥ 2400 U/mL [7–8]. It is worth noting that there is a high degree of overlap between tick-borne infections and HLH in terms of clinical presentation, with both presenting with fever and pancytopenia. The highest number of tick-borne infections associated with HLH has been reported in the United States, which may be related to tick-borne pathogen distribution and environmental exposure. While considering the diagnosis of HLH in the clinical setting, clinicians need to pay close attention to local epidemiology, patient habits, and rapid pathogenicity testing results [9–10]. In terms of HLH treatment, the most important therapeutic goal is to control the immune response. Even though there are currently few prospective studies on first-line treatment for adult HLH, there is a commonly used treatment regimen that combines corticosteroids with etoposide [11–12].

Currently, there are few reports on CNS Aspergillus fumigatus infection following the onset of HLH. Aspergillus fumigatus is an opportunistic pathogen and also an important pathogen causing fatal infections. Immunocompromised populations and patients with immunosuppressive related diseases such as hematologic malignancies, HIV infection, solid organ transplants, systemic lupus erythematosus and rheumatoid arthritis etc. are the most vulnerable. Risk factors for Aspergillus fumigatus infections also include age, ethnicity and long-term use of drugs, including corticosteroids immunosuppressants and a variety of broad-spectrum antimicrobial drugs [13–14]. It is important to note that CNS Aspergillus fumigatus infection differs from other types in terms of route of infection, clinical presentation, and prognosis. In terms of routes of infection, CNS Aspergillus fumigatus infection is most often caused by haematogenous dissemination or direct sinus invasion [15]. Pulmonary Aspergillus infection is mostly due to direct inhalation of spores, and exposure to water mist containing Aspergillus spores may also trigger infection [16]. Liver abscess Aspergillus infection is rarer and is mostly due to haematogenous dissemination or damage to the mucosal barrier of the gastrointestinal tract [17]. Clinical symptoms of CNS Aspergillus fumigatus infection often presents insidiously manifesting fever, headache, visual disturbances, hemiplegia and consciousness disorders. In terms of imaging characteristics, parenchymal space occupying lesions are generally more common than meningitis [18]. Pulmonary Aspergillus infection is mainly manifested by cough, haemoptysis, chest pain and dyspnoea. The main manifestations of liver abscess Aspergillus infection is fever, abdominal pain, weight loss, chills, night sweats, fatigue, and liver enzyme elevation [19]. In terms of prognostic differences, CNS Aspergillus infection carries a very high risk of mortality. Data from earlier studies have shown that the overall mortality rate from CNS Aspergillus in adults exceeds 90% [20]. With continuous improvement in Aspergillus treatment, systematic studies have shown improved prognosis in recent years. In a study that included 235 patients, the overall mortality rate for CNS Aspergillus infection was 45.1% [21]. In a retrospective study, Kourkoumpetis found that patients with CNS Aspergillus had a 57.1% mortality rate during hospitalisation, and only 14.28% of patients achieved a survival of more than 2 years [22].

The diagnosis of CNS Aspergillus fumigatus infection is highly challenging. Currently, the gold standard for diagnosis remains pathological diagnosis. Due to the operational difficulties associated with invasive examinations, more and more cases relied mainly on cerebrospinal fluid NGS for diagnosis. NGS is a DNA sequencing technology developed based on PCR and gene chips. With its high throughput rapid efficiency and high precision in describing the transcriptome and genome of pathogens, it can accurately analyze the type of pathogen. In recent years, NGS has developed rapidly, making it possible to confirm the infectious pathogen at an early stage, especially improving the detection rate of rare pathogens like CNS Aspergillus fumigatus, thereby better guiding clinical diagnosis and treatment [23]. We found that in this patient, the early changes in cerebrospillular fluid NGS correlated positively with clinical symptoms. As the clinical symptoms improved significantly, the levels of cerebrospinal fluid NGS also decreased significantly, thus we believe that the level of cerebrospinal fluid NGS in the early stages of the disease can reflect the effectiveness of treatment to some extent. However, in the later stages of the disease, although there was significant progression in clinical symptoms, the changes in cerebrospinal fluid NSG were not very significant.

Regarding the treatment strategy for CNS Aspergillus fumigatus infection, it is generally believed that voriconazole combine with Amphotericin B may effective. Amphotericin B is highly toxic and has poor CNS penetration, but is an effective treatment for neuroinfections caused by fungi which are not susceptible to agents with good CNS penetration (e.g., voriconazole). Among antifungal drugs, voriconazole, fluconazole, and flucytosine readily penetrate into the CNS, but itraconazole and posaconazole only penetrate to a minor degree. Voriconazole is recommended as primary therapy for CNS Aspergillus, while amphotericin B are reserved for intolerant or refractory patients [24]. Literature reports that combining amphotericin B lipid complex with voriconazole for the treatment of Aspergillus fumigatus patients is an effective treatment regimen with fewer adverse reactions and lower costs [25].

CNS Aspergillus fumigatus infection can cause cerebrovascular complications. On the one hand, hyphae can directly block cerebral blood vessels, leading to ischemic stroke. On the other hand, Aspergillus fumigatus can release elastase to break down elastin in the vessel walls while hyphae penetrating the vessel wall and growing, further leading to thinning of the vessel wall and ultimately forming mycotic aneurysms [26]. Both ischemic stroke and aneurysm impose a significant burden on patients, with ruptured aneurysms leading to subarachnoid hemorrhage, significantly increasing the patient’s mortality rate [27–28]. For mycotic aneurysm rupture leading to subarachnoid hemorrhage, there is currently no unified and standardized treatment protocol.

In conclusion, this case review underscores the necessity of comprehensive etiological screening in patients with HLH. Patients with HLH on immunosuppressive therapy may be at increased risk of invasive fungal infections, including CNS Aspergillus fumigatus, and close follow-up is necessary. Early diagnosis and monitoring of CNS Aspergillus fumigatus can be facilitated through cerebrospinal fluid NGS. In the present case, amphotericin B administration yielded notable therapeutic benefits. However, vigilant renal function surveillance is essential. Sudden clinical exacerbations in CNS Aspergillus fumigatus infection patients warrant consideration of potential cerebrovascular complications. It is important to acknowledge the limitations of this study. While the HLH case discussed herein exhibited a rare complication of CNS Aspergillus fumigatus infection which ultimately resulted in subarachnoid hemorrhage, it should be emphasized that such outcomes are not indicative of HLH as a whole. In fact, HLH cases with these specific characteristics are exceptionally uncommon.