RNA Viruses — Major Families and Diseases

• Positive-sense single-stranded: the genome is directly translatable, so naked RNA is infectious.
• Picornaviruses (naked, icosahedral): poliovirus, coxsackievirus (hand-foot-and-mouth, herpangina, myocarditis), rhinovirus (common cold, acid-labile), hepatitis A.
• Flaviviruses: dengue, yellow fever, Zika, West Nile, hepatitis C.
• Togaviruses: rubella, with its congenital triad of cataracts, deafness and patent ductus arteriosus.
• Coronaviruses, caliciviruses (norovirus, the classic cruise-ship and institutional outbreak).
• Negative-sense single-stranded: must carry their own RNA-dependent RNA polymerase.
• Orthomyxovirus (influenza) — segmented, permitting antigenic shift (reassortment, pandemics) as well as antigenic drift (point mutation, seasonal epidemics).
• Paramyxoviruses — measles (Koplik spots, subacute sclerosing panencephalitis), mumps (parotitis, orchitis, aseptic meningitis), RSV (bronchiolitis; palivizumab prophylaxis), parainfluenza (croup).
• Rhabdovirus (rabies) — bullet-shaped, Negri bodies, retrograde axonal transport.
• Filoviruses (Ebola), arenaviruses, bunyaviruses.
• Double-stranded: rotavirus, the leading cause of severe paediatric diarrhoea.
• Retroviruses: HIV and HTLV, using reverse transcriptase and integrase.

• Not stainable by Gram or acid-fast methods: viruses are identified by genome type, capsid symmetry, envelope and nucleic-acid detection rather than by staining. Growth requires living cells — shell-vial or tube cell culture, or embryonated eggs for influenza — but molecular testing has largely replaced culture in US clinical labs.

Structural features that predict behaviour

• Naked capsid families (picornavirus, calicivirus, reovirus/rotavirus, hepevirus): resist bile, detergents, drying and acid, so they transmit by the fecal–oral route and survive fomites. Rhinovirus is the acid-labile exception — it replicates in the cooler nasopharynx, not the gut, while hepatitis A is acid-stable.
• Enveloped families (orthomyxo-, paramyxo-, flavi-, toga-, corona-, rhabdo-, filo-, retrovirus): labile to alcohol, heat and drying; require respiratory droplet, arthropod, blood or sexual transmission.
• Segmented genomes — bunyavirus, orthomyxovirus, arenavirus, reovirus ("BOAR"): permit reassortment when two strains co-infect one cell.

Virulence factors tested on boards

• Influenza hemagglutinin: binds sialic acid and mediates fusion; neuraminidase cleaves sialic acid to release progeny virions — the target of oseltamivir.
• Paramyxovirus F (fusion) protein: fuses cells into multinucleated giant cells (Warthin–Finkeldey cells in measles); the target of palivizumab and nirsevimab in RSV.
• Rabies G glycoprotein: binds the nicotinic acetylcholine receptor at the neuromuscular junction, enabling retrograde axonal transport.
• Dengue NS1 and rotavirus NSP4 (a viral enterotoxin).
• Error-prone RNA-dependent RNA polymerase lacking proofreading — the structural basis of quasispecies, drift and rapid resistance.

Lab identification

• RT-PCR/multiplex respiratory panels are the workhorse; antigen immunoassays and IgM serology are adjuncts.
• Hemadsorption/hemagglutination identifies influenza, parainfluenza and mumps in culture; syncytial cytopathic effect suggests RSV or measles; Negri bodies (eosinophilic cytoplasmic inclusions in hippocampal and Purkinje neurons) are the histologic hallmark of rabies.

• Genomic instability drives epidemiology: RNA-dependent RNA polymerase has no 3'→5' exonuclease proofreading, so point mutations accumulate. In influenza this is antigenic drift — gradual HA/NA epitope change that erodes herd immunity and produces seasonal epidemics, requiring annual reformulation of vaccine.
• Segmentation permits antigenic shift: co-infection of one cell (classically swine, which bear both avian and human sialic-acid receptors) allows whole-segment reassortment, generating a novel HA. Because essentially no one has neutralizing antibody to the new HA, attack rates are high across all ages — the mechanism of pandemics. Drift = point mutation = epidemic; shift = reassortment = pandemic.
• Influenza ciliated-epithelium destruction: loss of the mucociliary escalator plus exposed basement-membrane adhesion sites explains secondary bacterial pneumonia, most commonly Streptococcus pneumoniae, followed by Staphylococcus aureus (including MRSA, classically with necrotizing/cavitary disease) and Haemophilus influenzae, typically as a biphasic fever after apparent improvement.
• Measles tropism for CD150/SLAM on memory lymphocytes, macrophages and dendritic cells produces lymphocyte depletion and transient anergy — hence post-measles susceptibility to pneumonia and diarrhoea, and reactivation of latent tuberculosis. Persistence of a defective virus in CNS neurons underlies subacute sclerosing panencephalitis years later.
• RSV bronchiolitis: F-protein-mediated syncytium formation sloughs bronchiolar epithelium; debris plus edema plugs airways. Because airway resistance varies inversely with the fourth power of radius, the same wall thickening that is trivial in an adult causes wheeze, air trapping and hypoxemia in an infant.
• Dengue capillary leak: non-neutralizing antibody from a prior infection with a different serotype opsonizes virus into Fc-receptor-bearing monocytes (antibody-dependent enhancement), amplifying viral load and cytokine release; NS1 injures the endothelial glycocalyx, producing plasma leak, hemoconcentration and shock.
• Poliovirus replicates in gut lymphoid tissue, then seeds anterior horn cells, causing asymmetric flaccid paralysis with intact sensation.
• Rotavirus NSP4 acts as an enterotoxin and villous injury strips brush-border lactase, giving combined secretory and osmotic diarrhoea.

Respiratory syndromes

• Influenza: abrupt fever, myalgia, headache and dry cough out of proportion to exam findings. Risk of severe disease — age <5 or ≥65, pregnancy and up to 2 weeks postpartum, chronic cardiopulmonary disease, immunosuppression, obesity, and residents of long-term care facilities (ACIP risk groups).
• RSV bronchiolitis: infant <2 years with coryza progressing to wheeze, tachypnea, retractions and apnea; prematurity, congenital heart disease and chronic lung disease predict hospitalization. RSV in elderly and immunocompromised adults mimics influenza.
• Parainfluenza croup: barking seal-like cough, inspiratory stridor, hoarseness, worse at night; radiographic steeple sign.
• Rhinovirus/coronavirus: common cold; rhinovirus is a leading trigger of asthma and COPD exacerbation.

Exanthems and systemic viral illness

• Measles: prodromal cough, coryza, conjunctivitis with Koplik spots, then a cephalocaudal maculopapular rash that becomes confluent; unvaccinated status is the essential stem clue. Complications: otitis media (most common), pneumonia (most common cause of death), encephalitis, SSPE.
• Rubella: milder rash with tender posterior auricular/occipital lymphadenopathy; maternal first-trimester infection causes the congenital triad already noted.
• Mumps: parotitis, orchitis in postpubertal males, aseptic meningitis, pancreatitis.
• Coxsackie A: hand-foot-and-mouth disease and herpangina (posterior oropharyngeal vesicles); coxsackie B: myocarditis, pericarditis, pleurodynia.

Arboviral and enteric

• Dengue: fever, retro-orbital pain, severe myalgia (breakbone fever), rash; warning signs — abdominal pain, persistent vomiting, mucosal bleeding, lethargy, hepatomegaly — herald plasma leak.
• Zika: mild febrile illness with conjunctivitis; congenital microcephaly. West Nile: encephalitis with flaccid paralysis in older adults.
• Rotavirus/norovirus: watery diarrhoea and vomiting; norovirus in cruise ships, schools and nursing homes.
• Rabies: hydrophobia, aerophobia, agitation, autonomic instability after a bat exposure that may be unwitnessed.

Respiratory viruses

• Initial test: rapid influenza molecular assay or multiplex RT-PCR from nasopharyngeal swab. Per the IDSA influenza guideline, rapid antigen tests have poor sensitivity — a negative antigen test during high local activity does not exclude influenza, and the next step is RT-PCR. In hospitalized patients, RT-PCR is preferred up front.
• RSV: antigen testing performs reasonably in infants (high viral load) but poorly in adults, where RT-PCR is required. The AAP bronchiolitis guideline states bronchiolitis is a clinical diagnosis — routine chest radiography and viral testing are not needed in the typical infant.
• Croup: clinical; radiography only when the diagnosis is uncertain.

Exanthems and systemic infection

• Measles: measles-specific IgM plus RT-PCR of throat/nasopharyngeal swab and urine; IgM may be falsely negative in the first days of rash, so PCR is added. Measles is immediately reportable to the public health department — this is a favourite "best next step."
• Dengue: within the first week, NS1 antigen and/or RT-PCR; after about 5 days, IgM serology. Follow serial hematocrit and platelet count: rising hematocrit with falling platelets signals plasma leak. The WHO scheme classifies dengue with/without warning signs and severe dengue.
• Hepatitis C: USPSTF recommends one-time screening in adults 18–79. Anti-HCV antibody is the initial test; HCV RNA confirms active infection (antibody alone cannot distinguish cleared from current infection).
• Enteroviral aseptic meningitis: CSF shows lymphocytic pleocytosis, normal glucose, mildly elevated protein; enterovirus CSF RT-PCR confirms and shortens antibiotic exposure.
• Rabies: no reliable antemortem serology early — use saliva RT-PCR, nuchal skin biopsy immunofluorescence and CSF/serum antibody; postmortem brain direct fluorescent antibody for rabies antigen is the confirmatory test, while Negri bodies on histology are suggestive but insensitive. Do not delay post-exposure prophylaxis for testing.
• Rotavirus: stool enzyme immunoassay.

Influenza (IDSA 2018 guideline)

• Neuraminidase inhibitors: oseltamivir (oral) — start within 48 hours of symptom onset for greatest benefit, but treat regardless of duration in hospitalized, severe, progressive or high-risk patients. Zanamivir is inhaled and avoided in asthma/COPD; peramivir is IV.
• Cap-dependent endonuclease inhibitor: baloxavir, a single-dose alternative in uncomplicated influenza.
• Resistance: adamantanes (amantadine/rimantadine) are no longer recommended because of near-universal M2 resistance in circulating influenza A, and they never covered influenza B.
• Add antibacterial coverage for suspected secondary bacterial pneumonia, including MRSA-active therapy when post-influenza necrotizing pneumonia is suspected.
• Prevention: ACIP recommends annual inactivated or recombinant vaccine for everyone ≥6 months. Live attenuated intranasal vaccine is avoided in pregnancy and immunocompromise.

Measles: supportive care plus vitamin A, which reduces morbidity and mortality in children (WHO/AAP). Post-exposure: MMR within 72 hours, or immunoglobulin within 6 days for infants, pregnant women and immunocompromised contacts. MMR is live — contraindicated in pregnancy and severe immunodeficiency.

• Drift versus shift: point mutation in HA/NA → antigenic drift → seasonal epidemic; whole-segment reassortment (only possible because influenza is segmented) → antigenic shift → pandemic. Segmented families: bunya, orthomyxo, arena, reo (BOAR).
• Cytoplasmic replication is the rule for RNA viruses; the exceptions are influenza (needs host nuclear cap-snatching) and retroviruses (integration). This is a favourite one-line distractor.
• Naked = tough: picorna, calici, reo and hepeviruses survive acid, bile and alcohol-based hand gel — which is why norovirus outbreaks require soap-and-water hand hygiene and bleach. Rhinovirus is the acid-labile picornavirus.
• A negative rapid influenza antigen test does not rule out influenza — the best next step in a high-risk or hospitalized patient is RT-PCR, and empiric oseltamivir should not be delayed for results.
• Post-influenza biphasic fever with cavitary or necrotizing pneumonia = secondary bacterial infection, most classically Staphylococcus aureus (MRSA possible); S. pneumoniae is the most common overall.
• Koplik spots precede the measles rash; the single best next step after diagnosing measles is notifying the public health department, and vitamin A is given to children. Do not choose an antiviral.
• Negri bodies and retrograde transport via the nicotinic acetylcholine receptor define rabies; after a bat exposure give wound care, immune globulin infiltrated locally, and vaccine — do not wait for animal testing.
• Severe dengue is strongly associated with (most often follows) prior infection with a different serotype via antibody-dependent enhancement, although severe disease can occur with primary infection; management is fluids, and aspirin/NSAIDs are contraindicated — aspirin in a febrile child also raises Reye syndrome.
• Anti-HCV antibody positive alone means exposure, not active infection — confirm with HCV RNA before treating; there is no HCV vaccine, but there are vaccines for hepatitis A and B.