How are viruses classified based on the diseases they produce?

Virus Classification Based on Disease Production

Viruses are classified by the diseases they produce through a syndromic approach that groups them by their primary clinical manifestations and affected organ systems, including neurological infections, respiratory diseases, gastrointestinal illnesses, sexually transmitted infections, and tissue-invasive syndromes.

Primary Classification Systems

Syndromic Classification by Organ System

Viruses are categorized based on the predominant clinical syndrome and anatomical site of disease:

• Neurological infections: Include arboviral encephalitides (St. Louis, Western equine, Eastern equine, California encephalitis serogroup, Powassan), enteroviruses causing meningitis, meningoencephalitis, myelitis, acute flaccid myelitis (AFM), and acute flaccid paralysis (AFP) 1

• Respiratory tract diseases: Encompass influenza viruses (types A and B), respiratory syncytial virus, adenoviruses, and coronaviruses causing upper and lower respiratory infections 1, 2, 3

• Gastrointestinal manifestations: Include enteroviruses and noroviruses causing acute hepatitis and gastroenteritis 1, 4

• Sexually transmitted infections: Such as herpes simplex virus (HSV-1 and HSV-2) causing genital and orolabial disease 1

• Systemic and tissue-invasive diseases: Include varicella zoster virus (VZV), human herpesvirus-6 and -7 (HHV-6, HHV-7), and human herpesvirus-8 (HHV-8) causing Kaposi's sarcoma 1, 4

Disease Severity Classification

Viruses are further stratified by disease severity and potential for complications:

• Self-limiting febrile illnesses: Most enterovirus infections in children present as uncomplicated febrile episodes 1

• Severe neurological complications: Certain enterovirus types (EV-A71, EV-D68) cause rhomboencephalitis, severe respiratory disease, and paralysis with significant morbidity and mortality 1

• Life-threatening disseminated disease: Occurs particularly in immunocompromised patients, with fatality rates exceeding 50% for untreated severe adenovirus pneumonia or disseminated disease 3

Clinical Presentation-Based Categories

Acute Neurological Syndromes

The CDC defines arboviral encephalitis as febrile illness with neurologic symptoms ranging from headache to aseptic meningitis or encephalitis, including confusion, altered sensorium, fever, meningismus, cranial nerve palsies, paresis, paralysis, sensory deficits, altered reflexes, convulsions, and coma 1

• AFM is distinguished from AFP by MRI changes in gray matter of the spinal cord, though both present with rapid limb weakness and low muscle tone 1

• Tissue-invasive viral infections require demonstration of virus in biopsy tissue by culture, DNA/RNA-based assay, immunohistochemical analysis, or in situ hybridization 1

Respiratory Illness Patterns

Influenza presents with abrupt onset of constitutional and respiratory symptoms including fever, myalgia, headache, severe malaise, nonproductive cough, sore throat, and rhinitis 1, 2

• Clinical definitions for influenza-like illness (fever plus cough) have sensitivity of 63-78% and specificity of 55-71% compared to viral culture 1

• Respiratory illness caused by influenza is difficult to distinguish from other respiratory pathogens based on symptoms alone 1, 2

Herpesvirus Disease Categories

HSV infections are classified as asymptomatic shedding, orolabial or genital disease, or tissue-invasive disease requiring organ dysfunction with viral detection in biopsy tissue 1

• VZV cutaneous infection is classified as probable (vesicular lesions on erythematous base) or definite (typical lesions with viral isolation or antigen demonstration) 1

• HHV-6 and HHV-7 disease includes febrile viral syndrome (fever with or without cytopenia and viral detection in blood) and tissue-invasive disease (organ dysfunction with viral detection in tissue or CSF) 1

Epidemic and Pandemic Potential Classification

The WHO maintains a list of diseases with epidemic or pandemic potential, including influenza, COVID-19, Ebola, Marburg, MERS-CoV, SARS, Zika, yellow fever, Chikungunya, Crimean-Congo hemorrhagic fever, Lassa fever, Rift Valley fever, Nipah virus, and Hendra virus 5

• These pathogens are classified by transmission mechanism: direct human-to-human, animal-to-human (zoonotic), vector-borne (mosquitoes, ticks), or environmental contamination 5

• Neurological manifestations occur in the majority of these epidemic diseases, including meningitis, encephalitis, intraparenchymal hemorrhage, seizures, peripheral neuropathies, and post-infectious syndromes 5

Chronic Disease and Cancer-Associated Classification

Viruses are categorized by their association with chronic conditions and malignancies:

• Hepatitis B and C viruses cause chronic liver disease and hepatocellular carcinoma 1, 4

• Epstein-Barr virus (EBV) causes lymphoma and carcinoma 4

• Human papillomaviruses (HPV) are involved in cervical cancer, head and neck cancers, and skin cancer 6, 4

• HHV-8 causes Kaposi's sarcoma 1, 4

Practical Diagnostic Approach

Laboratory Confirmation Requirements

Definite viral disease classification requires laboratory confirmation through:

• Fourfold or greater change in serum antibody titer 1

• Virus isolation or demonstration of viral antigen or genomic sequences in tissue, blood, CSF, or body fluids 1

• Specific IgM antibody by enzyme immunoassay in CSF or serum, with serum IgM confirmed by IgG demonstration via another serologic assay 1

Sample Collection Strategy

For suspected neurological enterovirus infections, respiratory and stool samples in addition to CSF and blood must be submitted, as viruses like EV-D68 are rarely detectable in CSF or stool 1

• RT-PCR targeting the 5' noncoding region (5'NCR) is recommended for enterovirus diagnosis due to sensitivity, specificity, and rapid turnaround 1

• VP1 capsid protein gene sequencing is required for enterovirus typing; 5'NCR sequences cannot be used due to frequent recombination events 1

Critical Pitfalls to Avoid

Do not rely on clinical presentation alone to distinguish viral etiologies, as respiratory illness caused by influenza cannot be differentiated from other respiratory pathogens based on symptoms, with clinical definitions showing only moderate sensitivity and specificity 1, 2

• Arboviral encephalitis cannot be distinguished clinically from other CNS infections 1

• Seasonality and geographic location must be considered when classifying arboviral diseases, as transmission patterns vary by region and local climatic conditions 1

• For herpesvirus infections, positive viral culture from bronchoalveolar lavage is insufficient for HSV pneumonitis diagnosis without histopathologic evidence, as it may reflect oropharyngeal shedding 1