Disseminated Aspergillosis with Mediastinal Invasion Causing Fatal Stroke in an Immunocompetent Young Man

Abstract

Introduction

Aspergillus flavus is a common cause of aspergillosis.

Case Presentation

A previously fit and well, immunocompetent 27-year-old male living in Australia developed disseminated A. flavus complex infection with mediastinal and cardiac invasion, superior vena cava obstruction and stroke, with fatal haemorrhagic transformation.

Conclusion

Aspergillus Flavus is a rare but important cause of serious disease in the immunocompetent.

Introduction

Aspergillus flavus complex is a common species cause of invasive aspergillosis, second only to Aspergillus fumigatus, accounting for 13% of cases in one study of infections from transplantation centres in North America [1]. It usually affects immunocompromised hosts, in particular those with prolonged neutropenia, allogeneic haematopoietic stem cell transplant recipients, solid organ transplant recipients, advanced acquired immunodeficiency syndrome (AIDS) patients and those on high-dose corticosteroids. It rarely causes invasive disease in the immunocompetent and risk factors are poorly defined but likely include diabetes mellitus, intravenous drug use, and indwelling venous catheters [2, 3].

Case Report

A 27-year-old Indian male was admitted to the Royal Adelaide Hospital in Adelaide, Australia, in August 2021 with a right middle cerebral artery acute ischaemic stroke (AIS). He had no significant medical history, was systemically well, and had lived in Australia since 2014. He awoke with left arm/leg weakness. On initial examination, he was afebrile and in sinus rhythm, with a moderate left facial droop, hemi-hypoesthesia, and mild left-sided neglect. Multimodal computed tomography (CT) brain imaging demonstrated a proximal right M2 occlusion with a moderately sized perfusion lesion (Fig. 1a–c). He was initially treated with aspirin and clopidogrel (endovascular thrombectomy and/or thrombolysis were precluded by mild symptoms and prolonged time from last-known-well to presentation).

Fig. 1.

a Top left.b Top right. c Bottom left. d Bottom right.

On day two post-symptom onset, he developed a junctional bradycardia with absent atrial contraction, suggesting a cardioembolic source for his AIS. On review, the inferior aspect of his CT angiogram demonstrated a mediastinal mass. Given the small infarct volume on magnetic resonance imaging and strong clinical suspicion of malignancy-related cardioembolism he was changed from aspirin and clopidogrel to apixaban (5 mg twice daily).

He underwent a CT Chest/Abdomen/Pelvis which demonstrated a large superior mediastinal mass causing superior vena cava obstruction. Given chronic (asymptomatic) bronchiectasis, tuberculosis was an initial diagnostic consideration and he was placed in isolation on full respiratory precautions. Following subsequent clinical deterioration (below) review of imaging further disclosed a 70 mm × 15 mm left anterior thigh superficial fascia lesion without inguinal or subdiaphragmatic lymphadenopathy, and multiple subtle sclerotic metastatic-appearing lesions throughout the axial skeleton and sternum (Fig. 2a–f).

Fig. 2.

a Top left. b Top middle. c Top right. d Bottom left. e Bottom middle. f Bottom right.

Pathology results are shown in Table 1. Transthoracic echocardiography showed a distorted aortic root with a mass in the interatrial septum towards the aortic root, with probable extension along the roof of the left atrium suspicious for neoplasm or infection. Left ventricular ejection fraction was normal (approx. 65%) with no mitral or aortic valvular abnormalities. Left atrial size was reduced due to the mass, with flow turbulence. Right ventricular size and function were normal.

Table 1.

Pathology results

Test	Reference range, SA pathology	On presentation to hospital	Day 3 of admission
Haemoglobin, g/L	135–175	129	99
White cell count, ×109	4–11	12.2	18.64
Neutrophils, ×109	1.8–7.5	6.9	16.67
Lymphocytes, ×109	1.1–3.5	1.36	1.12
Monocytes, ×109	0.2–0.8	0.6	0.5
Eosinophils, ×109	0.02–0.5	3.2	0.2
Basophils, ×109	<0.1	0.21	0.15
Platelets, ×109	150–450	370	550
Prothrombin time, s	12–16	19.2	28.7
International normalised ratio	0.9–1.2	1.4	2.2
Activated partial thromboplastin time, s	24–38	33	31
Apixaban level – anti-Xa activity assay, μg/L	40–230		124
Sodium, mmol/L	135–145	136	141
Potassium, mmol/L	3.5–5.2	4.3	4.8
Chloride, mmol/L	95–110	102	110
Bicarbonate, mmol/L	22–32	22	21
Urea, mmol/L	2.7–8.0	3.2	3.4
Creatinine, μmol/L	60–110	95	70
eGFR, mL/min/1.73m2	>60	>90	>90
Corrected calcium, mmol/L	2.10–2.60	2.45	2.44
Phosphate, mmol/L	0.75–1.50	0.82	0.77
Albumin, g/L	34–48	34	26
Globulin, g/L	21–41	59	48
Bilirubin, μmol/L	2–24	8	15
Gamma glutamyl transferase, U/L	0–60	46	30
Alkaline phosphatase, U/L	30–110	118	78
Alanine aminotransferase, U/L	0–55	27	14
Aspartate aminotransferase, U/L	0–45	18	25
Lactate dehydrogrenase, U/L	120–250	206	190
Glucose, mmol/L	3.2–5.5*	5.6	9.7
HbA1c, %	≤7	5.5
C-reactive protein, mg/L	0.0–8.0	55.4
Erythrocyte sedimentation rate, mm/h	1–10	37
NT-pro brain natriuretic peptide, ng/L	0–124	602
25-hydroxy vitamin D3, nmol/L	60–160	5
Thyroid stimulating hormone, mIU/L	0.50–4.50	2.92
Angiotensin-converting enzyme, U/L	20–70	36
Alpha fetoprotein	≤7	1
Human chorionic gonadotropin tumour marker, IU/L	≤0.3	<0.3
Beta-2 μglobulin, mg/L	0.6–2.9	2.3
Homocysteine, μmol/L	4–14	10
Alpha-galactosidase activity DBS 4MU, nmol/h/mL	2.0–6.9	4.7
Antithrombin, %	80–125	88
Protein C, %	65–130	77
Protein S, %	65–155	85
Lupus anticoagulant (via dRVVT)		Negative
Beta-2 glycoprotein 1 antibody, GU	≤19	<1
Cardiolipin IgG, GPL units	≤8	3
F2 (prothrombin) common variant gene F2:c.*97G>A		Not detected
F5 (factor V) common variant gene F5:c.1601G>A		Not detected
Anti-nuclear antibody		Speckled; 1:80
Extractable nuclear antigen		Negative
Anti-neutrophil cytoplasmic antibody		Negative
Rheumatoid factor, IU/mL	≤13	<13
Total IgG, g/L	7.00–16.00	28.12
IgG1, g/L	3.76–7.96	11.71
IgG2, g/L	2.25–7.41	5.81
IgG3, g/L	0.21–1.16	1.18
IgG4, g/L	0.12–0.96	6.10
IgA, g/L	0.70–4.00	2.48
IgM, g/L	0.40–2.30	1.83
IgE, kU/L	≤119	1,693
Tryptase, μg/L	<11.9	4.0
Paraprotein, g/L		0†
Kappa-free light chain, mg/L	3.00–19.00	54.75
Lambda-free light chain, mg/L	6.00–26.00	24.93
Kappa/lambda-free light chain ratio	0.25–1.65	2.20
Complement C3, g/L	0.90–1.80	1.58
Complement C4, g/L	0.10–0.40	0.27
Flow cytometry (blood)		‡
HIV 1/2 (p24 core antigen + HIV antibody)		Not detected
Mycobacterium tuberculum interferon-gamma release assay, IU/mL		Negative
Schistosoma IgG, s/co	Equivocal: 0.9–1.1	0.94
Strongyloides IgG, s/co	Not detected: <0.9	0.32
Toxoplasma gondii IgG, IU/mL	Not detected: <1.0	0.18

*Reference range shown for fasting glucose; actual specimens were not fasting.

^†Electrophoresis shows a diffuse hypergammaglobulinaemia.

^‡An expanded population of eosinophils was detected based on CD45 and side scatter. They comprised approximately 27% of total nucleated cells. There is no atypical expression of lymphoid markers. Interpretation: There is no evidence of B cell monoclonality. There is no atypical expression of T cell markers.

On day 3, the patient deteriorated neurologically, with progressive left hemiparesis and obtundation culminating in bilateral fixed and dilated pupils. Repeat non-contrast CT (Fig. 1d) demonstrated a large right parietal intraparenchymal haemorrhage with intraventricular and subdural haemorrhagic extension, obstructive hydrocephalus, 17 mm of midline shift and both parafalcine and uncal herniation. He received emergency right hemicraniectomy with haematoma evacuation and intracranial pressure monitor insertion.

On day 4 of admission, a left thigh lesion was noted on further radiological review, then palpated and biopsied. The patient was started on empiric meropenem (2 g 3 times daily) and voriconazole (6 mg/kg twice daily) therapy. Biopsy cultures ultimately grew A. flavus complex.

On day 6 of admission, there were no clinical signs of neurological recovery and he met clinical criteria for brain death [4]. Autopsy showed disseminated A. flavus complex infection involving the brain, mediastinum and left thigh. Angioinvasive right middle cerebral artery embolism with infiltration of the right frontoparietal brain parenchyma was present as the cause of haemorrhagic transformation, presumably embolic from aortic invasion. The 120 mm × 80 mm superior mediastinal mass-forming A. flavus complex infection demonstrated necrotising granulomatous and eosinophilic inflammation encasing the aorta, right pulmonary artery and the superior vena cava, and infiltrating both atria and right ventricular myocardium and endocardium. The 80 mm left thigh soft tissue lesion was confirmed to be granulomatous A. flavus complex mass.

Discussion

A. flavus is a common cause of cutaneous aspergillosis, fungal sinusitis, and keratitis but is only responsible for 10% of pulmonary infections [5]. Mediastinal and intracardiac Aspergillus infection is a rare phenomenon [6]. A. flavus infection leading to AIS was reported in an immunocompetent child [7], but mediastinal invasion leading to septic embolism resulting in adult stroke appears hitherto unreported.

Fungal pathogens most commonly implicated in AIS include hyphae-forming moulds such as Aspergillus and Mucor species, as well as yeasts including Candida and Cryptococcus species [3, 8]. These moulds are angioinvasive, increasing the likelihood of arterial thrombosis and embolism, in contrast to yeasts which may be more likely to cause multiple punctate strokes due to meningitis and effects on the microvascular circulation [3, 9].

Established risk factors for invasive aspergillosis in immunocompromised hosts include neutropenia and glucocorticoid therapy. Invasive aspergillosis in immunocompetent hosts is exceedingly rare, of unclear cause and was unsuspected in the current case.

Given the rapidly progressive course of invasive aspergillosis, early diagnosis and treatment are essential to prevent dissemination. In cases where cutaneous aspergillosis is suspected, skin biopsy and histopathological examination are required to confirm diagnosis. Similarly to this case, histopathology usually demonstrates diffuse nodular granulomatous mixed infiltrate consisting of lymphocytes, histiocytes, giant cells, septate hyphae, neutrophilic microabscesses, and eosinophils in the dermis. Diagnosis is confirmed via culture.

Once diagnosed, disseminated A. flavus infection should be treated with Voriconazole [10]. Other antifungal regimens containing Amphotericin B and Azoles are less effective [11]. Morbidity and mortality despite antifungal therapy remains high although this may be confounded by patient comorbidities.

It is important to maintain a high index of suspicion in order to identify patients with invasive fungal disease early. In patients who present with AIS, additional features suspicious for invasive fungal disease include fever, headache, risk factors (including immunocompromise, indwelling venous catheters or intravenous drug use) and unusual imaging findings such as a mediastinal mass or leptomeningeal enhancement (which may be seen in central nervous system yeast infection) [3].

In the current case, septic embolism was not initially suspected given the absence of fever and systemic symptoms. Haemorrhagic transformation rates in the setting of bacterial endocarditis-related stroke are high with both thrombolysis and anticoagulation [12]. The risk of such treatments may be higher yet in septic fungal emboli, due to angioinvasion, although it is possible that fatal haemorrhagic transformation may have supervened even with anticoagulant avoidance. Nevertheless, stroke treatment caution in the setting of suspected fungal mediastinal invasion would be warranted in future cases.

In summary, this report describes a rare occurrence of fulminant disseminated and mediastinal A. flavus complex infection causing stroke with fatal haemorrhagic transformation in an immunocompetent man. There were no clinically apparent risk factors for disseminated Aspergillosis although it was possible that mild bronchiectasis was a predisposition, or that both represented an undiagnosed immunodeficient state. Thorough skin examination at the time of admission may have led to earlier diagnosis and avoidance of anticoagulation. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000536594).

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient’s next of kin for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interests to declare.

Funding Sources

The authors have no funding sources to declare.

Author Contributions

R.Y. and R.G. were each major contributors in writing the manuscript; E.P.R., K.S., and T.K. each contributed to editing of the manuscript and analysing the case. All authors read and approved the final manuscript.

Funding Statement

The authors have no funding sources to declare.

Data Availability Statement

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.