What to know about adenovirus infection

Adenovirus infections can occur sporadically or in outbreaks and can be detected throughout the year.¹ At least 51 serotypes have been identified, and each serotype plays a role in distinct cases.² These viruses usually induce a mild cold or flu-like sickness. Adenoviruses can cause sickness in persons of all ages and at any time of year. 

Adenovirus has a non-enveloped icosahedral capsid (70-90 nm diameter) with 12 penton glycoprotein fibers ("spikes") linked to its vertices. These spikes are harmful and help the virus connect to the receptor. Naked DNA is infectious and can only replicate in actively developing cells.³

According to the Centers for Disease Control and Prevention (CDC), people who have weakened immune systems have a higher risk for adenovirus infections, especially with the adenovirus type 4 and 7, which are involved with severe complications.⁴

Humans are the reservoir for adenovirus. This means adenovirus can survive, grow, and reproduce in humans before reaching its target host species and manifesting the disease and symptoms it carries.

Adenoviruses are found all over the world and are most prevalent in areas where human excrement or sewage has been contaminated. Infections of adenovirus are all-year-round, but severe outbreaks are more prevalent in late winter, spring, and early summer. The virus infection can occur at any age; however, it is most common during childhood.³

What happens when someone has an adenovirus infection?

After the invasion of adenovirus into its hosts, several interactions with host cells occur. There are two infection forms or interactions that can occur: lytic infection and latent infection.

• Lytic infection happens when an adenovirus enters human epithelial cells and continues through its replication cycle. This process leads to the production of cytokines, cell destruction, and triggers the host's inflammatory response
• While the exact mechanism behind chronic or latent infections isn’t fully understood, it often involves silent infections in lymphoid tissue

In studies with rats, adenovirus has been shown to cause oncogenic transformation, primarily due to its powerful E1A proteins. These proteins change how rodent cells transcribe genes, ultimately leading to malignant transformation and cell death. Once inside the nucleus, E1A works by interacting with other regulatory proteins and transcription factors to activate the expression of additional viral genes necessary for replication.⁵

Adenovirus is most infectious in the first few days after the onset of symptoms. Some patients, particularly those with compromised immune systems, can carry the virus in their tonsils, adenoids, or intestines for several weeks or more. These people may not present symptoms, but they can still transfer the infection to others.⁴

Is there any importance to understanding neurological complications?

According to the World Health Organization, approximately three billion of the world’s population suffer from neurological disorders. Also, their recent data indicates that neurological disorders are currently the major cause of illness and disability globally. Since 1990, the total number of disabilities, illnesses, and premature deaths caused by neurological diseases has grown by 18%, with more than 80% of these neurological fatalities and health losses taking place in low- and middle-income countries.⁶

Neurological illnesses are diseases affecting both the central and peripheral nervous systems, i.e., the brain, spinal cord, cranial and peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscles. Some of these disorders include epilepsy, Alzheimer's disease and other dementias. There are also cerebrovascular diseases such as stroke, migraine, and other headache disorders; multiple sclerosis; Parkinson's disease; brain tumours; traumatic nervous system disorders caused by head trauma, and neurological disorders caused by malnutrition.⁷

Many bacterial (e.g., Mycobacterium tuberculosis, Neisseria meningitidis), viral (e.g., Human Immunodeficiency Virus (HIV), enteroviruses, adenoviruses, West Nile Virus, Zika), fungal (e.g., Cryptococcus, Aspergillus), and parasitic (e.g., malaria, Chagas diseases) illnesses can harm the nervous system. The subsequent neurological symptoms might be caused by either the illness or an immunological response.

Adenovirus infection causes central nervous system (CNS) dysfunction, which leads to disseminated disease in various parts of the body. CNS dysfunction can show in several ways, with meningitis and encephalitis being the most prevalent. Most of these individuals experienced modest CNS symptoms and may recover without additional issues. However, reports of this condition have been restricted to a small number of cases.¹

What are some neurological manifestations of adenovirus infection?

Encephalitis

Infections can induce brain inflammation, known as encephalitis. Bacteria, viruses, fungi, and parasites are the infectious causes of encephalitis. It has been proven that HAdV species B is related to a poorer clinical presentation and prognosis, whereas HAdV type 7 is particularly connected with severe lower respiratory tract infections.⁸ Previous investigations have found adenovirus in cerebrospinal fluid (CSF) and associated it with encephalitis. Adenovirus-related CNS disorders include meningitis, encephalitis, and encephalopathy. The prognosis of adenovirus-related CNS involvement is typically good, and risk factors linked with negative clinical outcomes include seizures, coagulopathy, and young age.⁹

Meningitis

Meningitis, or inflammation of the leptomeninges as a result of a central nervous system infection, can be brought on by an adenovirus infection. In immunocompetent people, adenovirus is an uncommon cause of meningitis; but, in patients with acquired immunodeficiency syndrome, it is a prominent cause.¹⁰

Acute disseminated encephalomyelitis (ADEM)

Acute disseminated encephalomyelitis (ADEM) is an uncommon inflammatory disease that causes extensive inflammation in the brain and spinal cord. This causes harm to the sheath that protects nerve fibers, called the myelin sheath. Typically, it occurs after contracting a bacterial or viral infection; vaccinations are less common causes.¹⁰ ADEM mostly affects children, with an annual incidence of 0.07 to 0.64 per 100,000 recorded cases.¹¹ The symptoms usually begin 1-3 weeks after infection and include fever, headache, nausea, vomiting, drowsiness, and confusion. Neurological symptoms can include vision loss, weakness, numbness, and difficulty coordinating movements. ADEM is considered a monophasic disorder, meaning it usually only occurs once.

Guillain-Barré syndrome (GBS)

A relationship between adenovirus and Guillain-Barré syndrome (GBS) may exist, as evidenced by research done in Peru in 2018 and 2019 that found two individuals to have an adenovirus infection during their diagnosis. The genotype ST2993 of Campylobacter jejuni was also identified, and this bacteria is thought to be a probable cause of GBS.¹² Although the association between GBS and adenovirus infection was not clearly established, it is worth putting into consideration for future studies.

FAQs

What is the mechanism of neurological involvement?

While circulating in the bloodstream (viremia), it penetrates the blood-brain barrier (BBB), (even though the mechanism is not fully understood) and enters the central nervous system (CNS). Adenoviruses have the ability to infect neurons once they have entered either the brain. The virus then builds up viral antigens, which can cause oxidative stress and immunological reactions.¹³

In response to viral components, activation of host pattern recognition receptors (PRRs) by the host’s immune cells, including microglia, and astrocytes, can trigger the release of inflammatory mediators to thwart viral invasion. Chronic stimulation of these receptors, however, may cause neurodegeneration and inflammatory damage.

Symptoms of neurological complications

Adenovirus infections have a variety of neurological involvement mechanisms that can result in meningitis and encephalitis as well as other disorders of the central nervous system (CNS). Seizures, altered consciousness, visual hallucinations, and lethargy are commonly reported CNS symptoms that can be caused by an adenovirus.

Diagnostic modalities (MRI, CSF analysis, PCR)

Imaging tests, laboratory testing, and clinical evaluations can all be used to identify the adenovirus responsible for brain infections.

• The best technique for detecting viral DNA and obtaining a precise and sensitive diagnosis is PCR testing. The study of cerebrospinal fluid (CSF) is essential for determining the presence of viral pathogens and inflammatory markers linked to CNS diseases
• Magnetic resonance imaging, or MRI, is another valuable diagnostic tool for brain infections because it facilitates aetiological diagnosis and disease evaluation. Particularly in cases where there is suspicion, MRI can detect focal damage and offer insights into the features of brain infections

Management and treatment

• Adenovirus infections usually resolve on their own and do not require any special therapy in addition to supportive care. Bed rest, isolation, water, and over-the-counter drugs are advised for mild instances
• Immunocompromised patients, such as those undergoing solid organ transplantation or hematopoietic stem cell transplantation, are treated with antiviral medication in order to reduce their risk of morbidity and death. Immunotherapy is combined with a number of antiviral medications, including Ganciclovir, Ribavirin, Cidofovir, and Brincidofovir

Preventive strategies of adenovirus infection

The prevention or control of disseminated adenovirus illness depends on the prompt beginning of antiviral therapy. It is crucial to routinely check the levels of adenovirus in stool and blood samples in order to identify invasive infections early on. 

Reduced viral burden, severe illness, and overall mortality can be achieved with early antiviral therapy initiation based on positive test results and preventive treatment.

Summary

The adenovirus diagnostic approach for cerebral infections makes use of CSF analysis to assess inflammatory markers, PCR for viral identification, and MRI for aetiological diagnosis and assessment of illness extension in the central nervous system. When combined, these diagnostic methods aid in accurately diagnosing and treating adenovirus-caused brain infections. For mild occurrences of adenovirus infections, supportive treatment is offered; for severe, possibly fatal infections in people with compromised immune systems, immunotherapy in conjunction with antiviral therapy is employed. Early intervention and adenovirus surveillance are critical for better outcomes in high-risk individuals. Meningitis, encephalitis, and acute disseminated encephalomyelitis (ADEM) are examples of neuronal infections brought on by adenovirus. These infections can cause long-term neurological damage and manifest as symptoms including fever, headache, confusion, and, in extreme situations, seizures.