While SARS-CoV-2 and similar coronaviruses are considered respiratory pathogens, a subset of patients with COVID-19 have presented with extrapulmonary disease along with neurological complications. A 2020 article published in BMC Neurology focused on a case where a 78-year-old immunocompromised patient had mental impairments after experiencing seizure-like activity in their home tested positive for SARS-CoV-2 and was found to have associated neuroinflammation.
The patient arrived at an academic medical center with the above symptoms as well as uncontrolled limb movements and ocular deviation, and was unresponsive for several minutes. This patient had not been previously diagnosed with dementia or confusion but reported that she began to experience some confusion and disorientation three days prior to her hospital admission.
Following four days of hospitalization, the patient was tested for SARS-CoV-2 and was positive for COVID-19.
Highly multiplexed functional analysis of plasma and CSF reveals signs of inflammation
In this case, the researchers used IsoPlexis’ CodePlex technology—a highly multiplexed cytokine assay—to analyze both cerebrospinal fluid (CSF) and plasma from the patient against three healthy controls. They found elevated levels of interleukin (IL)-6, IL-8, and interferon-gamma induced protein (IP)-10 in both the CSF and plasma of this patient, as well as a unique monocyte chemoattractant protein (MCP)-1 signature in the CSF but not plasma.
MCP-1, also known as CCL2, is one of the chemokines/cytokines that plays a role in regulating the migration or infiltration of monocytes and macrophages. CCL2 recruits different types of immune cells to sites of inflammation in the body.
However, when the patient’s CSF was tested for SARS-CoV-2, the first attempt via qRT-PCR was negative. The second attempt used targeted sequencing and identified a total of 60 reads aligning with SARS-CoV-2, but they were not above background. The final attempt by PCR did not detect any SARS-CoV-2. Notably, MCP-1/CCL2 was only present in CSF but not plasma, while the COVID-19 virus was found in the blood but not CSF of this patient.
Identifying unique signatures and indications of neuroinflammation in CSF, despite the absence of viral presence
Several recently-conducted studies have found evidence of similar neurological instances in subsets of COVID-19 patients. An April 2020 study from Wuhan, China, found that 36.4 percent of COVID-19 patients exhibited peripheral nervous system, skeletal muscle, or central nervous system (CNS) symptoms. A case series in France reported a similarly high rate of neurological symptoms in COVID-19 patients, where 65 percent of patients admitted to the ICU had confusion but no evidence of SARS-CoV-2 neuroinvasion by PCR of CSF with nonspecific EEG findings. It is still unclear, however, if the injury to the CNS observed in COVID-19 is caused by viral invasion or by inflammatory cytokines produced by immune cells in the CNS.
"Predicting which patients are likely to experience cytokine storm can help researchers formulate better therapeutics and potentially prevent the response from occurring."
While there is evidence that SARS-CoV-1 was found in the brain, the virus that causes MERS, a similar disease, was not found in CSF. Conversely, a case report in May 2020 detected the presence of SARS-CoV-2 in CSF but in the nasopharyngeal swab.
In the current case, the patient’s CSF did not test positive for the virus, but there was increased inflammation, which supports the possibility that the neurological symptoms seen in COVID-19 are a result of increased neuroinflammation rather than CNS invasion by SARS-CoV-2. Thus, treating host inflammation may also address the neurological symptoms of COVID-19.
“Specifically, CSF elevation of MCP-1 as well as emerging reports of macrophage induced damage in lung and other tissues suggests that specifically attenuating monocyte-incurred damage may prove beneficial,” wrote the authors.
Cellular and cytokine level monitoring is essential for predicting toxicities in infectious diseases, such as those related to cytokine storm seen in many COVID-19 patients. Predicting which patients are likely to experience cytokine storm can help researchers formulate better therapeutics and potentially prevent the response from occurring. IsoPlexis’ CodePlex solution can provide highly multiplexed cytokine data in an automated manner that doesn’t require advanced training.