Respiratory Viruses Flashcards
Viruses Covered
Respiratory Syncytial Virus
Parainfluenza Virus Types 1, 2, 3, 4,
Adenoviruses
Rhinoviruses
Enterovviruses
Coronaviruses
Human Metapneumovirus
Respiratory Tract Disease
More episodes of illness than any other organ system
- 75-80% of all acute morbidity and visits to physicians
- respiratory tract is main portal of entry for many organisms, so not surprising that it is the most common site of infection by microbial pathogens as in direct contact with the physical environment
- wide range of organisms can infect the respiratory tract, including viruses, bacteria, fungi and parasites
Upper respiratory tract
- colds
Lower respiratory tract
- 4th most common cause of death in developed countries
Global Burden of Respiratory Disease
Public health issue!
Leading killer of children < 5 yrs old , especially RSV
Pediatric ALRI < 5 yrs old
RIV> Influenza> Pneumococcal > HiB
Acute viral respiratory disease
Viruses account 80% or more of RTI’s
All age groups
3 - 4 viral illnesses per year per person, mostly in young children!
Abx have no effect but 60% get them!
Who is at greatest risk for acute viral respiratory disease?
The very young
The elderly
Chronically ill
Immunocompromised!
Viral respiratory illness
Children vs Adults
Children: implicated in 40-70% CAP, >90% of bronchiolitis, over 90% asthma exacerbation
Adults: 30-50% of cap, > 80% asthma exacerbation, 20-60% exacerbation of COPD
infection messes with your epithelial cells so you are predisposed to secondary bacterial infections in respiratory tract and can affect other organ systems
Location in Respiratory Tract - relates specific site of infection to various symptoms
Where do most infections occur?
Most infections are limited to upper airways
LRTIs common in defined populations
Cough, runny nose, sneezing, sore throat, ear pain, congestion
Systemic manifestations of fever, headache, chills malaise, myalgia also common
Last 7-10 days in most, 2 - 3 weeks in many, longer in some
Common cold
Pharyngitis
Pneumonia
Laryngitis
Laryngotracheobronchitis in infants (croup))
Tracheobronchitis
Bronchiolitis
Common cold: nasal obstruction, nasal discharge
Pharyngitis: sore throat, red throat with or without exudate
Pneumonia: cough, chest pain, rales
Laryngitis: hoarseness
Laryngotracheobronchitis in infants (croup)): hoarseness, barking cough, stridor
Tracheobronchitis: nonproductive cough, substernal pain
Bronchioliti: cough, dyspnea, wheezing
Common complications of viral infections
Secondary bacterial infections causing otitis media, sinusitis, pneumonia
Diagnosis of respiratory viruses
- clinical and epidemiological findings
Virus isolation in cell culture (time consuming, labor intensive and costly and not all respiratory viruses grow in culture): used to be gold standard but not anymore
Rapid antigen test
- cheap easy but poor predictive value outside of peak season
- IFA and EIA
- not as sensitive as cell culture
Detection of nucleic acids
- can test many viruses at the same time
- PCR, feasible and most sensitivity GOLD STANDARD
Serology- retrospective, seldom done in clinical setting
Specimen collection for detection of respiratory viruses
- close to clinical onset!
- nasopharyngeal aspirates, washes, swabs in VTM, throat swabs in VTM
- nasopharyngeal aspirates or nasal washes are good in young children
- combined thorat and nasopharyngeal swabs are more practical for older children and adults
- children shed virus at higher titers for longer periods of time than adults, upper airway specimens not always best for adults
Why test respiratory viruses?
Infection control
Individual patient management
- help manage special populations
- limit abx, lab tests, hospital procedures
- reduce sequellae
Surveillance
- rapid outbreak identification!
Virus SEasonality at CHOP
Rhinovirus > RSV> adenovirus> influenza A> HMPV> HPV 3 etc
Flu Season is more than just flu
Even during peak influenza season (DEc-Feb)–> see RSV and HMPV at high levels
Incidence highest in winter and lowest in Sumer for respiratory viruses
BUT adenoviruses and rhinoviruses are endemic in the US and seen all year round
Also tropical and semitropical areas dont have same seasonality
Many different respiratory viruses
Heterogeneous group, a real mixed bag
Over 200 distinct viruses belonging to 6 major families can infect human respiratory tract
- some viruses common and well established and you should recognize by name, some are newly identified and significance is still being established
- differ due to size, symmetric, nucleic acid type, lability, mode of replication, and pathogenic and epidemiological behavior
Common respiratory viruses characteristics
Worldwide
Short incubation (1 - 4 days)
Person to person spread
Similar pathogenesis
Increased risk of bacterial superinfection
Immunity imperfect-> reinfection common
Respiratory Virus Transmission
Person to person normally!
Super contagious
Direct contact, aerosolization of infective droplets during coughing and sneezing or indirectly by hand transfer of contaminated secretions or from contaminated objects to nasal or conjunctival epithelium
Eg RSV stable 3 - 30 hours on countertops
Eyes and nose major portals of entry
WASH HANDS
RV pathogenesis
Viruses enter via nose and eyes
–> infect ciliated respiratory epithelial cell slining upper and lower airways, multiply locally no systemic infection
–> cytolytic causing cell damage and death–> clearance mechanisms compromised (damage creates susceptibility to bacterial superinfections)
–> local and circulating Ab response and T cell recognition with release of cytokines
–> recruitment of neutrophils, NK cells, CD4+ and CD8+ T cells, macrophages, mononuclear cells, eosinophils
–> viruses have ways of evading the immune system
–> certain viruses interact with the immune system to promote immediate hypersensitivity reactions leading to virus-induced wheezing and asthma - CYTOKINE STORM
Cytokine storm
Immune mediated injury caused by immediate hypersensitivity reaction to virus
Respiratory Syncytial Virus (RSV) - who does it affect
Most common cause of bronchiolitis and pneumonia in infants and young children <1 yo
Most important agent of respiratory disease in infancy
Infects virtually everyone by 2 - 3 years of age and reinfections are common throughout life
RSV function and structure
Paramyxovirus family
Enveloped: single stranded RNA
120-300 nm
G and F proteins (surface glycoproteins mediate attachment of the virus to the host cell and fusion, respectively)
- F protein also mediates syncytium formation
Virus contains an RNA dependent RNA polymerase for transcription and replication
Other paramyxoviruses = measles, human parainfluenza, mumps, metapneumovirus
Two subgroups - antigenic types A and B
Significance of variants unknown
What proteins mediate RSV attachment, and fusion to host cell and synctitium formation?
G (attach)
F(form and syncytium)
Antigenic Subgroups of RSV
A - associated with more severe
B - less severe
Significance of variants is unknown
RSV epidemiology
Outbreaks?
Source of infection?
Who is infected?
Episodes?
Immunity?
Humans= only source of infections
Annual community outbreaks
50% of all families with children
Circulation is effeicient (2/3 of infants infected in 1st yr, all children by 2 - 3 yr)
Age peak of 2 - 5 mo
50% children have 2 + episodes, 40% infx produce lower respiratory tract diseases
Re infx common for all age groups, immunity imperfect and not completely cross protective against two strains
Serious RSV illness
Very young infants, premature infants
Children <2 - 3 yo
Elderly
Children and adults with chronic illness and compromised immune systems
Mortality = .5-1% but > 15% in impaired host
What is the single most important agent in respiratory disease in infancy?
Leading cause of lower respiratory illness in infants and young children worldwide?
RSV
RSV mortality
Leading viral cause of mortality in infancy
10x morality of influenza in infants < 1 yr
500 deaths per year
- 80% in infants < 1 yo
Syndromes of RSV infections in children
Bronchiolitis (most common)
Pneumonia
Tracheobronchitis
Croup
Asymptomatic
(Ascending–> descending, most common–> leas common)
Clinical Presentation of RSV disease
URI?
LRI?
Clinical findings?
Other?
Duration of illness?
URI = cough, rhinitis pharyngitis, fever
LRI = expiration wheezing, air trapping, tachpnea, dyspnea, rales (clicking rattling in lungs), rhonchi (snoring sound in lungs), retractions (sinking in of the chest wall above collarbone, between ribs and below rib cage), nasal flaring, grunting hypoxemia (low oxygenation of blood), irritability, dehydration, respiratory distress
Clinical findings: Hyperexpansion of lungs and hypercapnia (carbon dioxide retention- especially bad when young)
Other; otitis media, vomiting, conjunctivitis
Duration: 10 - 14 days
Retractions
Look at pic slide 26 of respiratory lecture
- see child with suprasternal and intercostal retractions and nasal flaring–> child cant breathe
Chest X ray: RSV bronchiolitis - children
Slide 27 of respiratory lecture
Hyperinflation of lungs (due to airtrapping tachypnea) with flattened diaphragm, horizontal ribs and increased hilar bronchial markings
See pulmonary insterstitial infiltrates with areas of pulmonary collapse
RSV pathogenesis: infx in respiratory tract - no viremia, respiratory epithelial cells killed by virus and cellular immune response–> necrosis of epithelium in medium to small airways–> mucus/fibrin plugs impeding airflow gas exchange and leading to pulmonary infiltrates
RSV in adults
Healthy adults frequent, mild influenza like
In elderly and immunocompromised (CHF, immune suppression, bronchiopulmonary insuffiency) it can the serious
2- 4% pneumonia deaths among elderly
Suspect RSV in all adults who present with fever and pulmonary infiltrates
Hospital associated infections - RSV spread
Concern in pediatric wards, nurseries, nursing homes, adult medical wards
Controlling spread can be difficult
Recovered rom counter tops for 3 - 30 h
Cloth gowns, gloves, paper tissue for 1 h
Skin 30 min
Max period of viral shedding is 3 - 8 days for immune competent and 3 - 4 weeks in young infants
WASH HANDS
RSV treatment
Supportive, maintain hydration and oxygenation and keep airways clear of mucus and debris
No vaccine
Palivizumab(synagogue) - humanized mouse monoclonal Ab for HIGH RISK children
- IM injections 1x/mo during RSV season, 5 doses given
Aersolized - Ribavirin
- drug to treat RSV lower respiratory tract, cost and risk of aersolized administration, used selectively
- generic antiviral for lower respiratory tract, not suggested for routine use
Human Metapneumovirus (HMPV)
What family?
Age?
Location?
What type of particles
RNA vs DNA?
Enveloped vs not enveloped?
Genotype?
Family: paramyxovirus
Not a new virus
All age groups all over the world
Pleomorphic particles, spherical, filamentous
SsRNA, single stranded negative sense RNA virus
Enveloped
No hemagglutin
4 genotypes of the virus that can be found in two major groups (A and B)
SEasonality of HMPV
Mid January – mid June
HMPV epidemiology/disease
Symptoms similar to RSV
Acute respiratory illness in children, elderly, those with underlying immune compromise and cardiopulmonary disease
Virtually all children infected by 5 to 10 yo, new infections throughout life
Clinical presentation from URI to severe bronchiolitis and pneumonia
HMPV treatment or vaccine?
None
Parainfluenza viruses
Family?
Size?
Enveloped/not enveloped?
Genetic material?
Proteins involved ?
Paramyxovirus family (with RSV, HMPV, mumps and measles)
120-300 mm
Enveloped
Nonsegments, ssRNA genome
Paramyxoviruses have hemagglutinin and neuraminidase activity (HN protein) and fusion (F protein)
- positive hemagglutination tests are parainfluenza and negative are HMPV
What is the major cause of croup, and an important cause of lower respiratory tract infection in infants and young children?
Parainfluenza virus
Parainfluenza virus antigenic types
Serotypes?
Four serotypes: 1, 2, 3, 4 (A&B)
Individual types are antigenically stable
- unlike influenza, no antigenic shift or drift
Differ in frequency of occurrence, disease spectrum, and epidemic patterns
Cause disease in larger airways of LRT
Important cause of LRI in infants and children (15-20%( of all non bacterial respiratory disease causing hospitalization
Differences in parainfluenza antigenic subtypes
PIV1 - major cause of acute viral croup, mostly in the fall and early winter, 6 - 12 mo yo
PIV3 and 2 (second and 3rd most frequent cases)
PIV2 - fall and early winter but not concurrent with PIV1
- less significant, 6 - 12 mo yo
PIV3 - mostly in the spring and summer- common cause of pneumonia and bronchiolitis , all throughout the year
- highest attack rates in 3 - 6 mo
PIV4 is least common and infrequent cause of acute LRtract disease and associated with mild URI
Viruses
1 & 2: Croup, 6 mo - 12 yr, Autumn
3: Bronchiolitis, Pnejmonia, < 6 mo, Endemic (spring)
4: URI, children, endemic
Parainfluenza croup
Virus infects epithelial cells of upper airways
Begins as URI with thin nasal discharge, sore throat, mild cough
Within 1 - 2 d, inspiration stridor, retractions, worsening barking cough (hoarseness due to narrowing in region of larynx and subglottic trachea)
Symptoms exacerbated at nigh, children wake up gasping for breath
Self limited, last 3 - 7 days in most and up to 7 - 14 days
STEEPLE SIGN - see pic on slide 42
Treatment of parainfluenza croup
Immunity?
Supportive care for mild disease
Oxygen, nebulized epinephrine and corticosteroids for severe infection
Immunity short lived so reinfections throughout life are common though less severe
Croup clinical pearls
Symptoms from inflamed larynx and subglottic airway, may close the airway in severe case
Dry barking seal life cough
6mo - 12 yrs, peak incidence at 2, more common in boys
Fall or early winter
10pm - 4 am ED visits, worst ending symptoms at night
Self-limited condition - last 3 - 7 days, up to 7 - 14 days in some
See treatment slide for treatment
Adenovirus: composition
Enveloped/ non enveloped
DNA vs RNA
Nonenveloped viruses
80 - 90 mm in size
Icosahedral capsid of. Hexon and Peyton capsomers
DsDNA (encodes 30 - 40 genes)
Fibers project from capsid at Peyton base and are major attachment for proteins (knobbed viruses–> classic shape)
Peyton base and fiber proteins determine serotypes, tissue tropism and disease
ADenovirus: Antigenic types
~ 100 types, 57 affect humans
Species A to G (varied tissue tropism)
- mainly b and C, some E: infect respiratory tract
- B and D: ocular
- primarily F, some a and G–> GI disease
Ubiquity and persistence in host tissues for days to years (prolonged infx without disease!)
Only 45% of infx result in disease
Serotypes 1-5, 7, 8, 21 important respiratory agents, 14 associated with sever pneumonia in civilian and military communities
ADenovirus epidemiology
Endemic in US, sporadic outbreaks
Children: 6 mo - 5 yrs and grade school and junior high
Epidemics occur in military recruits (primarily AdV types 4 & 7)
Spread by respiratory and fecal route
- resist drying, detergents, GI secretion
- aerosols, fingers, fomites (including medical instruments), poorly chlorinated swimming pools
- in day care, hospitals, clinics, children’s homes, physicians offices, industrial settings
Adenovirus multiple syndromes
Infants, young children,
School age children
Military recruits
Transplant recipients, AIDS patients, other immunocompromised
Many common diseases including multiple respiratory and GI syndromes, significant cause of conjunctivitis (pink eye)
Cause disseminated disease and high morbidity and mortality in immunocompromised patients, transplant reciepients and are a significant cause of nonstreptococcal exudative pharyngitis < 3 yo
Infants, young children,
- acute febrile pharyngitis
- **pneumonia
- pertussis like syndromes
School age children
- pharyngoconjunctivial fever
- pic on slide 49
Military recruits
- acute respiratory disease
Transplant recipients, AIDS patients, other immunocompromised
- disseminated diseas
- acute hemorrhagic cystitis
Pharyngoconjunctival fever
Slide 49
- foreign body sensation in right eye
Conjunctiva was injected and red with clear discharge
No foreign body–> give anti-inflammatories for possible allergic reaction–> next day eye was swollen and appearance of pale real conjunctiva was intensely red and granular
Patient complained of severe eye pain and burning, photophobia, and eye was constantly tearing
Over the next 2 - 3 days, develop:
- sore throat, cough, Coryza, stiff neck, malaise aches and pains, fever, vomiting, diarrhea, anorexia, lymphadenopathy, left eye conjunctivitis
- adenovirus from respiratory tract, persisted for 14 days infected from children
Rhinovirus Characteristics
Family? Genetic material? Enveloped? Size? Viral proteins? Proteins? Serotypes?
Picornaviridae: small RNA virus
Genus: enterovirus
Naked, nucleocapsid,
Capsid has 4 viral proteins: VP1, VP2, VP3, VP4
Attach to intracellular adhesion molecule 1(ICAM-1) on cells (member of Ig super family(
SsRNA genome (single stranded negative sense RNA)
> 100 sero/genotypes in three groups (A-C); 3 - 4 circulate at a time
Common cold virus
Acid labile (unlike enteroviruses) so they cannot replicate in GI tract
What is the common cold virus?
/ What is the most commonly identified virus from persons experiencing acute respiratory illness; seen in all age groups ?
Rhinovirus
Salient characteristics of rhinovirus
Antigenic diversity!
3 - 4 serotypes circulate at one time
Infection with one type appears to confer lasting type specific immunity but offers no protection against other types
By adulthood, we have Ab to about half the serotypes
Infections throughout the year but peak in the fall/ spring
When do rhinoviruses occur and in what population
All ages, especially older children and adults
All throughout the year, peak activity in fall and spring
Where is most viral infection in the rhinovirus?
Most viral replication is in nose; release of bradykinin and histamine causes “runny nose”
Rhinovirus Serious disease
Flu like illness
- significant cause of lower respiratory tract disease, more common than expected
Indirectly or directly cause many cases of acute sinusitis and otitis media
Important role of rhinoviruses as a cause of
- bronchiolitis in infancy,
- childhood pneumonia
- exacerbation of asthma, COPD, cystic fibrosis,
Enterovirus respiratory infections - associated with respiratory illness, seen in late summer/early fall
Treatment of rhinovirus
Zicam!
Corona virus characteristics
Enveloped/nonenveloped?
Shape/size
Genome?
Infection site?
Serotypes?
Enveloped virus
Petal or club shaped spikes (solar corona) created by spike protein peplomers
SsRNA genome, positive sense single stranded RNA
Phenotypically and genotypically diverse
Infect respiratory and GI tracts of mammals and birds
4 respiratory serotypes in man
SARS coV in 2003; MERs coV in 2012
SEasonality of common cold
In the winter corona virus is more common the cause
In the summer rhinovirus more commonly causes the common cold
What does RNA genome code for in the coronavirus?
Two non structural replicate polyproteins and four structural proteins
structural proteins
- spike (S): responsible for receptor binding
- envelop (E): virus assembly
- membrane (M) glycoproteins : virus assembly
- nucleocapsid (N) protein: internal protein binds to viral RNA to form ribonucleoprotein complexes
Replicate polyproteins directly translated from viral genome and used in viral transcription and replication
Coronavirus characteristics
Common viruses, people get in their life time
10-30% common colds
Can cause more serious LRTI
Can also cause enteric, hepatic, or neurological diseases
Can be found in other species, birds cats dogs pigs mice, horses whales and are widespread in bats!
Respiratory Viruses: prognosis and complications
Excellent for healthy individuals
Increased risk: young children, elderly, ill chornically ill, immunocompromised
Complications
- exacerbation of underlying respiratory disease
- development of chronic lung disease
- possible secondary bacterial infections
- apnea, respiratory failure
- acute otitis media
- sudden infant death syndrome in immunocompromised children
Respiratory Viruses: Immunity
Infection induces immunity only partially protective and of short duration
Ab acquired early in life but reinfection is common
Cell mediated immunity is likely to be pivotal in clearance of RVs and in recovery
- resistance to infection of upper respiratory tract due to secretory antibody
- resistance of lower respiratory tract due to circulating antibody
Illness is. Milder with reinfection
Ag variants may exist for which immunity is not completely cross protective
Only vaccines for influenza
RV treatment
No vaccines or therapeutics for most respiratory viruses
Good supportive care
Treatment
- aersolized ribavirin (RSV) for select patients,
- amantadine, rimantadine (influenza A)
- Zane I IR, oseltamivir (influenza A and B)
RSV: treat with aersolized ribavirin and prevent with palivizumab (humanized monoclonal ab)
Parainfluenza: ribavirin (limited studies)
Adenovirus: ribavirin, cidofovir - anecdotal
Rhinovirus: limited, pleconaril an dother canyon inhibitors
RV prevention
Immunoglobulin: Palivizumab (synagogue) humanized monoclonal antibody against RSV
Vaccine and antivirals (influenza)
RV control
Interrupt transmission: contact isolation, cohorting, gowns and gloves, HANDWASHING
Other causes of respiratory diseases
Certain bacteria and fungi but at lesser frequency than viruses discussed today
Bacterial infections may result of secondary infection following viral illness
- symptoms may persist longer than expected 10-14 days of viral illness and fever worse and get worse after a few days
Secondary infections: sinusitis, ear infections, pneumonia (productive cough for bacterial infections with more discrete foci unlike the diffuse interstitial infiltrates of viruses)
