COVID-19 pneumoniae and the respiratory failure are the most common clinical manifestations among hospitalized patients with SARS-CoV-2 infection. Complications of COVID-19 include ARDS, sepsis, septic shock, coagulopathy, acute cardiac injury, renal failure [1, 2].
The increasing prevalence of neurological manifestations and complications associated with COVID-19 have been also observed. Current literature suggests that gustatory and olfactory dysfunctions, myalgia, headache, altered mental status, confusion, delirium, dizziness, nausea and vomiting, as well as stroke, cerebral venous thrombosis, seizures, meningoencephalitis, Guillain–Barré syndrome are most common neurological symptoms and manifestations in COVID-19 patients . They can occur prior, during, and even after acute phase of SARS-CoV-2 infection .
However, in the presence of life-threatening respiratory failure in critically ill COVID-19 patients, neurological manifestations are usually undiagnosed . In our case, the cause of sudden worsening of the neurological symptoms and the deterioration of the patient's condition was meningitis. Microbiological cultures of various samples and CSF examination resulted in early confirmation of neuroinfection. Simultaneous imaging of the brain excluded vascular complications, which may also appear in the course of SARS-CoV-2 infections .
Streptococcus pneumoniae is one of leading pathogens of invasive bacterial diseases, including pneumonia, sepsis, and meningitis. [3, 4]. This pathogen is responsible for 25.1–41.2% of meningitis cases among all age groups. This clinical manifestation of bacterial infection is burdened with high mortality. Early diagnosis and the initiation of therapy significantly affect the course of the disease. Untreated properly, can be fatal in most cases .
Brueggemann et al. compared the incidence of invasive bacterial infection with S. pneumoniae, H. influenzae, and N. meningitidis during the COVID-19 pandemic in 26 countries with rates in previous years. They confirmed a significant reduction in invasive diseases in early 2020. The incidence of reported S. pneumoniae infections decreased by 68% at 4 weeks since the pandemic restrictions were introduced for global scale . Despite the decrease in the incidence of bacterial invasive infection, the suspicion of meningitis should be taken into account in the differential diagnosis of a disturbed consciousness, accompanied by acute respiratory failure, fever and a significant increase of inflammatory parameters. The clinical course of the neuroinfection was so severe in our patient, that mechanical support of ventilation was necessary to stabilize the patient’s condition. Only then, after exclusion of cerebral edema in CT scans, it was possible to perform a lumbar puncture to confirm meningitis.
Coronaviruses are known for their neurological tropism. Numerous reports based on previous SARS-CoV and MERS-CoV epidemics, provide clear evidence of various neurologic sequalae (i.e. encephalitis, seizures, encephalopathy, Guillain–Barre syndrome), which may occur in association with respiratory symptoms [15, 16]. Neuroinvasion may take the form of viral encephalitis, confirmed by the presence of viral RNA in the CSF in single cases [17, 18]. CSF examinations in COVID-19-associated meningoencephalitis show pleocytosis with predominance of lymphocytes and increased concentration of protein, which typical for viral infections. This suggests active intrathecal inflammation . In our patient result of CSF examination indicated bacterial etiology of neuroinfection.
Although classic abnormalities of CSF examination typically for bacterial meningitis was observed and S. pneumoniae was isolated from blood and bronchial wash, CSF culture was negative. Similar observations have been previously reported in literature . Bohr et al. in the retrospective study in 875 patients diagnosed with bacterial meningitis, not pretreated with antibiotics, showed positive CSF culture in 85% cases . In described case, a negative CSF culture could have been the result of using antibiotics before the lumbar puncture. The results of two large cohort studies confirmed a 4–18% decrease in culture positivity when empiric antibiotic therapy was administered prior to CSF sampling [20, 21].
Based on the studies conducted so far, it has been proven that viruses may promote the development of severe invasive bacterial infections, including meningitis, in selected patients [5, 6].
Klein et al. study concluded that bacterial co-infection should be considered in differential diagnosis in all patients hospitalized with influenza, but not all patients are co-infected. The predominant co-infecting organism was S. pneumoniae followed by Staphylococcus aureus. Bacterial co-infection is associated with more severe symptoms and higher mortality .
Identified bacterial or fungal co-infections among COVID-19 patients are not so common. Langford et al. meta-analysis estimated the presence of co-infections in 8.6% of over 30,000 analyzed patients . Also Palanisamy et al. reported secondary bloodstream infections in 8.5% COVID-19 ICU patients . Similar findings was proved in Rawson’s study of eighteen full texts reporting bacterial/fungal co-infection. Furthermore, they highlighted wide use of broad-spectrum antibiotics, despite the lack of microbiological confirmation of bacterial co-infection . Low rates of bacterial and fungal infection in COVID-19 patients were also reported from Spain and United Kingdom. Bacterial and fungal co-infections and superinfections in these countries were estimated at 3% and 6%, respectively .
Tocilizumab increases the risk of opportunistic and serious bacterial infection . In patients 65 years of age or older, receiving doses of 8 mg/kg, the incidence rates of infections reach 8.5 episodes per 100 patient-years. Other tocilizumab-related infection risk factors are coexisting lung disease and corticosteroid therapy . Therefore, regular clinical assessment of patients treated with anti-IL-6 agents is essential for the early diagnosis of developing infection .
In presented case, temporary improvement in general condition was achieved after implementation of targeted on cytokine storm treatment (tocilizumab plus dexamethasone), typical for the late phase of COVID-19. Pneumococcal pneumoniae, sepsis and meningitis were diagnosed during hospitalization, although no symptoms of invasive infection were found upon admission to the hospital. The course of co-infection with the SARS-CoV-2 and S. pneumoniae was life-threatening. The implemented antibiotic therapy, despite S. pneumoniae sensitivity to ceftriaxone (MIC ≤ 0.12 μg/ml), did not result in recovery. The patient died on the 5th day after the onset of pneumococcal infection.
Based on our experience we concluded, that co-infections with bacterial pathogens appear to be not common among COVID-19 patients, but may cause a sudden deterioration of the general condition. Not only vascular neurological complications, but also meningitis should be always considered in patients with sudden disturbances of consciousness. Anti-inflammatory treatment with the combination of corticosteroids and tocilizumab (or tocilizumab alone) pose a severe risk for secondary lethal bacterial or fungal infections. Thus, treating a high-risk population (i.e. elderly) with these anti-inflammatory agents, require daily clinical assessment, regular monitoring of CRP and procalcitonin, as well as standard culture of blood, urine and sputum in order to detect concomitant infections, as rapidly as possible.