Paramyxoviruses, Mumps, RSV, Parainfluenza, Measles, Influenza

Paramyxoviruses

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  • Single-stranded, negative-sense, linear, non-segmented RNA virus.

  • All members are antigenically stable.

  • Most contain 6 structural proteins:

    • 3 proteins complexed with RNA

      • Nucleoprotein → forms the nucleocapsid

      • P & L → involved in polymerase activity

    • 3 proteins participate in the formation of viral envelope

      • M protein → matrix protein → important in assembly.

      • Glycoproteins:

        • HN or G → for attachment

        • F (fusion) → for membrane fusion & hemolysin activity

  • 3 spikes in the envelope:

    • Hemagglutinin

    • Neuraminidase

    • Fusion protein → causes cell to cell fusion → Giant cell formation

  • Paramyxoviridae Genera Members

    • Respirovirus

      • Parainfluenza 1,3

    • Rubulavirus

      • Mumps

      • Parainfluenza 2,4a,4b

    • Morbillivirus

      • Measles

    • Henipavirus

      • Hendra, Nipah

    • Pneumovirinae

      • Pneumovirus

        • RSV

      • Metapneumovirus

        • Human metapneumovirus

Mumps Virus

  • Single serotype.

  • Neutralizing antibodies against the hemagglutinin.

  • Humans – natural hosts.

  • MOT: via droplets.

  • Mumps/ Viral parotitis:

    • An acute contagious disease involving the salivary glands.

    • Characterized by non-suppurative enlargement of one or both salivary glands.

    • Endemic worldwide.

    • Highest incidence → children 5-9 y/o

  • MOT:

    • Direct contact

    • Airborne droplets

    • Fomites

  • Primary replication → URT epithelial cells → viremia → salivary glands & other areas (meninges, testes, pancreas, ovaries, breast).

  • Involvement of the parotid glands is not an obligatory step in the infectious process.

  • IP: 2-4 wks (14-18 days).

  • Virus shedding: 3 days before up to 9 days after onset of gland swelling.

  • Clinical findings:

    • Prodromal period → anorexia & malaise.

    • Enlargement of parotid glands & other salivary glands with associated pain.

  • Complications of Mumps:

    • Orchitis

      • When bilateral → sterility.

      • Post-pubertal males have fibrous tunica albuginea which resists expansion → pressure necrosis of the spermatocytes.

    • Meningitis

      • Benign, self-limiting.

  • Mumps orchitis:

    • Testicular swelling

    • Edema, mononuclear cell infiltration, and focal hemorrhages.

    • Parenchymal swelling → compromise blood supply → areas of infarction.

  • Diagnosis:

    • Isolation & identification of the virus

      • Culture → monkey kidney cells

      • Immunofluorescence

      • CPE

      • Hemadsorption inhibition

    • Nucleic acid detection → PCR

    • Serology → ELISA or HI

  • Treatment & Prevention

    • No specific treatment.

    • Immunization → MMR → 2 doses.

Respiratory Syncytial Virus (RSV)

  • Replication initially occur in the epithelial cells of the nasopharynx → LRT → bronchiolitis & pneumonia.

  • Most common cause of bronchiolitis & pneumonia in infants (6wks-6 months; peak = 2 months).

  • IP: 3-5 days.

  • Virus shedding:

    • Infants & young children → 1-3 weeks

    • Adults → 1-2 days

  • Severe infection in infants → immunopathogenic mechanism → maternal antibodies passed to the infant may react to the virus → damage cell in the respiratory tract.

  • In older children & adults → mild infections like common colds.

  • Account for 1/3 of respiratory infections in bone marrow transplant patients.

  • Important cause of otitis media in infants especially during wintertime.

  • Immunity is incomplete → recurrent infections.

  • Laboratory diagnosis:

    • Antigen detection – immunofluorescence or ELISA

    • Culture – Human heteroploid cell lines (HeLa cells & HEp-2 cells)

    • Nucleic acid detection – PCR

    • Serology – immunofluorescence, ELISA or Nt tests

  • Treatment & Prevention:

    • Supportive care → removal of secretions, administration of oxygen

    • Antiviral drug → Ribavirin → aerosol for 3-6 days

    • Vaccine:

      • Immune globulin with high titer antibodies → marginal benefit

      • Humanized antiviral monoclonal antibodies

Parainfluenza Viruses

  • 4 serotypes.

  • Most common cause of croup (acute laryngotracheobronchitis) in children under 5 yrs of age (Parainfluenza 1 & 2).

  • Manifestation: harsh cough & hoarseness.

Measles Virus (Rubeola Virus)

  • Measles → an acute, highly infectious disease characterized by fever, respiratory symptoms & maculopapular rash.

  • Key immunologic features of measles:

    • Highly contagious

    • Only one serotype

    • No animal reservoir

    • Inapparent infections rare

    • Infections confers lifelong immunity

  • Humans are the only natural host for measles virus.

  • Entry into the RT → multiply → regional LN → multiplication → primary viremia → RES → multiply → secondary viremia → skin, RT, conjunctivae → replication.

  • Entire events occur during the IP (8-12 days).

  • Virus is present in tears, nasal & throat secretions, urine & blood during the prodromal phase (2-4 days).

  • Day 14 → maculopapular rash appear as circulating antibodies become detectable → viremia disappears & fever decreases.

  • Rash → due to cytotoxic T cell attacking the measles virus infected vascular endothelial cells in the skin.

  • In patients with defective CMI → no rash develops.

  • CNS is commonly involved in measles → encephalitis → may be due to autoimmune reaction.

  • Rare late sequelae → SSPE (subacute sclerosing panencephalitis) → develop years after initial measles infection & due to virus that remains in the body after acute infection.

  • Clinical findings

    • IP 8-12 days → 7- 11 days illness

    • Prodromal phase (2-4 days)

      • 3 C’s → cough, coryza, conjunctivitis

      • fever

      • Koplik spots → “grains of salt” → appear 2 days before the rash

    • Eruptive phase (5-8 days) → maculopapular rash starting from the head → chest → trunk → extremities → 5-10 days → desquamation

    • In partially immune individuals → prolonged IP, diminished prodromal manifestations, (-) Koplik spots, mild rash

  • Complications:

    • Otitis media → most common (5-9%)

    • Secondary bacterial pneumonia → most common life-threatening complication (10% & 20-80%)

    • Giant cell pneumonia → in CMI deficient individuals

    • CNS complications

      • Acute encephalitis

      • Postinfectious encephalomyelitis (acute disseminated encephalomyelitis) → neurological sequelae

      • SSPE → progressive mental deterioration, involuntary movements, muscular rigidity & coma

  • Immunity

    • Infection confers lifelong immunity

    • Cellular immunity → essential for recovery & protection

    • Immunoglobulin def. → recover from measles & resists reinfection

    • CMI def → do very poorly

  • Treatment, prevention & control

    • Vitamin A treatment → decrease morbidity & mortality

    • Vaccine → MMR or MMRV

    • Contraindications to vaccine:

      • pregnancy

      • allergy to eggs or neomycin

      • immune compromise

      • recent immunoglobulin administration

  • Comparison of Rubeola and Rubella:

    • Property | Rubeola (Measles) | Rubella (German Measles)

    • Common name | Measles | German measles

    • Etiology | Paramyxovirus | Togavirus

    • MOT | Inhalation of droplets | Inhalation; transplacental

    • Enanthem | Koplik’s spots | Forschemer’s spots

    • Fever | + | +

    • 3 C’s (coryza, cough, conjunctivitis) | + + + (with photophobia) | + (mild) - + (w/o photophobia)

    • Exanthem | Maculopapular with desquamation | Maculopapular; pruritic w/o desquamation

    • Brawny desquamation | + | -

    • Lymphadenopathy | - | +

    • Arthralgia | - | +

    • Congenital infection | - | +

    • Vaccine | + | +

Hendra Virus & Nipah Virus Infections

  • Zoonotic

  • Natural hosts for both viruses → fruit bats

  • Reasons for emergence:

    • Ecologic changes (land use)

    • Animal husbandry practices

  • 1998-1999 → severe encephalitis due to Nipah virus in Malaysia → transmitted from pigs to humans

  • Hendra virus – an equine virus → caused human fatalities in Australia

  • Classified as Biosafety Level 4 pathogens

Influenza

  • Commonly called “the flu”.

  • A contagious respiratory illness caused by influenza viruses (Family Orthomyxoviridae).

  • Infection with influenza viruses can result in illness ranging from mild to severe with life-threatening complications.

  • 1918 Spanish flu pandemic: Estimated 20 to 50 million deaths worldwide.

  • Influenza is Highly Contagious

    • Virus spread via water droplets, and small particle aerosols when coughing or sneezing

    • Virus enters the body through nose, mouth and eye

  • Viral Titers Peak Early:

    • Peak of viral replication and rapid onset of symptoms occur within 0-5 days.

  • Influenza - Clinical Signs and Symptoms

    • Incubation period for influenza is 1-4 days, with an average of 2 days

    • Adults: infectious from the day before symptoms begin through approximately 5 days after onset

    • Children: infectious for >10 days, and young children can shed virus for <6 days before their illness onset

    • Immunocompromised persons can shed virus for weeks or months

  • Resolves after a limited number of days for the majority of persons, although cough and malaise can persist for >2 weeks

  • Young children can have initial symptoms mimicking bacterial sepsis with high fevers; <20% of children hospitalized with influenza can have febrile seizures

  • Influenza infection has also been associated with:

    • Encephalopathy

    • Transverse myelitis

    • Reye syndrome

    • Myositis

    • Myocarditis

    • Pericarditis

  • Influenza - Hospitalization & Deaths

    • Populations at risk for complications, hospitalizations, & deaths:

      • >65 years old & young children

      • Persons of any age with certain underlying health conditions:

        • Cardiovascular and pulmonary (including asthma), metabolic e.g. DM, Hgbpathies, immunosuppression

        • Receiving long term ASA

  • Seasonal

    • In colder countries, flu is largely seen during colder months, and they vaccinate prior to this season (e.g. October).

    • In tropical countries, flu is seen all year round.

  • Influenza virus types

    • Three: Influenza A, B, and C

    • Influenza types A or B viruses cause epidemics; influenza A may cause pandemics

    • Getting a flu shot can prevent illness from types A and B influenza but not from type C

    • Influenza type C causes mild respiratory illness; not thought to cause epidemics

  • Influenza A virus

    • Contains surface proteins HA and NA. The influenza A virus genome includes:

      • PB2

      • PB1

      • PA

      • HA

      • NP

      • NA

      • M1

      • M2

      • NS1

      • NS2

      • RNP

  • Influenza Replication

    • The entire Influenza A virus genome is 13,588 bases long and is contained on eight RNA segments that code for 11 proteins

    • RNA synthesis takes place in the cell nucleus, while the synthesis of proteins takes place in the cytoplasm

    • Viral proteins are assembled into virions and leave the nucleus, migrating towards the cell membrane.

    • Host cell membrane has patches of viral transmembrane proteins (HA, NA, and M2) and an underlying layer of the M1 protein, which assist the assembled virions to budding through the membrane

  • Influenza A virus divided into subtypes based on HA and N proteins on surface

    • 18 HA, 11 N

    • Nomenclature based on: site of origin, isolate number, year of isolation, subtype

    • Example: influenzaA/Johannesburg/33/94(H3N2)

  • Drift or shift

    • “Antigenic drift" - small changes in the virus that happen continually (influenza A and B)

    • “Antigenic shift” - abrupt, major change in the influenza A viruses, resulting in new H &/or new H and N proteins that infect humans (influenza A only)

  • Influenza subtypes in humans

    • Current subtypes of influenza A viruses found in people are A(H1N1) and A(H3N2)

    • Influenza B virus is not divided into subtypes

    • Influenza A(H1N1), A(H3N2), and influenza B strains are included in each year's influenza vaccine

    • Protection is serotype specific

  • Recorded human pandemic influenzas since 1885 (early sub-types inferred)

    • Includes: Russian influenza, Spanish influenza, Asian influenza, Hong Kong influenza, and Swine Flu pandemic.

  • Most recent Flu Pandemic: novel A(H1N1)

    • Quadruple reassortant: 2 NA bird flu genes, 1 swine flu, human flu

    • Thrives in lower respiratory tract

    • More contagious

    • Has now become seasonal flu

    • Resistant to amantadine, rimantadine

  • Avian Influenza

    • Many subtypes of influenza A virus subtype of avian influenza

      • Low pathogenicity avian influenza (LPAI)

      • Highly pathogenic avian influenza (HPAI)

        • First recognized in Italy in 1878

        • Extremely contagious in birds

        • Rapidly fatal, high mortality (almost 100% in a few days)

        • Documented in humans: H5N1, H7N3, H7N7, H7N9, and H9N2, H10N8

  • Treatment of Influenza

    • Antiviral Medications:

      • Antiviral drugs: adamantanes: amantadine, rimantadine; neuraminidase inhibitors: zanamivir, oseltamivir

      • Antiviral treatment lasts for 5 days and must be started within the first 2 days of illness.

  • Flu vaccination

    • Inactivated vaccines: the whole virus vaccine, split virus vaccine (disrupted by detergent), and subunit vaccine (H and N purified). Some formulations include adjuvants

    • Live, attenuated influenza vaccines have been based on a temperature-sensitive variant vaccine virus strains that replicate well in the nasopharynx but poorly in the lower respiratory tract

  • Vaccination should be given once a year preferably from February to June

  • The Southern Hemisphere vaccine which is made available starting February of each year is recommended to cover the expected increase in influenza activity from June to November. “Try not to be a man of success, but rather try to become a man of value” - Albert Einstein