Viral Infections of the Viral Infections of the Respiratory TractRespiratory Tract

- Major portal of entry

- Most common afflictions in humans

Considerable impact on quality of life and productivity of society

Respiratory tract

- Wide range of clinical manifestations: from self-limited to devastating

-Children half a dozen each year, adults two or three. - Most caused by viruses.

Respiratory tract

-Influenza virus killing the elderly and respiratory Syncytial virus killing the very young

Altogether over 200 known viruses

- Majority are trivial colds and sore throats

-Serious lower respiratory tract infections tend to occur at the extremes of life

Respiratory tract infection

High prevalence:

Large number of infectious agents and serotypes

Efficiency of transmission

Incomplete immunity

Frequency:

Higher in children under 4 years

It declines in teenagers

Rises again in parents

Lowest in the elderly

Major reservoir

schoolchildren

Coronaviruses

Adenoviruses

EnterovirusesRhinoviruses

MetapneumovirusBocavirus

Parainfluenzaviruses 1-4

Respiratory Syncytial virus

Influenza A, B, C viruses

Respiratory viruses

• Short incubation period (2-7 days)

• Large number of virions, even before symptoms

• Small number necessary to infect

• Epidemic outbreaks

When the proportion of uninfected

susceptible persons in the community

falls, the epidemic burns itself out.

Characteristics of Infection

• Inhaled droplets > 10 m Ø are

trapped in turbinates of the nose

Viral Entry

• Inhaled droplets 5 -10m Ø often

reach the trachea and bronchioles

Described according to the anatomical site of maximal involvement

Clinical features

• Above the epiglottis

URTI

• Below the epiglottis

LRTI

• Spreading:

• Inhalation

• Direct contact

• Transmission: respiratory route

• Shedding: sneezing, coughing or talking

• Sneeze:

–106 droplets < 10m evaporation smaller-

suspended in the air for several minutes

–Larger droplets fall to the ground

Epidemiology (1)

Epidemiology (2)

* Sneezing:1.940.000 viral particles

• Some viruses remain infectious for

prolonged periods

* To begin an infection:

Adenovirus: 7 Influenza A virus: 3 Enterovirus: 6

Mea

n a

nn

ual

illn

ess

inci

den

ce

Age group (yr)

7

6

5

4

3

2

1

0 1 1–2 3–4 5–9 10–14 15–19 20–24 25–29 30–39 40–49 50–59 60

Mean Annual Incidence of Respiratory Illnesses per Mean Annual Incidence of Respiratory Illnesses per Person-YearPerson-Year

Females

Males

30

25

20

15

10

5

0

Per

cen

t

RV Parainfluenza viruses

Per

cen

t

Respiratory syncytial virus (RSV) Influenza virus30

25

20

15

10

5

0Jan Apr Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jan Apr Sep Oct Nov Dec Jan Feb Mar Apr May Jun

Seasonality of Respiratory Agents: Proportion Seasonality of Respiratory Agents: Proportion Isolated in Each Calendar Month During 6 YearsIsolated in Each Calendar Month During 6 Years

Sore throatCoughActivity restrictionLower respiratory symptomsHeadache

Coryza

Per

cen

t

RV RSV Parainfluenza virus

Hemolyticstreptococci

Influenza A Influenza B

0

20

40

60

80

100

Characteristics of VRIs of Known EtiologyCharacteristics of VRIs of Known Etiology

Respiratory Viruses and Asthma• Viruses cause asthma exacerbations in adults and

children

• RVs cause ~60% of virus-induced exacerbations of asthma

• RVs directly infect the bronchial airways

• The response to viral infection is shaped by the host’s antiviral response

• VRIs in early childhood may protect against the development of asthma

Viruses Detected in Adult Patients Viruses Detected in Adult Patients Hospitalized with AsthmaHospitalized with Asthma

54.5%

6.1%

27.3%

3% 3%Influenza AInfluenza BRVAdenovirusRSVHerpes

6.1%

2 episodes of “common cold” beforeage 1 yr decrease risk of asthma by age 7by ~50%

• Other viral infections— eg, herpes, varicella, measles—also protective

• Reported LRI with wheeze in the first 3 years of life increases risk of asthma

2 episodes of “common cold” beforeage 1 yr decrease risk of asthma by age 7by ~50%

• Other viral infections— eg, herpes, varicella, measles—also protective

• Reported LRI with wheeze in the first 3 years of life increases risk of asthma

Respiratory Infections in Infancy May Protect Respiratory Infections in Infancy May Protect Against Development of AsthmaAgainst Development of Asthma

Off

ice

visi

ts (

1000

)

0

5000

10,000

15,000

20,000

25,000

Office visits

Antibiotic prescription

Bacterial prevalence

Acute Respiratory Infections (ARIs):Acute Respiratory Infections (ARIs):PrimaryPrimary Care Office Visits, Antibiotic Use, and Care Office Visits, Antibiotic Use, and

Bacterial Prevalence in US, 1998Bacterial Prevalence in US, 1998

30%

76%

70%

62%

59%

URI Otitis media Sinusitis Pharyngitis Bronchitis0

20

40

60

80

100

An

tibio

tic Rx an

d estim

atedb

acterial prevalen

ce (% o

f visits)

• Patients who expect antibiotics receive them more often

• Strongest predictor of receipt of antibiotics for ARI isMD perception of patient expectation

• Public beliefs about antibiotic effectiveness– Useful for VRI: 55%– Useful for bacterial but not viral illness: 21%

Use of Antibiotics: Patient Expectations, Use of Antibiotics: Patient Expectations, Physician Perceptions, Public BeliefsPhysician Perceptions, Public Beliefs

Running nose & Sneezing

“Doc, make it go away quickly, some strong antibiotics will do!”

Sore throat

“Doc, it is so bad …..you must give me antibiotics!”

Facial pain & Congestion

“Doc, give me something, my head is exploding…. I normally take antibiotics straight away!”

Painful ear

“Doc, she ‘s been crying all night…… you must give her antibiotics please!”

Nagging Cough

“Doc, my cough is killing me …. this wouldn’t have happened if you had given me antibiotics in the first place !”

SummarySummary• VRIs are the most common infectious diseases worldwide

• RVs are predominant cause of VRIs in all age groups

• Transmission requires relatively close contact

• Family and school major sites of transmission

• RV infections peak in autumn, with minor spring peaks

• RVs cause AOM, sinusitis, and bronchitis in otherwise healthy people

Common Viral RT Infections

• Rhinitis

• Sinusitis

• Pharyngitis

• Laryngitis

• Tracheitis

• Bronchitis

• Bronchiolitis

• Pneumonia

Rhinitis• Common colds are the most prevalent entity of all

respiratory infections and are the leading cause of patient visits to the physician, as well as work and school absenteeism.

• Rhinitis is the most common manifestation of common cold.

• Characterized by variable fever, inflammatory edema

of the nasal mucosa, and an increase in mucous secretions.

Rhinitis

Copious watery nasal discharge,congestion, sneezing, and a mild sore throat or cough. Little or no fever

LRTI in 60% in elderly persons

common in young children

50% last longer than 1 week and 25% last up two weeks

Rhinitis

Acute inflammation of the mucosa may contribute to the pathogenesis of otitis and sinusitis.

Abnormalities observed in the sinus cavity in these patients appear to result from the entrapment of secretions and resolve 2 to 3 weeks later.

Causative Agents of Rhinitis

• Rhinoviruses

• Coronaviruses

• Parainfluenza Viruses

• Respiratory Syncytial Virus

• Adenoviruses

• Enteroviruses ( Coxsackie, ECHO)

• Influenza

• Rhinoviruses with more than 100 serotypes are the most common pathogens, causing at least 50% of colds in adults.

• Coronaviruses may be responsible for more 10-20%

of cases. • Parainfluenza viruses, Respiratory Syncytial virus,

Adenoviruses and Influenza viruses have all been linked to the common cold syndrome.

• All of these organisms show seasonal variations in

incidence.

• The cause of about 30% of cold syndromes has not been determined.

Rhinoviruses

• Family Picornaviridae

• Numerous serotypes

• Optimum temperature of growth

• Acid stability

• Mode of transmission

• Infectivity and replication

- Rhinovirus (major) ICAM-1

- Rhinovirus (minor) LDL-R

Genus RhinovirusSpecies More than 100

Responsible for about 50% of common colds

• > 100 serotypes of Rhinovirus

• Re-infection can occur• Infections year-round, most prevalent in fall and spring

• Incubation period about 2 days

• Symptoms peak on the 2nd and 3rd days

• They cause the most prevalent acute respiratory illness.

• Very high attack rate (>90%)

• Mostly as mild common colds with rhinorrhea, nasal obstruction, fever, sore throat, cough and hoarseness lasting for a few days.

• Serious lower respiratory illness is common in infants.

• Secondary bacterial infection of sinuses and middle ear.

• Spread by contaminated hands more than respiratory droplets.

• Common cold is not caused by a change in weather, loss of sleep, going outside with wet hair, or fatigue.

• Risks for contracting a cold are due to exposure to the causative viruses through personal contact.

• 75% of patients infected with rhinovirus will have symptoms.

Pathogenesis and Pathology • The viruses appear to act through direct invasion

of epithelial cells of the respiratory mucosa with destruction and sloughing of these cells and loss of ciliary activity.

• There is an increase in both leukocyte infiltration and nasal secretions, including large amounts of protein and immunoglobulin, suggesting that cytokines and immune mechanisms may be responsible for some of the manifestations of the common cold.

• Pathology: inflammatory changes with hyperemia, edema and inflammation of the columnar epithelial cells lining the nasopharynx followed by desquamation.

Clinical Manifestations • After an incubation period of 48-72 hours, classic

symptoms of nasal discharge and obstruction, sneezing, sore throat and cough occur in both adults and children.

• Myalgia and headache may also be present but fever is rare.

• After 2 – 3 days, nasal discharge becomes thicker, cloudy, and yellowish in color as systemic symptoms improve.

• Hoarseness, cough, and sore throat may last up to 7 – 10 days.

• The duration of symptoms and of viral shedding varies with the pathogen and the age of the patient.

• Complications are usually rare, but sinusitis and otitis media may follow.

Clinical Features and Duration of Illness in Clinical Features and Duration of Illness in Adults with RV ColdsAdults with RV Colds

Clinical featureRV %

positive

First symptom (% of subjects) Sore throat Stuffy nose Runny nose Sneezing

3917178

Most bothersome symptom (% of subjects)

Runny nose Stuffy nose Sore throat Malaise

36201910

Median duration of symptoms (days) Cold episode Sleep disturbance Interference with daily activities

1147

RV Infection in the ElderlyRV Infection in the Elderly• In persons 60–90 years of age with RV

infection, median duration of illness was16 days

• 19% were confined to bed; 26% had restriction of daily activities

• 63% had lower respiratory tract symptoms;43% consulted their physician

• Burden of RV infection in the elderly appears to exceed that of influenza

Diagnosis

• Made on clinical grounds – patient symptoms,

nasal examination showing reddened, edematous mucosa, narrowed nasal passages, and watery discharge

• Laboratory and/or imaging only indicated if other conditions are strongly suspected

• Viral isolation/culture is not practical

Management/Treatment

• No curative treatment

• Supportive therapy – 10 treatment– Fluids, rest, humidification, and decongestants– Analgesics, cough suppressants, mucolytics, and

antihistamines are also helpful

• Short term use of zinc lozenges (zinc gluconate 10-15 mg q 2 hrs) has shown to reduce duration of subjective symptoms if begun early in the course of disease

• Inappropriate prescribing of antibiotics is common due to – Patient beliefs/misinformation of cold being

bacterial in origin– Rural location– Female gender– Patients with purulent secretions

• Antibiotics should be considered if symptoms last longer than 10-14 days, due to an 80% chance of a secondary infection occurring

SinusitisSinusitis• Sinusitis is an extremely common part of the

common cold syndrome

• RVs have been detected in 50% of adult patients with sinusitis by RT-PCR of maxillary sinus brushings or nasal swabs

• Frequency of association of RV infection with sinusitis suggests that common cold could be considered a rhinosinusitis

Sinusitis

Signs and symptoms

• Patient may complain of a ‘feeling of fullness’ and pressure over the involved sinuses, nasal congestion, and purulent nasal discharge

• Other associated symptoms include sore throat, malaise, low grade fever, headache, toothache, and cough >1 weeks duration

• Symptoms may last 10 – 14 days

SinusitisDiagnosis • Based on clinical signs and symptoms

• Physical examination may reveal patient described symptoms – palpate over sinuses, observe for structural abnormalities such a deviated nasal septum

• Sinus radiographs may reveal cloudiness and air fluid levels

• Limited coronal CT are more sensitive to inflammatory changes and bone destruction

SinusitisManagement/Treatment• 2/3 of untreated patients will improve symptomatically

within 2 weeks

• Antibiotics may be appropriate in certain patients

• Supportive therapy such as humidification, antihistamines, analgesics, and/or vasoconstrictors may relieve congestion and fullness

• OTC decongestant sprays for use of more than 5 days duration should be discouraged

Pharyngitis• Fewer than 25% of patients with a sore throat have

true pharyngitis

• Primarily seen in 5 – 18 year old population, it is common in adult women

• Most common cause is viral; most common agent is rhinovirus; Self-limiting; usually lasts 3-4 days

• Group A, beta-hemolytic streptococcus is the primary bacterial pathogen in 1/3 cases

• Early detection reduces incidence of acute rheumatic fever and post streptococcal pharyngitis

Pharyngitis• Sore throat is the prominent symptom

• Erythema

• Swelling of the affected tissues• Exudates: inflammatory cells overlaying mucous membranes

• Low-grade fever, mild general symptoms

• Difficult to differentiate from streptococcal infection

Caused by the same viruses that cause common cold and Adenovirus, Enteroviruses and Influenza virus.

Viral Causes of Pharyngitis• Rhinoviruses• Adenoviruses• Coronaviruses• Epstein-Barr Virus• Herpes Simplex Virus• Parainfluenza Viruses• Respiratory Syncytial Virus• Influenza Viruses• Coxsackie Viruses

Adenoviruses

Adenoviruses51 serotypes

• Immunity correlates with the presence of type- specific neutralizing antibodies

• Endemic or epidemic, often during summer

• Incubation period 4-7 days

• Moderate to severe pharyngitis, sometimes exudative

• Fever and systemic symptoms

• Rhinitis and follicular conjunctivitis are common

Adenovirus51 serotypes

Pharyngo-conjunctival fever sporadic or epidemicassociation with swimming pools

Epidemic acute respiratory disease in military recruits pneumonia in 10-20%

Nosocomial transmission: epidemic keratoconjunctivitis

Pneumonia in immunocompromised patientsBMT recipients: mortality 60%

Pathogenesis

• Epithelial cells are the primary target.

• E1B and E4 proteins inhibit transport of host mRNA from the nucleus to the cytoplasm causing cell death

• The penton protein has been shown to be directly toxic to cells and it has been found in the blood of several fatal cases of adenoviurs pneumonia.

• Entry by the mouth, the nasopharynx or via the conjunctiva.

• The lower stereotypes (1,2,5 and 6) are ubiquitous particularly in young children

• Endemic spread takes place by the fecal oral route to new pools of susceptible infants and children.

• May be transmitted in swimming pools, via medical equipment (tonometer), and via respiratory droplets.

• Site of initial replication is commonly the oropharynx and spread is mostly local.

• Virermic spread is rare.

• Latency has been shown to be common among humans (in tonsils and adenoids)

Adenovirus Clinical Syndromes

• They infect the respiratory tract as well as the eye, gastrointestinal tract, urinary bladder, and the liver.

• On occasions, these viruses may cause

disease in other organs such as CNS and the pancreas.

• Most human disease is associated with only one-third of the serotypes.

• Many adenovirus infections are subclinical

Respiratory Disease• Endemic Adenovirus Respiratory Infections of

young children

- Represent 5% of the acute respiratory disease in children(<5y) most commonly as pharyngitis or

pharyngoconjunctival fever - Most common serotypes are 1,2,5 and 6 and occasionally 3, 4 and 7. - Responsible for 10% of the pneumonias of childhood. - Most patients recover but epidemics of adenovirus 7 have resulted in considerable mortality.

Acute Respiratory Disease• Primarily affects military recruits (types 4, 7 and

occasionally 3). • Frequently occurs under conditions of fatigue

and crowding.

• Characterized by fever, pharyngitis, cervical adenitis, cough, hoarseness and rhinitis.

• Some cases have had a fatal outcome

(pneumonia).

• Pertussis – like syndrome - It is associated with adenovirus type 5.

• Infections of the Eye - Acute follicular conjunctivitis types 3 and 7 but other types (1,2,4,6,9,10,15,17,20,22) have been incriminated.

- Epidemic Keratoconjunctivitis

- Types 8, 11, 19 and 37.

- Followed by corneal subepithelial infiltration which may persist for a long period but it

resolves completely with return of visual acuity

to normal.

- Outbreaks can be traced to eye clinics

where an instrument (Tonometer) or a solution

acts as a vehicle.

Viral Causes of Pharyngitis• Rhinoviruses• Adenoviruses• Coronaviruses• Epstein-Barr Virus• Herpes Simplex Virus• Parainfluenza Viruses• Respiratory Syncytial Virus• Influenza Viruses• Coxsackie Viruses

Viral Infections of the Lower Respiratory Tract

Laryngotracheo Bronchitis (Croup)

- An acute viral inflammation of larynx, trachea, and bronchi that is common in young children.

- It is often preceded by a "cold".

- Accompanied by pyrexia, hoarseness, croaking cough, stridor, restlessness (respiratory insufficiency).

- Can be fatal - i.e. life-threatening disease.

Acute BronchitisAcute Bronchitis• Inflammation of bronchi, accompanied by fever,

cough, wheezing and "noisy chest".

• Respiratory virus infection associated with cough– Influenza virus: 75%–93% of cases– Adenovirus: 45%–90%– RVs: 32%–60%– Coronaviruses: 10%–50%

• 40% of nonasthmatic patients with acute bronchitis had FEV1 80% of predicted

• Bronchial reactivity remained increased up to 5 weeks after an episode of acute bronchitis

Acute Bronchiolitis- Inflammation of terminal bronchioles in young children.

- Bronchiole diameter is larger during inspiration than during expiration and this leads to hyperinflation of air sacs distal to bronchiole.

- Complete plugging of bronchiole with air resorption

leads to collapse. These features can be seen on x-ray.

- These changes cause respiratory embarrassment and

can be life-threatening. - Clinically, there is fever, rapid respiration, exhausting

cough and wheezing.

Pneumonia & Bronchopneumonia - Acute respiratory disease accompanied by

fever, restlessness and cyanosis.

- Often not much clinical "consolidation".

- Again, can be life-threatening.

Causative Agents

• Paramyxoviruses

- Parainfluenza viruses

- Respiratory Syncytial Virus (RSV)

- Measles virus

• Influenza

• Coronaviruses

• Adenoviruses

• Enteroviruses

• Rhinoviruses

Parainfluenza Viruses

Pathogenesis and Pathology• Initially, the mucous membranes of the nose

and throat are involved.

• Obstruction of the paranasal sinuses and eustachian tubes may also occur.

• Many patients with mild disease may have limited involvement of the bronchi as well.

• In more extensive infections there is a tendency

for HPIV-1 and 2 to involve the larynx and upper tarchea, resulting in croup.

• Such infections may extend also to the lower trachea and bronchi, with accumulation of inspissated mucous and resultant atelectasis and pneumonia.

• When HPIV-3 produces severe disease, infection of the small air passage is likely with the development of bronchopneumonia, bronchiolitis, or bronchitis.

• Lower respiratory tract involvement also occurs commonly during primary HPIV-1 and 2 infection; about 25% of primary infections produce bronchitis or pneumonia.

• The mechanisms responsible for localization and severity of human parainfluenza viruses' disease are not known.

• Severe respiratory tract disease caused by HPIV1, 2, and 3 generally occurs in the first 3-5 years of life.

• Primary infections and reinfections occur and most persons have had primary infections before the age of 5 years.

Clinical Features

• Most infections are asymptomatic, especially in older children and adults.

• The incubation period is 2-6 days.

• Fever and a spectrum of respiratory infections are caused by HPIVs; rhinorrhea/rhinitis, pharyngitis, croup, bronchiolitis and pneumonia.

• In children, the most common type of illness consists of rhinitis, pharyngitis, and bronchitis, usually with fever.

• Severe acute laryngotracheobronchitis (Croup) is noted in only 2-3% of primary HP1V1 or 2 infections.

• When croup develops, the initial symptoms of rhinitis, pharyngitis, fever, and cough progress.

• After several days, subglottic region becomes narrower, the cough worsens and becomes brassy, “seallike”, or barking, with hoarseness and stridor.

• At this stage, most children recover uneventfully after 24-48 hours.

• In some children, however, air hunger develops, with cyanosis, sternal and intercostal retraction, and progressive airway obstruction.

• HP1V3 is an important cause of bronchiolitis in young infants and children below 2 years of age.

• When bronchiolitis or pneumonia develops, fever persists and the cough progresses and becomes somewhat productive.

• It is accompanied by wheezing, tachypnea, retraction, and in severe cases cyanosis.

• A combined bronchopneumonia-croup syndrome occurs in some patients.

• Rarely, parainfluenza viruses are associated with otitis media, parotitis, and aseptic meningitis.

• Prolonged (persistent) and particularly severe infections are known to occur in the immunocompromised

Respiratory Syncitial Virus

• RSV is the most important cause of viral lower respiratory tract disease in infants and children worldwide.

• RSV is also an important agent of disease in immunosuppressed adults and the elderly.

• RSV grows poorly in tissue culture and most experimental animals, does not shut off host macromolecular synthesis, and it is unstable.

• Consequently, research on RSV was impeded.

• RSV survives on surfaces for up to 6 hours and on gloves for less than 2 hours.

• The virus loses activity with freeze-thaw cycles, in acidic conditions and with treatment by disinfectants.

• Classified into two types, RSV-A and RSV-B, on the basis of variation in the G glycoprotein

• RSV utilizes ICAM-1 as its receptor.

Pathogenesis• RSV is transmitted via large droplets, through fomites

and via hands

• The mechanism of virus spread from upper to lower respiratory tract is assumed to be via the respiratory epithelium or through aspirated secretions.

• The virus is capable of cell-to-cell spread without emergence into the extracellular fluid.

• Viremia has not been described during infection of

normal infants and children

Pathogenesis• RSV causes the release of

– Interleukins– Leukotrienes– Chemokines

• This results in inflammation and tissue damage

• Presence of eosinophils and eosinophilic cationic protein in blood is associated with recurrent wheezing episodes post RSV infection

Pathogenesis• Bronchiolitis

– Virus induced necrosis of bronchiolar epithelium– Hypersecretion of mucous– Round cell infiltration and edema of the surrounding

submucosa• This leads to

– Formation of mucous plugs– Hyperinflation/collapse of distal airways

• Can also result in interstitial pneumonia• Infants are particulary at risk due to small size of

normal bronchioles

Pathology• Lower respiratory tract involvement (signs) usually

appear 1-3 days after the onset of illness (rhinorrhea)

• Inflammatory infiltration, edema, and excessive mucous production cause obstruction of small bronchioles, with either collapse or emphysema of distal portions of the airway.

• In those instances in which pneumonia occurs, the interalveolar walls thicken as a result of mononuclear cell infiltration, and the alveolar spaces may fill with fluid.

• There is usually a patchy appearance of these pathologic changes, even though disease may be widespread.

• Severe infections are observed in:

- Preterm infants (<35 weeks gestational age)

- Those with chronic lung disease

- Those with cyanotic congenital heart disease

- Immunocompromised hosts.

Clinical Course

• RSV is the most frequent cause of bronchiolitis but it is an infrequent cause of croup.

• Incubation period is 4-6 days.

• The clinical spectrum ranges from an upper respiratory infection (bad cold) in older children and adults to bronchiolitis and /or pneumonia in young children and infants.

• In 25% to 40% of infections the respiratory tract below the larynx is involved.

• Asymptomatic infection is probably uncommon.

• If the disease is mild, the symptoms may not progress and in most instances, uneventful recovery occurs after an illness of 7 to 12 days.

• Cough can persist for 3 weeks.

• In more severe cases coughing and wheezing progress and the child becomes dyspneic.

• Hyperexpansion of the chest is evident and there may be intercostal and subcostal

retractions. The child refuses feeding.

• Severe tachypnea is common, and in advanced disease, as the child tires and hypoxia becomes more extreme, listlessness and respiratory failure occur.

• In young infants; apnea, lethargy, irritability and poor feeding are common.

• Radiologically, there is atelectasis, streaking and hyperinflation.

• Almost all infants who require hospitalization are hypoxemic on admission and remain so for a prolonged period.

• This hypoxemia is probably due an abnormally low ventilation/perfusion ratio.

• In infants with underlying cardiac or respiratory disease, the progress of symptoms may be rapid.

• Measurable respiratory abnormality is seen either immediately or several years after RSV illness.

• Infections of older children and adults are usually mild.

• Asthma has been linked to RSV infection.

Clinical Manifestations• Pharyngitis / rhinorrhea are first signs

• Cough after 1-3 days +/- sneezing and low grade fever. Following cough – wheezing

• Symptoms may not progress beyond this stage

• Auscultation reveals diffuse rhonchi, fine rales /crackles and wheezing

Clinical Manifestations• If illness progresses

cough/wheezing

–Air hunger RR, intercostal /subcostal retractions

–Chest hyperexpansion

–Restlessness

–Peripheral cyanosis

Clinical Manifestations• Severe life-threatening illness

–Central cyanosis

–Tachypnea > 70 breaths/min

–Listlessness

–Apneic spells

–Chest hyperexpanded

–Little to no breath sounds

Clinical Manifestations

• CXR

–10% normal

–Air trapping/ hyperexpansion in 50%

–Peribronchial thickening/interstitial pneumonia in 50-80%

–Segmental consolidation in 10-25%

–Pleural effusion rare

Diagnosis• Clinical diagnosis• Suspect from

– Clinical picture– Season of year– Typical outbreak– Contacts

• Lab tests offer little information• WBCs are normal or elevated• Throat cultures are normal• Hypoxemia is frequent

– Often more marked than anticipated– If severe – hypercapnia and acidosis

Diagnosis• Definitive diagnosis depends on the laboratory

by isolation of the virus or by direct antigen detection.

• Specimens are best obtained by aspiration or gentle washing out of nasopharyngeal secretions.

• Direct immunoflourescence or molecular tests(PCR) are as sensitive and specific as virus isolation.

Treatment• Highly effective antiviral therapy for RSV

infection is not yet available.

• Treatment of severe RSV disease of the lower respiratory tract requires considerable supportive care.

• Improvements in supportive care have clearly made the major impact on mortality from severe bronchiolitis or pneumonia over the past decade (44% vs 9.4%).

• Ribavirin is the only antiviral treatment available.

Epidemiology• RSV is major cause of bronchiolitis and

pneumonia especially in children < 1yr of age

• Most important respiratory tract pathogen in early childhood

• Temperate climates – epidemics in winter lasting 4-5 months

• Otherwise infection is sporadic and uncommon

Epidemiology• It has a worldwide distribution and most children have

had an RSV infection by 4 years of age.

• In certain settings such as day-care centers, the attack rate approaches 100% during epidemics.

• Reinfection also appears to be frequent especially in the first two years of life.

• RSV is a major cause of nosocomial infection.

• It causes annual epidemics.

Epidemiology• Infection uncommon in first 4 wks of life

– Thought to be due to transplacentally transmitted anti-RSV antibody

– Not so if premature and receive less than full complement of maternal IgG

• Peak incidence at 2-7months of age and decrease thereafter

• Bronchiolitis is uncommon after the 1st birthday

Epidemiology• 1-3 infants hospitalized per 100 primary infections

• RSV is responsible for– 45-75% of cases of bronchiolitis– 15-25% of childhood pneumonias– 6-8% of cases of croup

• 1.5:1 Male:Female ratio

• All races are equally susceptible

Epidemiology• Incidence increases with

– Lower SES– Crowded living conditions

• Incubation period is about 4 days

• Virus shedding continues for 5-12 days (have been documented for up to 3wk)

• In Britain, RSV is the single major pathogen in respiratory infections of childhood. The figures from Newcastle by Gardner are startling:

• under 1 year of age: – 78% of Bronchiolitis – 38% of LTB – 36% of Pneumonia – 35% of Bronchitis – 12% of minor respiratory illness,

• were all caused by RSV.

• Pediatric hospital wards are flooded with patients with community-acquired RSV every winter, and failure to follow fastidious infection control procedures inevitably leads to nosocomial transmission.

• The consequences of RSV infection can be especially

dire for children with underlying conditions such as prematurity, cardiac and pulmonary disease, or immunosuppression.

• Nosocomial RSV infection in immunocompromised adults results in prolonged, substantial illness and even death.

• RSV also takes a heavy toll on members of the nursing and medical staff, with attack rates in some studies approaching 50%.

• Bronchiolitis does not develop in health-care providers because, as adults, they have considerably larger airways than infants; however, severe colds and reactive airway disease do develop.

• Because winter is the busiest time of year on pediatric

wards, ill staff members seldom take time off to recuperate, thus serving as efficient vectors in the chain of disease transmission.

• Since RSV is a respiratory virus, one might be tempted to speculate that it is transmitted primarily by droplet nuclei or droplet contact. However, a study clearly demonstrated that contact transmission predominates.

• Freshly infected infants, who were producing copious secretions, were placed in a crib in a room reserved for the study. Volunteers were brought into the room and assigned to one of three groups.

- "Cuddlers" performed routine care, picked the baby up, and played with the child.

- "Touchers" had extensive contact with objects in the baby's environment, which had been contaminated heavily with secretions.

- "Sitters" sat right next to the crib for 3 hours but did not touch anything in the baby's environment.

• None of the 14 sitters developed RSV infection, but five of the seven cuddlers and four of the 10 touchers became ill.

• Infants secrete enormous concentrations of RSV, often more than 107/mL of nasal discharge, and the concentration of virus diminishes only slowly over a period of days.

• Moreover, RSV survives well on fomites; for

example, virus can be cultured for >5 hours on impervious surfaces such as bed rails.

• Thus, care givers have numerous opportunities

to contaminate their hands during routine care, and unless they wash their hands, virus will be transmitted by indirect contact to other infants.

• Furthermore, symptomatic infection has a high probability of developing in care givers who touch their eyes or nose with contaminated fingers.

• Studies at Children's Hospital, Boston, provide considerable support for the key role of contact with contaminated secretions in RSV transmission, as well as the value of wearing gowns and gloves when caring for infected patients.

• The magnitude of the effect was by far the greatest at

the peak of the winter epidemic in the community, when the ward was crowded with infected infants.

• Thus, simple barrier precautions, including wearing gloves when touching contaminated objects, proved extremely effective in limiting RSV transmission.

• It was found that hand washing and cohorting were effective in reducing the nosocomial infection rate.

• For RSV, using a hand antisepsis agent that contains detergent or alcohol is critical.

• Some investigators have advocated performing rapid tests for RSV on all symptomatic infants during the annual RSV season, cohorting RSV-positive patients, and placing them on gown and glove precautions.

• A reduction in nosocomial infection in a newborn nursery was noted when rapid testing was combined with cohorting, visitation restrictions, and gowns, gloves, and masks.

• Once the virology laboratory has documented that the RSV season has started, a child with bronchiolitis will likely have RSV, and screening only children who have atypical symptoms may be sufficient.

Prevention• Hand washing

• Isolation and cohort nursing

• Protective gear; gowns, gloves, masks and goggles

• There are no licensed vaccines.

• Candidates for immunoprophylaxis– Infants with lung disease– Premature

• 28 wk – prophylaxis to 12 months• 29-32wk – prophylaxis for 6 months

Genus Enterovirus

• Great variety of clinical syndromes including respiratory manifestations

• Numerous serotypes related to respiratory illness

• Pharyngitis is a common manifestation concomitant with other respiratory clinical findings that could be more prominent.

Coxsackie Viruses• Coxsackie A viruses are usually associated with

surface rashes (exanthemas) whereas Coxsackie B viruses typically cause internal disease.

• Illnesses include nonspecific febrile disease and common cold-like or influenza-like respiratory diseases, pharyngitis, croup, and pneumonia.

• Enteroviruses 68, 69, and 71 cause respiratory illness in infants and children (pneumonia, bronchiolities).

Recently Discovered New Viruses

• Since 2001 five new viruses have been identified in patients with LRTIs– Human metapneumovirus (hMPV)– Coronaviruses

• SARS• NL63• HKU1

– Human Bocavirus

Identification of hMPV

• New virus first identified in 2001 by van den Hoogen et al.

• Isolated unidentifiable virus from 28 stored NPA from epidemiologically unrelated young children with RTI over 20 years

• Grew slowly in tertiary Monkey Kidney cells• CPE indistinguishable from hRSV• EM revealed paramyxovirus -like pleomorphic

particles• Sequence alignments showed it was most

closely related to avian pneumovirus

hMPV Epidemiology

• Appears to be ubiquitous – Serological studies and RT-PCR detection

have found hMPV throughout the world (Netherlands, Canada, Finland, USA, Australia, Japan, India, Brazil, UK, Hong Kong, Argentina, etc..)

• Serological studies in Netherlands: • 25% of children 0.5-1 yr• 55% 1-2 yr• 70% 2-5 yr• 100% 5-10 yr

hMPV Pathogenesis

• Clinically resembles RSV and has been detected in patients with upper or lower respiratory tract disease.

• Early reports:

– hMPV was found in ~10% of children with lower respiratory tract infections in which no other cause of infection was identified

– responsible for 6% of hospitalizations in children < 3 y.o. with viral resp. infection

hMPV Age/Seasonal Distributionn=115 cases

Clinical Symptoms for Metapneumovirus Positives

• Cough• Runny nose• Breathlessness• Vomiting• Weak, lethargy• Congestion• Fever• Pneumonia• Bronchiolitis• Wheezing• Hematological malignancy, lymphoma

Human Bocavirus•Discovered by Allander et al. at the Karolinska Institute

in Sweden in 2005 while screening respiratory

specimens for new viruses.

•Developed a molecular test using PCR and

sequencing and detected unidentified Coronaviruses

and a Parvovirus provisionally named Bocavirus

•Bocavirus was detected in 17 children (3.1%) with

LRTI

•HBoV has not yet been isolated in culture

Human Bocavirus •Sloots et al. detected HBoV in 5.2% of 324 NP specimens from hospitalized children in Brisbane in late autumn and winter•HBoV was the second most prevalent respiratory virus following RSV •Children between 6-24 months were most at risk for HBoV infection•Co-infections with HBoV were uncommon compared with HKU1 which was commonly found as a co-infection

Human Bocavirus •HBoV was detected in 18/318 (5.7%) NP specimens collected from hospitalized children presenting with LRTI in Tokyo by PCR •All patients had fever, cough or respiratory stress and 8/18 had positive chest X-ray findings with a clinical dx of bronchiolitis, bronchitis, laryngotracheitis, or pneumonia•16/18 were in hospital for 3-9 days •17/18 infections were from January to May in 2003 and 2005•Patient ages were from 7 months to 3 years with a mean age of 21 months

Pathophysiology of cough• Mucous secretions are normally removed by

ciliary beating.

• When this defense mechanism is impaired or overwhelmed by increased secretions, cough then becomes an important means of secretion removal.

• For cough to be effective, the linear velocity of gas traveling through the airways should be high.

• Since the linear velocity of gas is related to flow and the cross-sectional area of the airways,

- cough is most effective when expiratory flows are great (effort independent) and

- dynamic compression (effort dependent) leads to a reduction of the cross-sectional area of the larger downstream airways.

• Cough failures may be related to either - inadequate generation of expiratory flow rates (that is,

in obstructive lung disease or inspiratory muscle weakness),

- failure to dynamically compress the airways (that is, in expiratory muscle weakness or increased collapsibility),

- alterations in airway geometry (that is, in bronchiectasis), or

- abnormal quantity or quality of mucous production (that is, in chronic bronchitis).