Defined neuroaspergillosis in immunocompetent patients following COVID-19 infection: two cases and literature review

doi:10.21203/rs.3.rs-5302117/v1

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Defined neuroaspergillosis in immunocompetent patients following COVID-19 infection: two cases and literature review

https://doi.org/10.21203/rs.3.rs-5302117/v1

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In recent years, the advent of the SARS-Cov-2 pandemic has seen the emergence of neurological aspergillosis as a rare complication in immunocompetent patients infected with this pathogen. Neuroaspergillosis is a rare but serious infection of the central nervous system, typically observed in patients with compromised immune systems.

This article presents a case series of two patients with aspergillosis associated with SARS-CoV-2 infection at Peking Union Medical College Hospital and offers a literature review on this topic. This study included two cases of neuroaspergillosis associated with SARS-CoV-2 infection. A search was conducted on PubMed for reports of neuroaspergillosis related to SARS-CoV-2, and a literature review was subsequently performed. The study examined the characteristics of the patients, the clinical manifestations, the treatment, and the prognosis.

The findings revealed that the primary symptoms of neuroaspergillosis associated with SARS-CoV-2 infection included impaired consciousness, focal neurological deficits, and headaches, with a high mortality rate. The clinical diagnosis and treatment of the disease were challenging due to the difficulty of early detection and diagnosis.

This study reviews the mechanism, clinical manifestations, diagnosis, and treatment strategies of neuroaspergillosis in immunocompetent patients after SARS-CoV-2 infection. Furthermore, it discusses the clinical characteristics of the disease through two cases. Early diagnosis and treatment are essential for effective management of the disease.

neuroaspergillosis

COVID-19

central nervous system

next-generation sequencing

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the novel coronavirus, primarily affects the respiratory system, leading to novel coronavirus infection (COVID-19). This can manifest in a range of symptoms, including fever, cough, and fatigue[1]. In light of the existing knowledge regarding other coronaviruses and respiratory viruses, the potential involvement of the central nervous system (CNS) in the pathogenesis of SARS-CoV-2 has garnered significant attention. It is plausible that some patients may present with varying degrees of neurological symptoms^{[2, 3]}.

CNS aspergillosis has the highest mortality rate among invasive aspergillosis. Neuroaspergillosis is typically observed in individuals with immunosuppressed states, including those with HIV infection, organ transplantation, and prolonged administration of immunosuppressive medications[4]. The mortality rate of aspergillosis in immunocompetent patients is approximately 20%, while in immunocompromised patients, it can reach as high as 85%. Patients with immunosuppression typically have a documented history of immune system dysfunction, and Aspergillus often invades multiple sites. Aspergillosis of the central nervous system in immunocompetent patients typically manifests as an isolated brain lesion, which presents a significant diagnostic challenge^[5–8].

Due to the non-specific and heterogeneous nature of the clinical presentation of CNS mycobacteriosis, clinical diagnosis is difficult and diagnosis of CNS mycobacterial infections based on symptoms in the early stages can be challenging in immunocompetent patients. Symptoms may vary depending on the degree of intracranial involvement and may present as acute, subacute or chronic episodes. These symptoms include headache, seizures, focal neurological signs of mass effect and focal neurological deficits^{[9, 10]}.

This study presents two cases of SARS-CoV-2 infection with neurological aspergillosis in immunocompetent patients who were recently treated at Peking Union Medical College Hospital. The clinical manifestations, imaging, laboratory tests, treatment regimens, and outcomes of these two patients were analyzed in detail, and a review of the existing literature was conducted to explore the possible mechanisms, clinical manifestations, and management strategies of the disease. It is hoped that this will provide more clues to a better understanding of the mechanism of SARS-CoV-2 infection-related neuroaspergillosis and provide a reference for a more effective treatment of such patients.

The study included two patients with normal immune systems who were diagnosed with neuroaspergillosis and had contracted SARS-CoV-2 at Peking Union Medical College Hospital(I-23PJ1643). The diagnosis of neuroaspergillosis was made in accordance with the Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium^[11].

The study collected the patients' clinical manifestations, serum and cerebrospinal fluid results, neuroimaging data, treatment and results was approved by the Peking Union Medical College Hospital Ethics Committee. A literature review was conducted in PubMed using the keywords "neuroaspergillosis," "central nervous system aspergillosis," and "invasive cerebral aspergillosis." Additionally, the terms "Covid-19" and "case reports" were included in the search. Articles and case reports related to the topic of interest were selected, with the exclusion of those with immunosuppressed backgrounds.

3.1 Case 1

A 69-year-old man with history of lung cancer brain metastasis who was diagnosed with COVID-19 during the peak of the pandemic in China. The patient had previously received chemotherapy and immunotherapy for left lung adenocarcinoma, resulting in disease stability for 18 months. A ventriculoperitoneal shunt surgery was performed six months prior to presentation to address normal pressure hydrocephalus, which led to a stable postoperative condition. The patient had no comorbidities such as diabetes, hormone use, or immunosuppressive therapy.

The patient presented with symptoms of cough, wheezing, and fever, with a maximum temperature of 37.6°C. A throat swab COVID-19 antigen test confirmed the presence of the virus, and the patient was subsequently treated with budesonide nebulization at home.

However, ten days after the initial symptoms, the patient's wheezing worsened, accompanied by productive cough with yellow sputum. Additionally, he experienced seizures and transient loss of consciousness, prompting him to seek urgent care at Peking Union Medical College Hospital.

Upon arrival at the emergency department, the patient exhibited a body temperature of 37.7°C, Arterial blood gas analysis revealed a partial pressure of oxygen of 79 mmHg, a partial pressure of carbon dioxide of 27 mmHg, a lactate level of 2.8 mmol/L, a white blood cell count of 12.13 × 10^9/L with 85.7% neutrophils, and pulmonary CT findings indicative of increased lung texture.

The patient was promptly initiated on treatment with budesonide for anti-infective therapy. However, his condition rapidly deteriorated, and on the following day, he developed worsening respiratory distress and aggravated consciousness impairment, necessitating endotracheal intubation in the emergency department. Subsequently, we improved sputum culture and lumbar puncture.

The lumbar puncture pressure was 170 mmH2O, and the cerebrospinal fluid was sent for routine examination, biochemical analysis, and NGS pathogen sequencing. The routine examination of the cerebrospinal fluid showed a total white blood cell count of 293 cells/mm^3 with 50.2% monocytes and a cerebrospinal fluid protein level of 1.56 g/L.

Consider diagnosing lung infection while not ruling out intracranial infection. Administer a combination of vancomycin and meropenem for anti-infection treatment. On the second day, the patient was transferred to the neurosurgery ward. We collected cerebrospinal fluid again from the VP drainage tube, which showed a white blood cell count of 130 and a polymorphonuclear ratio of 73.8 on routine examination. Cerebrospinal fluid analysis revealed an elevated glucose level of 10.1 and an elevated protein level of 1.15. At the same time, we sent another sample for NGS (Next-Generation Sequencing) and bacterial culture. On the third day, the patient underwent VP shunt removal surgery, as well as an external ventricular drain (EVD) placement and tracheostomy.

The sputum culture on that day indicated multidrug-resistant Acinetobacter baumannii. Unfortunately, the patient's pneumonia worsened, leading to respiratory and circulatory failure, and the patient passed away.

The sputum culture report then indicated infection with Acinetobacter baumannii and Aspergillus fumigatus (smoke-colored new Satoa fungus). Subsequently, a postmortem examination was performed. The postmortem results indicated extensive fungal pneumonia in both lungs, extensive lung necrosis, and lung abscess. Meningitis of the meninges was possibly fungal in nature (Fig.1).

Fig. 1

1A. The brain CT and brain MRI.

1B. grayish-yellow abscess foci is discernible upon visual examination of the brain tissue.

1C. Focal inflammatory cell infiltration in the meningeal fibrous tissue and perivascular area.

1D. Fungal spores in brain tissue.

1E. Fungal hyphae and clusters in nodules of lung tissue

1F.Areas of coagulative necrosis and a large inflammatory cell infiltrate in the lung tissue.

3.2 Case 2

30-year-old female with pregnant (19 weeks and 4 days) developed symptoms such as cough and sputum production. A throat swab test confirmed a positive result for COVID-19 antigen. The patient did not receive any specific treatment but recovered on her own. 25 days later, she experienced dizziness after exertion, which gradually worsened. She had unsteadied gait and poor movement in the right limbs, followed by drowsiness and unresponsiveness the next day.

An enhanced MRI of the head revealed a large, elongated T1T2 signal shadow with blurred margins and uneven internal signals in the left temporal lobe. Patchy enhancement was observed after contrast administration, along with partial enhancement of the meninges and compression and displacement of the adjacent lateral ventricle, resulting in midline shift to the right with accompanying herniation of the brain falx. Chest CT showed a nodular high-density shadow in the upper right lung with calcification.

The next day patient's drowsiness worsened, she appeared indifferent, unable to respond verbally, and had right-sided hemiplegia and an emergency surgery under general anesthesia was performed to remove the brain lesion.

The postoperative brain tissue pathology showed granulomatous inflammation with Langhans giant cells and caseous necrosis, along with infiltration of chronic inflammatory cells, suggestive of a possible tuberculosis infection. Special staining revealed acid-fast staining (-), positive staining with PAS (Periodic Acid-Schiff), positive staining with silver stain (six-amine silver), and positive staining with fungal immunofluorescence. Postoperative blood tests showed a white blood cell count (WBC) of 11.5×10⁹/L. Multiple lumbar punctures were performed, with the patient reporting a pressure of 200+ mmH₂0. Cerebrospinal fluid (CSF) analysis showed a change from pale yellow and clear to pale yellow and turbid, with WBC counts of 90×10⁶/L (predominantly monocytes), 1800×10⁶/L (predominantly polymorphonuclear cells), and 310×10⁶/L. The Pan's test was positive.CSF biochemical analysis showed elevated protein levels (PRO) of 635mg/L↑, 1778mg/L↑, and 1418mg/L↑, decreased glucose levels (GLU) from 2.34mmol/L↓ to 0.84mmol/L↓, and a decreased chloride level (Cl) from 119mmol/L↓ to 120mmol/L. CSF GM test was positive, while CSF bacterial and fungal tests were negative.

A week later CSF NGS (Next-Generation Sequencing) revealed Aspergillus. Based on the pathology, staining, and NGS results, fungal infection (Aspergillus infection) was considered possible, and the patient received voriconazole 0.2g intravenous every 12 hours for anti-infection treatment, as well as treatment for intracranial pressure reduction, antiepileptic measures, and enteral nutrition through a gastric tube. The patient's drowsiness gradually decreased, right-sided hemiplegia improved, and she became responsive. Blood tests and CRP (C-reactive protein) levels returned to normal.

Due to concerns about the side effects of voriconazole, it was switched to isavuconazole 200mg intravenous once daily after using voriconazole 50 days.

Subsequently, the patient gradually developed adhesions in the right ventricle of the brain and hydrocephalus in the left ventricle. The patient noticed a decline in muscle strength compared to before, increased dizziness, and decreased mobility in the right limbs (e.g., inability to perform fine activities like holding chopsticks and needing assistance while walking). There were no changes in vision or visual field. A repeated lumbar puncture showed a self-reported pressure of 80+ mmH₂0, and CSF analysis and biochemistry were negative 6 months later. (Fig.2)

Fig. 2

2A. The brain MRI.

2B. Postoperative brain tissue.

2C. Fungal spores in left temporal lobe.

2D. Fungal fluorescence staining in left temporal lobe.

2E. Langhans giant cells and caseous necrosis in sphenoid sinus.

2FFungal fluorescence staining in sphenoid sinus.

Among the seven previously reported cases, three were male and four were female. The principal neurological manifestations were impaired consciousness, focal neurological symptoms, headache, and nausea. Most patients underwent surgical intervention following the onset of neurological symptoms and the identification of intracranial lesions. At present, pharmacological treatment primarily entails the use of Voriconazole, Amphotericin B, or a combination of these agents.

The primary clinical diagnosis of SARS-CoV-2-related aspergillosis is based on imaging evidence and the identification of neurological symptoms in conjunction with tissue biopsy, cerebrospinal fluid analysis, or tissue culture, as well as next-generation sequencing analysis.

The overall treatment effect for patients receiving treatment is favorable; however, the combination of other complications ultimately results in multiple organ failure, which is the primary cause of mortality in patients with a co-infection of SARS-CoV-2 and aspergillosis. Neurological aspergillosis is not suspected or diagnosed in a timely manner, resulting in delays in the complete diagnosis and treatment process (Table.1).

Table.1

Cases/ (year)	case number	Age	Sex	Neurological symptoms/ Physical finding	Location of infection	Hydrocephalus	Diagnostic method	Medicine treatment	Surgery	OUTCOME
Tamara et al. 2023^[12]	1	69	Male	vision loss	Lungs vitreum Cerebral	Absent	vitreous PCR and brain MRI	Voriconazole	plana vitrectomy	Survived
Subhashree et al. 2023^[13]	2	51	Female	sudden onset headache, vomiting, hemiparesis	Lung Cerebral	Absent	Serum GM + Culture and Brain MRI, Autopsy Pathology	Voriconazole	frontal craniotomy and abscess drainage	Expired
Rajeev etn al. 2023^[14]	3	33	Female	headache followed by left-sided weakness, Generalized seizure	Lung Cerebral	Absent	Biopsy Pathology, brain CT/MRI	Voriconazole, antiepileptics	Right frontoparietal craniotomy with abscess drainage and excision	Survived
Kazem et al. 2023^[15]	4	11	Female	Vomiting, loss of consciousness, Edematous brain with cortical lesions	Lung Cerebral Bone marrow	Absent	Biopsy Pathology	amphotericin B, Voriconazole	Left frontal osteoplastic craniotomy and brain biopsy	Survived
C.G. Videla et al. 2023^[16]	5	19	Male	Encephalopathy	Lung Cerebral	Absent	Autopsy Pathology	amphotericin B	erythropheresis and transjugular intrahepatic portosystemic shunt	Expired
Samuel et al. 2022^[17]	6	58	Female	Confusion, dysarthria, and stupo	Cerebral	Absent	Biopsy Pathology	amphotericin B, Voriconazole	Cerebral Lesion resection via a transcortical approach	Survived
Atousa et al. 2021^[18]	7	35	Male	Facial Palsy	Lung Cerebral	Absent	BAL sample Culture, Brain MRI	amphotericin B, Voriconazole	N.A.	Expired

Aspergillosis is caused by several species of Aspergillus, which are ubiquitous in the environment, typically found in soil and decaying plant matter.

The spores can enter the lungs, sinuses, and other cavities through the respiratory tract, where they subsequently colonize the affected areas. Neuroaspergillosis is a rare but serious opportunistic infection of the central nervous system that typically affects patients with impaired immune function^{[4, 19, 20]}. However, recent studies have demonstrated that such infections may occur even in immunocompetent individuals, particularly following infection with SARS-CoV-2^{[2, 3]}. This study, based on two cases of neuroaspergillosis associated with SARS-CoV-2 infection and a comprehensive literature review, aims to explore the pathogenesis, clinical manifestations, diagnosis, and treatment strategies of the disease in immunocompetent patients.

The two cases described in this study were of immunocompetent patients who developed neuroaspergillosis after a SARS-CoV-2 infection. In previous clinical studies, the onset of invasive aspergillosis was frequently observed in patients with a preexisting malignancy or chronic immunosuppression. Typical risk factors include severe and prolonged neutropenia, high-dose steroid therapy, or conditions that cause chronic impairment of cellular immune responses, such as bone marrow or solid organ transplantation and AIDS^[20]. Additionally, immunosuppression due to chronic diseases such as diabetes carries an inherent risk. Hematogenous spread can result in three common pathological forms, namely meningitis, abscess formation, and vascular lesions. These pathological features are largely attributable to the vascular invasiveness of the Aspergillus filaments, which can invade medium and large arteries, leading to secondary thrombosis and infarction. The subsequent purulent changes are due to the direct invasion of the filaments from the vascular wall to necrotic tissue, leading to encephalitis and later abscess formation^{[21, 22]}.

Although immunosuppression is a recognized risk factor for neural varicosis, the intricate response of the immune system following SARS-CoV-2 infection may have heightened susceptibility. The cytokine storm induced by SARS-CoV-2, particularly the overexpression of IL-6 and IL-1, along with the reduction of T lymphocytes, may be a crucial factor contributing to this form of infection^{[23, 24]}. Prior research has demonstrated that SARS-CoV-2 infection can disrupt and compromise the host immune system through various mechanisms, including a reduction in T lymphocytes and an increase in interleukin (IL-1 and IL-6) levels. This can create an environment conducive to the invasion of opportunistic pathogens such as Aspergillus^[25–27]. Furthermore, direct damage to vascular endothelial cells and alveolar epithelial cells in patients with SARS-CoV-2 infection may contribute to increased neurologic susceptibility, leading to the development of neurotropic aspergillosis^[28–30].

In case reviews, patients with COVID-19-associated neural aspergillosis have been found to present with a variety of clinical manifestations, including headache, fever, impaired consciousness, and focal neurologic deficits ^[12–18]. These symptoms are like those associated with other central nervous system infections or tumors, which can lead to delays in clinical diagnosis. Therefore, early imaging and laboratory tests are essential for the early recognition and treatment of such infections^{[31, 32]}. Imaging plays a crucial role in the diagnosis of neural varicose disease. Magnetic resonance imaging (MRI) and CT scans can demonstrate low-density foci within the brain parenchyma. However, these imaging manifestations lack specificity and may be confused with other lesions.

Further confirmation of the diagnosis requires the performance of a brain tissue biopsy or cerebrospinal fluid analysis in conjunction with pathology and microbiology testing, the objective of which is to identify the presence of Aspergillus. However, even after a comprehensive diagnostic evaluation and aggressive treatment, the prognosis of neurotropic aspergillosis remains poor, primarily since such infections are often identified in the late stages of the disease process^{[33, 34]}.

Metagenomic next-generation sequencing (mNGS) is a high-throughput sequencing technology that does not rely on in vitro culture and allows for the non-targeted detection of clinical nucleic acid sequences of pathogens in specimens, which has high application value for the pathogenic diagnosis of infectious diseases. In a diagnostic test, when the cutoff value of the number of specific sequences is 2 (≥ 2 is positive), the sensitivity and specificity of cerebrospinal fluid mNGS for the diagnosis of ICA are 85.7% and 84%, respectively. mNGS of cerebrospinal fluid has been demonstrated to effectively identify pathogens of infectious central nervous system diseases, which is of great significance for the diagnosis of cerebral aspergillosis^[35–37].

Therapeutically, neurotropic aspergillosis is typically treated with one of three antifungal medications: voriconazole, amphotericin B, or echinocandins. However, it should be noted that individual differences may exist regarding the susceptibility of Aspergillus to these antifungal drugs. Different Aspergillus species may respond differently to the drugs in question^{[33, 38, 39]}. Despite the theoretical efficacy of antifungal therapy for Aspergillus infections, its actual efficacy is often suboptimal due to the invasive nature and late diagnosis of Aspergillus neuropathies. In recent years, with the global spread of infections from the SARS-CoV-2 virus, there have been increasing reports of cases of Aspergillus infection in patients without underlying immune deficiencies^[40]. This phenomenon has attracted widespread attention. The emergence of these cases indicates that SARS-CoV-2 infection may enhance the susceptibility of immunocompetent patients to Aspergillus infections via a complex mechanism that affects the host immune system. These cases further underscore the significance of prompt diagnosis and aggressive treatment. In the context of the ongoing pandemic, clinicians must remain vigilant for the potential emergence of Aspergillus neurologicus as a complication, particularly in immunocompetent patients. If patients present with unexplained neurological symptoms and conventional treatment proves ineffective, the possibility of neurotropism should be considered, and relevant imaging and laboratory tests should be conducted without delay^{[41, 42]}.

In conclusion, the two cases presented in this study, along with the findings of the literature review, indicate that neural varicose mycosis may emerge as a rare yet significant complication in immunocompetent patients following SARS-CoV-2 infection. This finding suggests that, in the context of the ongoing SARS-CoV-2 pandemic, the pathogenesis of neural aspergillosis may involve complex immune and inflammatory responses. Currently, therapeutic options rely heavily on antifungal drugs, but given the complexity of the disease and the variability between patients, further research is needed to optimize diagnostic and therapeutic strategies and improve patient prognosis.

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All authors agree to publish the results/data/figures in this manuscript.

Competing interests:

All authors have no competing interests.

Funding:

National High Level Hospital Clinical Research Funding(2022-PUMCH-C-032)

Author Contribution

Chang Jianbo and Fang Ziyuan analyzed the result and wrote the main manuscript text. Wei Junji analyzed the result and revised the manuscript. Liu Ziyuan, Pan boju, Zhao Jing, Li Ji, Zhang Dong, Ruan Guiren, Ma Xiaojun, Zhang Guojie, Zhang Xiao, Mei Tao collected the data.

Acknowledgements:

Not applicable.

Data Availability

Data is provided within the manuscript or supplementary information files.

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Defined neuroaspergillosis in immunocompetent patients following COVID-19 infection: two cases and literature review

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1. Introduction

2. Materials and methods

3. Case Descriptions

4. Literature review

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Version 1