Coronavirus disease 2019 (COVID-19)-associated brain abscesses caused by Pseudomonas aeruginosa and Aspergillus fumigatus: two case and a review of the literature

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected over 505 million people and had caused 6.2 million deaths worldwide by 23 April 2022 [1]. Bacterial and fungal superinfections are increasingly reported in respiratory viral infections and have been related to increased morbidity and mortality [2‐4].

Emerging evidence suggests that the number of bacterial superinfections in patients with COVID-19 is rising [5, 6]. Previous studies have proposed that the epithelial damage and immune dysregulation caused by COVID-19 can facilitate adhesion and invasion of the bacteria [3, 7]. Klebsiella spp., methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Enterobacter spp., Streptococcus pneumoniae, and Pseudomonas aeruginosa have all been isolated from patients with COVID-19 [8, 9].

Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative bacteria that commonly causes nosocomial infections in immunocompromised patients and patients with structural lung disease [10]. Biofilm production results in higher antimicrobial resistance and allows chronic colonization of P. aeruginosa in the host [11]. An increased abundance of P. aeruginosa has been found in the nose of patients with COVID-19, which was positively associated with viral RNA load [12]. P. aeruginosa has also been isolated from endotracheal tube secretions and blood cultures of patients with COVID-19 [9]. In this article, we report the first case of COVID-19-associated brain abscess caused by P. aeruginosa.

Fungal coinfections, including aspergillosis, mucormycosis, candidiasis, histoplasmosis, and cryptococcosis, have been widely reported among patients with COVID-19. These infections involve different organs, such as the lungs, heart, and brain [4, 13]. The suggested factors that predispose patients with COVID-19 to invasive fungal infections include immune dysregulation, lymphopenia, inflammatory state, corticosteroid use, intubation and mechanical ventilation, broad-spectrum antibiotic use, and indwelling catheters [14, 15]. Aspergillus spp. are known to cause invasive and life-threatening infections in immunocompromised patients [16]. The most frequently reported Aspergillus spp. infection in patients with COVID-19 is COVID-19-associated pulmonary aspergillosis (CAPA) [17, 18]. A review study showed that the incidence of CAPA was 15.1% among intensive care unit (ICU)-admitted patients with COVID-19 and that it was associated with increased mortality. Corticosteroids and immunosuppressant drugs conferred the highest risk for aspergillosis in these patients [19]. A few studies have also reported cases of extrapulmonary aspergillosis in patients with COVID-19 [20, 21]. In this article, we report a case of post-COVID-19 brain abscess caused by Aspergillus fumigatus.

A 34-year-old Iranian woman presented to our hospital with progressive weakness of the left upper limb (started 10 days earlier with a wrist drop) and severe, sharp, nonpulsatile headaches accompanied by dizziness lasting 3–4 hours for 2 days. She also mentioned lower limb paresthesia 2 weeks before presentation. She had a history of COVID-19 infection a month prior to the presentation that was medically treated at home with remdesivir and corticosteroid injections, followed by oral prednisolone. She reported no fever, vomiting, or seizures and had no history of trauma or injection drug use. Neurological examination revealed an afebrile and oriented woman with decreased motor force in the left upper limb (3/5 proximally and 1/5 distally), a bilateral sensory level at T4, a left upward plantar reflex, and a mildly ataxic gait.

Initial laboratory results showed a normal leukocyte count (8500/µl, normal 4000–10,000), thrombocytopenia (97,000/µl, normal 140,000–440,000), elevated aminotransferases (ALT 171 IU/l, normal 5–40 and AST 113 IU/l, normal 5–40), increased lactate dehydrogenase (LDH 524 U/l, normal 225–500), elevated fasting blood sugar (FBS 201 mg/dl, normal 70–100), elevated hemoglobin A1c (7.4%, normal 3–6), normal erythrocyte sedimentation rate (ESR < 16 mm/h, normal < 20) and normal C-reactive protein (CRP < 6 mg/l, normal < 6).

Computerized tomography (CT) scan of the head revealed multiple round hypodense lesions with rim enhancement in the right frontal lobe (10 × 12 mm), left frontal lobe (10 × 10 mm), and right parietal lobe (23 × 28 mm) with surrounding vasogenic edema in favor of multiple brain abscesses. Paranasal sinuses were normal. Magnetic resonance imaging (MRI) of the head also showed multiple ring-enhancing round lesions with peripheral edema and with central diffusion restriction in both cerebral hemispheres consistent with brain abscesses. Abscesses had internal small foci of blooming artifact from blood product and hemorrhage. Cervical MRI revealed an intraaxial mass with peripheral enhancement and peripheral edema in favor of abscess formation at the level of C2–3 (Fig. 1A, B). CT scan of the chest showed multilobar peripheral ground-glass opacities in favor of resolving COVID-19 infection. Abdominal ultrasound, which was performed because of elevated aminotransferases, showed increased parenchymal echo of the liver suggestive of grade 1 fatty liver disease, and a round 5 mm lesion in the right kidney suggestive of angiomyolipoma.

Empiric therapy was started with vancomycin, ceftriaxone, metronidazole, cotrimoxazole, and liposomal amphotericin B. Blood cultures, sputum smear and culture for tuberculosis, rheumatologic panel, viral hepatitis panel, HIV antibody, and COVID-19 polymerase chain reaction (PCR) test came back negative. Serology results (IgM and IgG) for Toxoplasma gondii were positive. Two weeks after admission, the patient developed sudden worsening of the headache, and dysarthria, and facial asymmetry and right-sided weakness emerged. Repeated brain CT scan and MRI showed an increase in the number and size of the previous lesions, with new abscesses in the left thalamus with secondary hemorrhage (Fig. 1C). Ceftriaxone and metronidazole were discontinued, and meropenem was added to the antibiotic regimen.

The patient was scheduled for a stereotactic biopsy and drainage of the parietal lobe brain abscess and the intramedullary cervical abscess. Drained fluid from the abscesses was sent for microbiological evaluation, which revealed a moderate number of polymorphonuclear (PMN) cells, but no organisms. Despite appropriate medical therapy, the patient’s neurological symptoms did not improve, and she became increasingly lethargic. One month after admission, the patient entered cardiac arrest and could not be resuscitated. The brain MRI that was performed a few days before her death had shown an increase in the size of previous lesions as well as recollection of pus in the drained abscesses of the right parietal lobe and cervical spine (Fig. 1D).

A 45-year-old Iranian man presented to our hospital with lethargy and right-sided weakness that started a week earlier. He also reported an episode of loss of consciousness lasting 5 minutes, which was not accompanied by jerking movements or gaze according to the witnesses, and the patient regained consciousness after 30 minutes. He did not report any headaches, dizziness, fever, or history of head trauma. He had a history of COVID-19, 3 months ago, which was complicated by pleural effusion and pneumothorax and led to ICU admission. He was discharged from the previous hospital 3 weeks prior to these presentations. Other than the mentioned conditions, his past medical history included ischemic heart disease for which he underwent coronary artery bypass grafting (CABG) 7 years ago. His current medications included aspirin and metoprolol.

Physical examination revealed an afebrile man who maintained eye contact but had limited verbal communication and was only able to obey two-step verbal commands following multiple repetitions. His motor strength was decreased in both right upper and lower limbs (4/5) and he had a right upward plantar reflex. He was unable to walk due to generalized weakness.

Initial laboratory results showed leukocytosis (17,600/µl, normal 4000–10000), anemia (11.4 g/dl, normal 14–18), thrombocytopenia (108,000/µl, normal 140,000–440,000), hyponatremia (125 mEq/l, normal 136–145), increased erythrocyte sedimentation rate (ESR 36 mm/hour, normal < 20) and normal C-reactive protein (CRP < 6 mg/l, normal < 6).

MRI of the brain revealed multiple high signal lesions with significant peripheral enhancement in the subcortical and deep white matter in both hemispheres suggestive of brain abscesses. Mucosal thickening of paranasal sinuses in favor of chronic sinusitis was also observed (Fig. 2C). CT scan of the paranasal sinuses showed mucosal thickening in both maxillary sinuses. It also revealed punctuate and irregular calcifications, fluid level, and air bubbling in the left maxillary sinus suggestive of acute sinusitis superimposed on a fungus ball (Fig. 2B). CT scan of the chest revealed loculated hydropneumothorax connected to a large parenchymal abscess in the right lower lobe (Fig. 2A). Echocardiography was performed to assess for possible endocarditis, which revealed no vegetations.

The patient’s neurological symptoms did not improve, and his consciousness deteriorated. He was intubated and underwent mechanical ventilation. Repeat imaging of the brain showed multiple hypodense lesions with rim enhancement in frontal and occipital lobes with surrounding vasogenic edema suggestive of brain abscesses. One of the lesions had developed an intraventricular part, causing dilation of the left ventricular frontal and temporal horns and midline shift. Evidence of ventriculitis in the left ventricular occipital horn was also observed, and opacifications were seen in bilateral mastoid air cells. The patient was scheduled for a ventriculoperitoneal shunt placement to relieve the obstructive hydrocephalus caused by the intraventricular abscess. PCR of the pleural fluid revealed Klebsiella pneumonia, hence, the antibiotic regimen was changed to meropenem, colistin, and linezolid based on the resistance profile. Eventually, PCR of the brain abscess fluid revealed Aspergillus fumigatus as the culprit organism, and antifungal therapy was changed to voriconazole.

Despite appropriate medical therapy, the patient’s condition did not improve. Forty days after admission, he entered cardiac arrest and could not be resuscitated.

We report the first case of brain and intramedullary abscesses caused by Pseudomonas aeruginosa and a rare case of brain abscesses caused by Aspergillus fumigatus in two post-COVID-19 patients. A few studies have reported invasive cerebral infections with unusual organisms in patients with COVID-19 (Table 1). Two studies reported fungal brain abscesses associated with trichosporonosis and phaeohyphomycosis, both in patients with diabetes[22, 23]. This suggests that COVID-19 infection can predispose patients to unusual infections with unusual pathogens. There are multiple reports of invasive rhino–orbital–cerebral mucormycosis in patients with COVID-19, most of them being diabetic [24]. COVID-19 has been associated with the development and exacerbation of diabetes mellitus (DM) [25]. Higher blood sugar levels are closely associated with worse outcomes in patients with COVID-19, as patients with diabetes have impaired phagocytic activity, T cell function, neutrophil chemotaxis, and disrupted innate and adaptive immunity [26‐28]. COVID-19 itself is also associated with immunosuppression and disrupts the activity of both innate and adaptive immune systems [29]. One study reported decreased number and impaired function of T lymphocytes and NK cells in hospitalized patients with COVID-19, which were more prominent in critically ill patients [30]. Our first patient did not have a history of DM but had elevated FBS and HbA1c levels suggesting undiagnosed DM. She also had high blood sugar levels throughout her admission, ranging from 176 to 435 mg/dl (normal 70–115). The relative immunocompromised state caused by her DM and COVID-19 may have predisposed her to the invasive P. aeruginosa infection with a poor prognosis. In addition, she received corticosteroid therapy for her COVID-19 infection, which may have contributed to her immunosuppression.

Our second patient had a recent history of severe COVID-19 leading to ICU admission. The severe COVID-19-induced immunosuppression might have made him susceptible to invasive aspergillosis. There have been two previous reports of Aspergillus brain abscesses in patients with COVID-19. Similar to our second patient, both of these patients had a history of recent ICU admission due to COVID-19 [31, 32]. Corticosteroid therapy, intubation and mechanical ventilation, and ongoing inflammation in ICU patients are risk factors that predispose them to invasive fungal infections [33].

The reported fungal brain abscesses following COVID-19 were mostly associated with contiguous spread from paranasal sinus involvement. In our second patient, imaging showed evidence of sinusitis, which suggests that the sinuses were the primary source of Aspergillus infection. However, a study reported a case of a brain abscess caused by A. fumigatus in a diabetic patient with COVID- 19 without sinonasal involvement, which had occurred through hematogenous spread from the lung. The authors suggested that a brain MRI should be obtained in patients with COVID-19 presenting with neurological symptoms either during their disease or after recovery to rule out brain abscesses, even without any evidence of rhino-orbital involvement [32]. In our first patient, a CT scan of the head showed no involvement of paranasal sinuses or orbits. In another study, P. aeruginosa caused malignant external otitis in a 65-year-old man with uncontrolled DM, which progressed to involve the temporal bone and skull base and caused multiple cranial nerve palsies. The patient’s clinical course was complicated by COVID-19 infection, and he passed away [34]. This points out that concomitant DM, COVID-19, and P. aeruginosainfection are associated with a poor prognosis. Our first patient had no otorrhea or otalgia and there was no evidence of ear infection in the physical examination or brain imaging. These findings suggest that P. aeruginosa has likely spread to the brain through a hematogenous route in our first patient, which justifies the coexistence of an intramedullary abscess.

There have been a few reports of Pseudomonas spp. causing complications in patients with COVID-19 (Table 2). Pseudomonas aeruginosa caused multiple skin abscesses on the forearm of an otherwise immunocompetent patient with COVID-19 [35]. In another study, Pseudomonas putida, an opportunistic bacteria causing infections in immunosuppressed patients, caused an exacerbation of bronchiectasis in a 70-year-old patient with COVID-19 who was otherwise immunocompetent. COVID-19 has been associated with worse outcomes in patients with bronchiectasis [36]. Our first patient was the first case of COVID-19 complicated by P. aeruginosa brain abscesses. Gregorova et al. reported a patient with COVID-19 that contracted recurring ventilator-associated pneumonias (VAP) with antibiotic-resistant P. aeruginosa, which led to a lengthy hospital stay in the intensive care unit. They speculated that COVID-19 infection resulted in a heightened immune system response that was further stimulated by the recurring P. aeruginosa infections. This led to bystander activation of T cells specific for antigens unrelated to either SARS-CoV2 or P. aeruginosa, which caused the more severe disease and complications experienced by this patient [37].

Unfortunately, P. aeruginosa has been demonstrating increasing antibiotic resistance. Perez et al. recovered P. aeruginosa isolates from hospitalized patients during the COVID-19 pandemic and found a high resistance rate among them, probably caused by the production of New Delhi metallo-β-lactamases (NDMs) [38]. Liu et al. evaluated critically ill hospitalized patients with COVID-19 with bacterial infection and found that P. aeruginosa was the pneumonia organism that most commonly developed antimicrobial resistance, acquiring resistance to many broad-spectrum beta-lactam/beta-lactamase inhibitors, third-generation cephalosporins, and sometimes carbapenems [8]. However, another study found that P. aeruginosa isolates obtained from blood cultures and endotracheal tube aspirate cultures of patients with COVID-19 were 90% susceptible to imipenem [9]. PCR analysis of the P. aeruginosa strain in our first patient did not reveal the existence of any antibiotic resistance genes. However, she did not respond to extensive antibiotic therapy.

The most recent Infectious Diseases Society of America (IDSA) guidelines recommend voriconazole as the choice treatment for central nervous system (CNS) aspergillosis, and liposomal amphotericin B should be given only if the patient does not respond to treatment [39]. Both of the previously reported cases of Aspergillus brain abscesses in patients with COVID-19 responded to voriconazole [31, 32]. However, our second patient did not respond to either medication. This could be a result of his weakened immune system or the development of antifungal resistance in the pathogen. Antifungal resistance has been reported in previous cases of aspergillosis in patients with COVID-19 [40, 41].

The immune dysregulation induced by COVID-19 and its treatments can predispose patients, especially immunosuppressed ones, to bacterial and fungal infections with unusual and opportunistic pathogens in unusual sites, including the central nervous system. Pseudomonas aeruginosa and Aspergillus fumigatus should be considered as crucial causes of central nervous system infection in any patient with COVID-19 presenting with neurological symptoms and evidence of brain abscess in imaging, regardless of sinonasal involvement. These patients should get started on appropriate antimicrobial therapy immediately, as any delay in diagnosis or treatment will be associated with adverse outcomes. Because of the increasing rate of antimicrobial resistance, antimicrobial therapy should be tailored according to the pathogen’s antibiotic resistance profile.