ABSTRACT

We report a case of COVID-19-associated meningoencephalitis with a fatal outcome in a male patient with concomitant influenza A, who had been hospitalized at the beginning of 2022, in the Northeastern region of Brazil. He died due to cardiopulmonary arrest after developing status epilepticus on the third day of hospitalization. The SARS-CoV-2 RNA was detected in cerebrospinal fluid and Influenza A was detected in the nasopharyngeal swab. Meningoencephalitis due to COVID-19 is a rare manifestation and physicians must be aware of this complication, mainly during the pandemic. In viral co-circulation situations, the possibility of respiratory coinfections should be remembered.

COVID-19; Meningoencephalitis; Influenza A; Coinfection

INTRODUCTION

Coronavirus disease 2019 (COVID-19) caused by a betacoronavirus SARS-CoV-2 was discovered in Wuhan, China, in December 2019¹1. World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19: 11 March 2020. [cited 2023 Feb 6]. Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020
https://www.who.int/director-general/spe... . COVID-19 usually manifests as a respiratory illness and can lead to acute respiratory failure and death. Millions of cases have been reported worldwide. The World Health Organization (WHO) declared the COVID-19 outbreak a global pandemic and it continues to have a major impact on health care and social systems worldwide. In Brazil, despite the vaccination efforts, severe cases are registered in each new wave²2. Silva FJ, Farias LA, Holanda PE, Nunes FR, Miyajima F, Damasceno LS. COVID-19-associated meningoencephalitis in a Brazilian patient: case report and literature review. Rev Inst Med Trop Sao Paulo. 2022;64:e14.. The emergence of more contagious variants, such as delta (B.1.617) and omicron (B.1.1.529), played a big part in the spread of the virus, which made it harder to beat the pandemic¹1. World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19: 11 March 2020. [cited 2023 Feb 6]. Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020
https://www.who.int/director-general/spe... ,³3. Tutal Gursoy G, Yuksel H, Mulkem Simsek I, Oral S, Erdogan Kucukdagli F, Karaman A, et al. Neurological presentations in patients with COVID-19 in cytokine storm. Can J Neurol Sci. 2021 In Press..

Furthermore, several extrapulmonary symptoms of COVID-19 have caught the attention of clinicians around the world. A variety of neurological symptoms and syndromes, caused by SARS-CoV-2, have been reported such as meningoencephalitis, myelitis, and acute encephalomyelitis (ADEM)³3. Tutal Gursoy G, Yuksel H, Mulkem Simsek I, Oral S, Erdogan Kucukdagli F, Karaman A, et al. Neurological presentations in patients with COVID-19 in cytokine storm. Can J Neurol Sci. 2021 In Press.. Though knowledge about SARS-CoV-2 infection in the central nervous system (CNS) is developing rapidly, the pathogenesis of CNS involvement still needs to be understood. Two main theories are currently accepted: direct viral involvement during the viremic phase, and indirect mechanisms mediated by cytokine storms³3. Tutal Gursoy G, Yuksel H, Mulkem Simsek I, Oral S, Erdogan Kucukdagli F, Karaman A, et al. Neurological presentations in patients with COVID-19 in cytokine storm. Can J Neurol Sci. 2021 In Press.,⁴4. Caricchio R, Gallucci M, Dass C, Zhang X, Gallucci S, Fleece D, et al. Preliminary predictive criteria for COVID-19 cytokine storm. Ann Rheum Dis. 2021;80:88-95..

During the first month of 2022, Brazil experienced a high number of influenza cases simultaneously with the third wave of COVID-19. During this period, 63,981 cases of COVID-19 were identified as being from variants of concern (VOC), split between 33,266 (52.0%) cases of VOC Delta, 25,164 (39.3%) cases of VOC Gamma, 5,093 (8.0%) cases of VOC Omicron, and 458 (0.7%) cases of VOC Alfa or VOC Beta⁵5. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Boletim Epidemiológico Especial: doença pelo novo coronavírus – COVID-19: semana epidemiológica 1: 2/1 a 8/1/2022. [cited 2023 Feb 6]. Available from: https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/covid-19/2022/boletim-epidemiologico-no-95-boletim-coe-coronavirus.pdf
https://www.gov.br/saude/pt-br/centrais-... . The cases of influenza were primarily influenza A (H3N2). Other respiratory viruses were also reported, such as influenza B and respiratory syncytial virus (RSV), but in much lower numbers⁵5. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Boletim Epidemiológico Especial: doença pelo novo coronavírus – COVID-19: semana epidemiológica 1: 2/1 a 8/1/2022. [cited 2023 Feb 6]. Available from: https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/covid-19/2022/boletim-epidemiologico-no-95-boletim-coe-coronavirus.pdf
https://www.gov.br/saude/pt-br/centrais-... .

Here, we document a case of COVID-19-associated meningoencephalitis with a fatal outcome in a male patient with concomitant influenza A who had been hospitalized during the beginning of 2022, in Northeastern Brazil. Medical records were reviewed during the patient’s hospitalization at the Hospital Sao Jose de Doencas Infecciosas (HSJ), an infectious disease center in Fortaleza city, Ceara State, Brazil. This case report is part of a cohort study approved by the Research Ethics Committee of the Hospital Sao Jose de Doencas Infecciosas (HSJ) (CAAE Nº 55499022.8.0000.5044).

CASE REPORT

A 31-year-old male patient, with no previous comorbidities, presented to the emergency department with a headache, a stiff neck, behavioral changes and aggressiveness, two days after getting over flu-like symptoms. He had a five-day history of runny nose, fever, and cough. The patient had previously received two inactivated vaccine doses for SARS-CoV-2. During physical examination, the patient was disoriented and had a seizure which was reversed with anticonvulsant drugs. He was sent to the intensive care unit (ICU) because of sensory deficits and drowsiness. Cranial tomography findings were normal. Cerebrospinal fluid (CSF) analysis revealed white blood cell count of 553 cells/mm³3. Tutal Gursoy G, Yuksel H, Mulkem Simsek I, Oral S, Erdogan Kucukdagli F, Karaman A, et al. Neurological presentations in patients with COVID-19 in cytokine storm. Can J Neurol Sci. 2021 In Press. (91% lymphocytes and 8% monocytes), glucose of 60 mg/dL, protein of 61.6 mg/dL, lactate dehydrogenase of 32 mg/dL, and negative CSF Gram stain. SARS-CoV-2 RNA was identified in the CSF through qPCR using the Allplex^™ SARS-CoV-2/FluA/FluB/RSV Assay (Allplex; Seegene). Chest radiography findings were unremarkable. Influenza A was detected by qPCR in the nasopharyngeal and oropharyngeal swabs by using the same assay.

The patient only had neurological symptoms and no respiratory manifestations. After three days in the ICU, despite the antiepileptic drugs, he presented with status epilepticus requiring sedation, analgesia and invasive mechanical ventilation. Immediately thereafter, he suddenly went into cardiopulmonary arrest and death, despite prompt cardiopulmonary resuscitation. Figure 1 shows the chronology of the case, including the clinical aspects and outcomes.

Figure 1
Case chronology, including clinical aspects and outcome.

DISCUSSION

The maintenance of circulating respiratory viruses, such as COVID-19 and influenza, raises the possibility of coinfection. Studies in animal models have shown that simultaneous or sequential infection by H1N1 and SARS-CoV-2 may increase lung damage despite the lowered SARS-CoV-2 viral loads caused by prior H1N1 infection⁶6. Zhang AJ, Lee AC, Chan JF, Liu F, Li C, Chen Y, et al. Coinfection by severe acute respiratory syndrome coronavirus 2 and influenza A(H1N1)pdm09 virus enhances the severity of pneumonia in golden Syrian hamsters. Clin Infect Dis. 2021;72:e978-92.. Aloisame et al.⁷7. Alosaimi B, Naeem A, Hamed ME, Alkadi HS, Alanazi T, Al Rehily SS, et al. Influenza co-infection associated with severity and mortality in COVID-19 patients. Virol J. 2021;18:127. investigated 48 COVID-19 patients and found viral coinfection in 27 of them, with influenza A H1N1 (n = 17) and human adenovirus (n = 10) being the most common. The same study also identified viral coinfections as a factor that increased ICU admission and mortality in these patients. The clinical impact of influenza virus and SARS-CoV-2 coinfection on each corresponding disease is still unknown. In the reported case studies, the use of influenza antivirals in these patients makes it difficult to assess the true impact of coinfection without any therapeutic intervention⁷7. Alosaimi B, Naeem A, Hamed ME, Alkadi HS, Alanazi T, Al Rehily SS, et al. Influenza co-infection associated with severity and mortality in COVID-19 patients. Virol J. 2021;18:127.,⁸8. Lawson A, López-Candales A. COVID-19 and seasonal influenza. Postgrad Med. 2022;134:148-51..

In our case, it is possible that the first flu-like symptoms were related to influenza A, followed by the neurological symptoms related to COVID-19. However, it is worth noting that influenza A may also manifest itself with neurotropism. Influenza A may manifest as meningitis, encephalitis, acute flaccid paralysis, or acute necrotizing encephalopathy. In this case, influenza A in the CSF was ruled out by qPCR⁹9. Giovacchini N, Coppi M, Aiezza N, Baccani I, Malentacchi F, Pollini S, et al. Rapid screening for SARS-CoV-2 VOC-Alpha (202012/01, B.1.1.7) using the Allplex™ SARS-CoV-2/FluA/FluB/RSV Assay. Int J Infect Dis. 2021;113:207-9.. There are few cases of meningoencephalitis due to COVID-19 confirmed by PCR in CSF³3. Tutal Gursoy G, Yuksel H, Mulkem Simsek I, Oral S, Erdogan Kucukdagli F, Karaman A, et al. Neurological presentations in patients with COVID-19 in cytokine storm. Can J Neurol Sci. 2021 In Press.,¹⁰10. Dharsandiya M, Shah K, Patel K, Patel T, Patel A, Patel A. SARS-CoV-2 viral sepsis with meningoencephalitis. Indian J Med Microbiol. 2020;38:219-21.

11. Freij BJ, Gebara BM, Tariq R, Wang AM, Gibson J, El-Wiher N, et al. Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child. BMC Pediatr. 2020;20:429.

12. Morvan AC, Kerambrun H. Fatal necrotizing encephalitis associated with COVID-19. Neurol Clin Pract. 2021;11:e214-5.

13. Ziemele D, Ķauķe G, Skrējāne K, Jaunozoliņa L, Karelis G. A fatal case of COVID-19-associated acute necrotizing encephalopathy. Eur J Neurol. 2021;28:3870-2.-¹⁴14. Mierzewska-Schmidt M, Baranowski A, Szymanska K, Ciaston M, Kuchar E, Ploski R, et al. The case of fatal acute hemorrhagic necrotizing encephalitis in a two-month-old boy with Covid-19. Int J Infect Dis. 2022;116:151-3.. The first death attributed to COVID-19-related meningitis occurred in India, in a 58-year-old male patient with positive RT-PCR for SARS-CoV-2 in the nasopharyngeal swabs. In the Indian case, RT-PCR was not performed in CSF¹⁰10. Dharsandiya M, Shah K, Patel K, Patel T, Patel A, Patel A. SARS-CoV-2 viral sepsis with meningoencephalitis. Indian J Med Microbiol. 2020;38:219-21.. Moreover, SARS-CoV-2 detected by RT-PCR in CSF is a rare finding in meningoencephalitis cases registered in the scientific literature³3. Tutal Gursoy G, Yuksel H, Mulkem Simsek I, Oral S, Erdogan Kucukdagli F, Karaman A, et al. Neurological presentations in patients with COVID-19 in cytokine storm. Can J Neurol Sci. 2021 In Press.,⁹9. Giovacchini N, Coppi M, Aiezza N, Baccani I, Malentacchi F, Pollini S, et al. Rapid screening for SARS-CoV-2 VOC-Alpha (202012/01, B.1.1.7) using the Allplex™ SARS-CoV-2/FluA/FluB/RSV Assay. Int J Infect Dis. 2021;113:207-9.,¹⁰10. Dharsandiya M, Shah K, Patel K, Patel T, Patel A, Patel A. SARS-CoV-2 viral sepsis with meningoencephalitis. Indian J Med Microbiol. 2020;38:219-21.. To the best of our knowledge, few cases were reported of meningoencephalitis by COVID-19 confirmed by RT-PCR with fatal outcomes and associated with other viral infections, as in this case.

SARS-CoV-2, influenza virus (Flu), and RSV are major pathogens that primarily target the human respiratory system. Both viruses present non-specific symptoms, and their circulation periods may coincide as described by our case which occurred during influenza A season⁴4. Caricchio R, Gallucci M, Dass C, Zhang X, Gallucci S, Fleece D, et al. Preliminary predictive criteria for COVID-19 cytokine storm. Ann Rheum Dis. 2021;80:88-95.,⁸8. Lawson A, López-Candales A. COVID-19 and seasonal influenza. Postgrad Med. 2022;134:148-51.. The Allplex^™ SARS-CoV-2/FluA/FluB/RSV Assay (Allplex; Seegene) was the assay performed in our case. The Allplex^™ SARS-CoV-2/FluA/FluB/RSV Assay is a multiplex real-time PCR assay intended for the detection of the N, RdRP, and S genes of SARS-CoV-2, Flu A and B viruses, and RSV A/B in a single tube⁹9. Giovacchini N, Coppi M, Aiezza N, Baccani I, Malentacchi F, Pollini S, et al. Rapid screening for SARS-CoV-2 VOC-Alpha (202012/01, B.1.1.7) using the Allplex™ SARS-CoV-2/FluA/FluB/RSV Assay. Int J Infect Dis. 2021;113:207-9.. The Allplex kit was developed to perform a rapid and suitable diagnosis of respiratory infection of the most common agents⁹9. Giovacchini N, Coppi M, Aiezza N, Baccani I, Malentacchi F, Pollini S, et al. Rapid screening for SARS-CoV-2 VOC-Alpha (202012/01, B.1.1.7) using the Allplex™ SARS-CoV-2/FluA/FluB/RSV Assay. Int J Infect Dis. 2021;113:207-9.. A Korean study analyzing the three commercially available tests (PowerChek^™ SARS-CoV-2, Influenza A&B Multiplex Real-time PCR Kit, STANDARD™ M Flu/SARS-CoV-2 Real-time Detection Kit; and Allplex^™ SARS-CoV-2/FluA/FluB/RSV Assay) found that all three kits had positive and negative predictive values greater than 92% and ≥ 0.95 kappa value in the detection of SARS-CoV-2 and flu A/B; all three kits did not cross-react with common respiratory viruses¹⁵15. Yun J, Park JH, Kim N, Roh EY, Shin S, Yoon JH, et al. Evaluation of three multiplex real-time reverse transcription PCR assays for simultaneous detection of SARS-CoV-2, influenza A/B, and respiratory syncytial virus in nasopharyngeal swabs. J Korean Med Sci. 2021;36:e328.

Most deaths related to SARS-CoV-2 neurological syndromes were attributed to brain complications such as hemorrhage and brain herniation with subsequent cerebral death¹⁰10. Dharsandiya M, Shah K, Patel K, Patel T, Patel A, Patel A. SARS-CoV-2 viral sepsis with meningoencephalitis. Indian J Med Microbiol. 2020;38:219-21.

11. Freij BJ, Gebara BM, Tariq R, Wang AM, Gibson J, El-Wiher N, et al. Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child. BMC Pediatr. 2020;20:429.

12. Morvan AC, Kerambrun H. Fatal necrotizing encephalitis associated with COVID-19. Neurol Clin Pract. 2021;11:e214-5.

13. Ziemele D, Ķauķe G, Skrējāne K, Jaunozoliņa L, Karelis G. A fatal case of COVID-19-associated acute necrotizing encephalopathy. Eur J Neurol. 2021;28:3870-2.-¹⁴14. Mierzewska-Schmidt M, Baranowski A, Szymanska K, Ciaston M, Kuchar E, Ploski R, et al. The case of fatal acute hemorrhagic necrotizing encephalitis in a two-month-old boy with Covid-19. Int J Infect Dis. 2022;116:151-3.. Five fatal cases of COVID-19-associated neurological complications have been reported – two meningoencephalitis cases, two acute necrotizing encephalitis (ANE) cases, and one case with both hypothesized meningoencephalitis and ANE simultaneously¹⁰10. Dharsandiya M, Shah K, Patel K, Patel T, Patel A, Patel A. SARS-CoV-2 viral sepsis with meningoencephalitis. Indian J Med Microbiol. 2020;38:219-21.

11. Freij BJ, Gebara BM, Tariq R, Wang AM, Gibson J, El-Wiher N, et al. Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child. BMC Pediatr. 2020;20:429.

12. Morvan AC, Kerambrun H. Fatal necrotizing encephalitis associated with COVID-19. Neurol Clin Pract. 2021;11:e214-5.

13. Ziemele D, Ķauķe G, Skrējāne K, Jaunozoliņa L, Karelis G. A fatal case of COVID-19-associated acute necrotizing encephalopathy. Eur J Neurol. 2021;28:3870-2.-¹⁴14. Mierzewska-Schmidt M, Baranowski A, Szymanska K, Ciaston M, Kuchar E, Ploski R, et al. The case of fatal acute hemorrhagic necrotizing encephalitis in a two-month-old boy with Covid-19. Int J Infect Dis. 2022;116:151-3.. Two cases occurred in children; the first was a 5-year-old girl with COVID-19 meningoencephalitis and simultaneous CNS tuberculosis, which quickly evolved to severe cerebral hypertension and encephalopathy, turning into brain herniation a few days later. This last case had CDC protocol confirmed SARS-CoV-2 in CSF with a brain biopsy¹¹11. Freij BJ, Gebara BM, Tariq R, Wang AM, Gibson J, El-Wiher N, et al. Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child. BMC Pediatr. 2020;20:429.. The second case was a 2-month-old child with signs of both meningoencephalitis and ANE confirmed by magnetic resonance imaging (MRI); the child had multiple hemorrhagic foci and needed orotracheal intubation, but died¹¹11. Freij BJ, Gebara BM, Tariq R, Wang AM, Gibson J, El-Wiher N, et al. Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child. BMC Pediatr. 2020;20:429.,¹⁴14. Mierzewska-Schmidt M, Baranowski A, Szymanska K, Ciaston M, Kuchar E, Ploski R, et al. The case of fatal acute hemorrhagic necrotizing encephalitis in a two-month-old boy with Covid-19. Int J Infect Dis. 2022;116:151-3.. Complications related to COVID-19 meningoencephalitis were described as recurrent seizures, cerebral hypertension, multiple hemorrhagic foci, encephalopathy, sepsis, cardiac arrest, and death¹⁰10. Dharsandiya M, Shah K, Patel K, Patel T, Patel A, Patel A. SARS-CoV-2 viral sepsis with meningoencephalitis. Indian J Med Microbiol. 2020;38:219-21.

11. Freij BJ, Gebara BM, Tariq R, Wang AM, Gibson J, El-Wiher N, et al. Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child. BMC Pediatr. 2020;20:429.

12. Morvan AC, Kerambrun H. Fatal necrotizing encephalitis associated with COVID-19. Neurol Clin Pract. 2021;11:e214-5.

13. Ziemele D, Ķauķe G, Skrējāne K, Jaunozoliņa L, Karelis G. A fatal case of COVID-19-associated acute necrotizing encephalopathy. Eur J Neurol. 2021;28:3870-2.-¹⁴14. Mierzewska-Schmidt M, Baranowski A, Szymanska K, Ciaston M, Kuchar E, Ploski R, et al. The case of fatal acute hemorrhagic necrotizing encephalitis in a two-month-old boy with Covid-19. Int J Infect Dis. 2022;116:151-3.. In our case, we hypothesized the possibility of cerebral hypertension complicated with status epilepticus.

Status epilepticus (SE) and epileptic seizures have been reported during COVID-19¹⁶16. Kheradmand M, Hemasian H, Khorvash F, Najafi MR, Ghadimi K, Forouharnejad K, et al. Status epilepticus due to COVID-19: a cases series and literature review. Am J Neurodegener Dis. 2022;11:34-45.,¹⁷17. Thongsing A, Eizadkhah D, Fields C, Ballaban-Gil K. Provoked seizures and status epilepticus in a pediatric population with COVID-19 disease. Epilepsia. 2022;63:e86-91.. A recent systematic review with 39 patients presenting COVID-19-related SE concluded that this could be an underreported manifestation related to COVID-19 infection, although the exact mechanisms are still not fully understood¹⁶16. Kheradmand M, Hemasian H, Khorvash F, Najafi MR, Ghadimi K, Forouharnejad K, et al. Status epilepticus due to COVID-19: a cases series and literature review. Am J Neurodegener Dis. 2022;11:34-45.. Many mechanisms have been hypothesized, such as (1) neural damage due to systemic inflammatory syndrome during cytokine release³3. Tutal Gursoy G, Yuksel H, Mulkem Simsek I, Oral S, Erdogan Kucukdagli F, Karaman A, et al. Neurological presentations in patients with COVID-19 in cytokine storm. Can J Neurol Sci. 2021 In Press.,⁴4. Caricchio R, Gallucci M, Dass C, Zhang X, Gallucci S, Fleece D, et al. Preliminary predictive criteria for COVID-19 cytokine storm. Ann Rheum Dis. 2021;80:88-95.,¹⁶16. Kheradmand M, Hemasian H, Khorvash F, Najafi MR, Ghadimi K, Forouharnejad K, et al. Status epilepticus due to COVID-19: a cases series and literature review. Am J Neurodegener Dis. 2022;11:34-45.; (2) the increase of blood viscosity due to COVID-19, in which hyperviscosity is a known trigger factor for SE¹⁶16. Kheradmand M, Hemasian H, Khorvash F, Najafi MR, Ghadimi K, Forouharnejad K, et al. Status epilepticus due to COVID-19: a cases series and literature review. Am J Neurodegener Dis. 2022;11:34-45.,¹⁷17. Thongsing A, Eizadkhah D, Fields C, Ballaban-Gil K. Provoked seizures and status epilepticus in a pediatric population with COVID-19 disease. Epilepsia. 2022;63:e86-91.; and (3) direct action of the virus inducing encephalitis or meningitis¹⁰10. Dharsandiya M, Shah K, Patel K, Patel T, Patel A, Patel A. SARS-CoV-2 viral sepsis with meningoencephalitis. Indian J Med Microbiol. 2020;38:219-21.

11. Freij BJ, Gebara BM, Tariq R, Wang AM, Gibson J, El-Wiher N, et al. Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child. BMC Pediatr. 2020;20:429.

12. Morvan AC, Kerambrun H. Fatal necrotizing encephalitis associated with COVID-19. Neurol Clin Pract. 2021;11:e214-5.

13. Ziemele D, Ķauķe G, Skrējāne K, Jaunozoliņa L, Karelis G. A fatal case of COVID-19-associated acute necrotizing encephalopathy. Eur J Neurol. 2021;28:3870-2.-¹⁴14. Mierzewska-Schmidt M, Baranowski A, Szymanska K, Ciaston M, Kuchar E, Ploski R, et al. The case of fatal acute hemorrhagic necrotizing encephalitis in a two-month-old boy with Covid-19. Int J Infect Dis. 2022;116:151-3.,¹⁶16. Kheradmand M, Hemasian H, Khorvash F, Najafi MR, Ghadimi K, Forouharnejad K, et al. Status epilepticus due to COVID-19: a cases series and literature review. Am J Neurodegener Dis. 2022;11:34-45.,¹⁷17. Thongsing A, Eizadkhah D, Fields C, Ballaban-Gil K. Provoked seizures and status epilepticus in a pediatric population with COVID-19 disease. Epilepsia. 2022;63:e86-91.. In general, these mechanisms may be divided as direct (direct action by the virus) or indirect (related to cytokine storm and blood viscosity)³3. Tutal Gursoy G, Yuksel H, Mulkem Simsek I, Oral S, Erdogan Kucukdagli F, Karaman A, et al. Neurological presentations in patients with COVID-19 in cytokine storm. Can J Neurol Sci. 2021 In Press.,⁴4. Caricchio R, Gallucci M, Dass C, Zhang X, Gallucci S, Fleece D, et al. Preliminary predictive criteria for COVID-19 cytokine storm. Ann Rheum Dis. 2021;80:88-95.,¹⁶16. Kheradmand M, Hemasian H, Khorvash F, Najafi MR, Ghadimi K, Forouharnejad K, et al. Status epilepticus due to COVID-19: a cases series and literature review. Am J Neurodegener Dis. 2022;11:34-45.,¹⁷17. Thongsing A, Eizadkhah D, Fields C, Ballaban-Gil K. Provoked seizures and status epilepticus in a pediatric population with COVID-19 disease. Epilepsia. 2022;63:e86-91.. Intriguingly, COVID-19-related SE is not observed only in adults during viremic and immune phases but also in children, and even during post-COVID-19 phase¹⁶16. Kheradmand M, Hemasian H, Khorvash F, Najafi MR, Ghadimi K, Forouharnejad K, et al. Status epilepticus due to COVID-19: a cases series and literature review. Am J Neurodegener Dis. 2022;11:34-45.,¹⁷17. Thongsing A, Eizadkhah D, Fields C, Ballaban-Gil K. Provoked seizures and status epilepticus in a pediatric population with COVID-19 disease. Epilepsia. 2022;63:e86-91.. Rarely, some reports bring up the role of vaccination and status epilepticus but the results come down to anecdotal evidence¹⁶16. Kheradmand M, Hemasian H, Khorvash F, Najafi MR, Ghadimi K, Forouharnejad K, et al. Status epilepticus due to COVID-19: a cases series and literature review. Am J Neurodegener Dis. 2022;11:34-45..

In this case, no antiviral treatment was performed. Remdesivir was only approved in Brazil in March 2021 for cases of pneumonia requiring supplemental oxygen. Currently, new drugs such as nirmatrelvir plus ritonavir, for the treatment of COVID-19 in adults who do not require supplemental oxygen, and baricitinib, which reduced mortality in hospitalized adults with COVID-19 in need of oxygen, are also already part of the therapeutic arsenal against this disease¹⁸18. Marconi VC, Ramanan AV, de Bono S, Kartman CE, Krishnan V, Liao R, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021;9:P1407-18.,¹⁹19. Lamb YN. Nirmatrelvir plus ritonavir: first approval. Drugs. 2022;82:585-91.. However, none of these drugs had their impact assessed in relation to CNS infections. In addition, no antiviral drugs were available in the period of the hospitalization.

Our case report presentation has some limitations. First, it is a single case report which may have many unknown and undetected variables involved in the outcome. Second, RT-PCR targeting other respiratory viruses were not available at our center to rule out other respiratory coinfections. Third, the Allplex^™ SARS-CoV-2/FluA/FluB/RSV Assay is well established for respiratory samples, but there is a lack of evidence regarding the CSF. Finally, interleukin-6 levels and MRI that could aid the diagnosis were not available at our center at the time of diagnosis. To the best of our knowledge, this is the first report of COVID-19-related meningitis diagnosed by this method, and not the RT-PCR following the CDC protocol.

CONCLUSION

COVID-19 involvement of the CNS has shown many neurological manifestations that have been evident during the pandemic. Our case is rare due to the clinical presentation, the simultaneous Flu A infection, and the diagnostic tool used to achieve the COVID-19-related meningitis. Another important learning point to be mentioned is that it is essential to ensure that we are well prepared to deal with future influenza seasons, with the expectation that additional COVID-19 waves may coincide during the seasonal influenza in years to come. Currently, Brazil is facing the emergence of new, more contagious Omicron subvariants (BQ.1), which raises the possibility of new waves, even during the Influenza circulation period²⁰20. Fernandes Q, Inchakalody VP, Merhi M, Mestiri S, Taib N, Moustafa Abo El-Ella D, et al. Emerging COVID-19 variants and their impact on SARS-CoV-2 diagnosis, therapeutics and vaccines. Ann Med. 2022;54:524-40..

ACKNOWLEDGMENTS

The authors would like to acknowledge the Hospital Sao Jose de Doencas Infecciosas (HSJ) in Fortaleza city, Brazil, for their valuable support.

REFERENCES

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