Viral Infections of the Respiratory Tract

Viral Infections of the Respiratory Tract

Respiratory tract - Major portal of entry - Most common afflictions in humans - Wide range of clinical manifestations: from self-limited to devastating Children half a dozen each year, adults two or three. - Most caused by viruses. Considerable impact on quality of life and productivity of society

Respiratory tract 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 Influenza virus killing the elderly and respiratory Syncytial virus killing the very young Altogether over 200 known viruses

Respiratory tract infection
High prevalence: Large number of infectious agents and serotypes Efficiency of transmission Incomplete immunity Major reservoir schoolchildren Frequency: Higher in children under 4 years It declines in teenagers Rises again in parents Lowest in the elderly

Respiratory viruses Influenza A, B, C viruses
Metapneumovirus Bocavirus Parainfluenzaviruses 1-4 Respiratory Syncytial virus Adenoviruses Enteroviruses Rhinoviruses Coronaviruses

Characteristics of Infection
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.

Viral Entry Inhaled droplets > 10 m Ø are
trapped in turbinates of the nose Inhaled droplets 5 -10m Ø often reach the trachea and bronchioles

Clinical features URTI LRTI Above the epiglottis
Described according to the anatomical site of maximal involvement Below the epiglottis LRTI

Epidemiology (1) Transmission: respiratory route
Shedding: sneezing, coughing or talking Sneeze: 106 droplets < 10m  evaporation  smaller- suspended in the air for several minutes Larger droplets fall to the ground Spreading: Inhalation Direct contact

Epidemiology (2) Some viruses remain infectious for prolonged periods
* Sneezing: viral particles * To begin an infection: Adenovirus: 7 Influenza A virus: 3 Enterovirus: 6 Some viruses remain infectious for prolonged periods

Mean Annual Incidence of Respiratory Illnesses per Person-Year
7 6 5 4 3 2 1 Females Males illness incidence Mean annual Monto and Ullman reported on a longitudinal, long-term, community-based study of acute respiratory illness in families in Tecumseh, Michigan. The frequency and characteristics of respiratory illnesses were determined and related to causative agents and environmental variables during a 6-year period. The study found that up to the age of 2, boys had more respiratory illnesses than girls. At age 3, the sex ratio reversed, and there was a higher frequency of illness in females at all ages. One interesting phenomenon was an increased incidence in the 20- to 29-year age group. Investigators attributed this increase to the fact that people start their families at this age and to the consequent increase in exposure to viral agents from young children, who have high rates of illness. The study also found an inverse relationship between income and annual frequency of respiratory illness, which was attributed by the investigators to crowding and an increased chance of transmission. Monto AS, Ullman BM. Acute respiratory illness in an American community: the Tecumseh study. JAMA. 1974;227: 1 1–2 3–4 5–9 10–14 15–19 20–24 25–29 30–39 40–49 50–59 60 Age group (yr)

Parainfluenza viruses Respiratory syncytial virus (RSV)
Seasonality of Respiratory Agents: Proportion Isolated in Each Calendar Month During 6 Years 30 25 20 15 10 5 RV Parainfluenza viruses Percent 30 25 20 15 10 5 Respiratory syncytial virus (RSV) Influenza virus The seasonality of infection with various respiratory viruses has been well established by long-term longitudinal studies1 and short-term studies during the cold season2 and confirmed with viral isolation techniques.2 Although RVs are isolated in all months of the year, the peak occurs at the beginning of the school year, presumably because contact among children increases. School attendance is associated with high RV illness rates in the family.1 Studies using RT-PCR techniques to detect RV RNA have confirmed the fall peak in incidence of RV infection in adults with self-diagnosed colds.2 The autumn peak of RV illness differs from the seasonal peak of influenza virus, which occurs in the winter months (December through early April, depending on the virus type).3 1. Monto AS. Studies of the community and family: acute respiratory illness and infection. Epidemiol Rev. 1994;16: 2. Arruda E, Pitkäranta A, Witek TJ, Jr, Doyle CA, Hayden FG. Frequency and natural history of rhinovirus infections in adults during autumn. J Clin Microbiol. 1997;35: 3. Monto AS, Sullivan KM. Acute respiratory illness in the community: frequency of illness and the agents involved. Epidemiol Infect. 1993;110: Percent Jan Apr Sep Oct Nov Dec Feb Mar May Jun Jan Apr Sep Oct Nov Dec Jan Feb Mar Apr May Jun

Characteristics of VRIs of Known Etiology
Coryza Cough Sore throat Activity restriction 100 Headache Lower respiratory symptoms 80 60 Percent 40 20 RV RSV Parainfluenza virus Hemolytic streptococci Influenza A Influenza B

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 Hospitalized with Asthma
Influenza A Influenza B RV Adenovirus RSV Herpes 3% 3% 6.1% 27.3% 54.5% Teichtahl and colleagues documented the incidence of respiratory infections in adults hospitalized with acute asthma in a prospective study during a 12-month period. Serologic studies were performed on NPAs, and they were cultured for viral and bacterial pathogens. These researchers reported that 37% (29) of 79 adults hospitalized for asthma had evidence of recent respiratory infection compared with 9% (5) of the control group of 54 elective-surgery patients; 29% (23) of the 79 asthma patients had viral infections indicated by serologic tests and culture of NPAs. The authors speculated that the lower rates of respiratory infection in adults with asthma exacerbations than in children were due in part to the adults’ delayed presentation for management and more rapid clearing of viruses, leading to increased difficulty in virus isolation. Teichtahl H, Buckmaster N, Pertnikovs E. The incidence of respiratory tract infection in adults requiring hospitalization for asthma. Chest. 1997;112: 6.1%

Respiratory Infections in Infancy May Protect Against Development of Asthma
2 episodes of “common cold” before age 1 yr decrease risk of asthma by age 7 by ~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

Antibiotic Rx and estimated bacterial prevalence (% of visits)
Acute Respiratory Infections (ARIs): Primary Care Office Visits, Antibiotic Use, and Bacterial Prevalence in US, 1998 25,000 100 Office visits Antibiotic prescription Bacterial prevalence 20,000 80 Office visits (1000) 15,000 60 Antibiotic Rx and estimated bacterial prevalence (% of visits) 76% 62% Syndromes most likely caused by infection with respiratory viruses are a common cause of visits for medical care and are frequently treated with antibiotics. This common practice has contributed to the emergence and spread of resistance to antibiotics commonly used for community-acquired infections, especially respiratory tract infections. Gonzales and colleagues used the 1998 National Ambulatory Medical Care Survey, a sample survey of US ambulatory physician practices, to estimate primary care office visits and antibiotic prescription rates for acute respiratory infections (ARIs). In 1998, an estimated 84 million ambulatory office visits for ARIs (otitis, sinusitis, pharyngitis, bronchitis, and nonspecific URI) resulted in 45 million antibiotic prescriptions in the US. Approximately 25 million patients sought care for nonspecific URIs; 30% were treated with antibiotics, although bacterial prevalence was estimated to be only approximately 5%. In the US, approximately 75% of antibiotic prescriptions for ambulatory patients are given to treat five ARIs: otitis media, sinusitis, pharyngitis, bronchitis, and nonspecific URI. These viral infections account for a large proportion of unnecessary and inappropriate prescriptions. Gonzales R, Malone DL, Maselli JM, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis. 2001;33: 10,000 40 70% 59% 30% 5000 20 URI Otitis media Sinusitis Pharyngitis Bronchitis

Use of Antibiotics: Patient Expectations, Physician Perceptions, Public Beliefs
Patients who expect antibiotics receive them more often Strongest predictor of receipt of antibiotics for ARI is MD perception of patient expectation Public beliefs about antibiotic effectiveness Useful for VRI: 55% Useful for bacterial but not viral illness: 21% Antibiotic prescribing is highly influenced by patient expectation of and demand for antibiotics. Surveys of patients and physicians show that patients who expect antibiotics are more likely to get them.1-3 Physicians, concerned with patient satisfaction during a visit, are often influenced by patient expectations and demands but often incorrectly perceive patient expectations. 1,3 Surveys have also shown that failure to provide an antibiotic did not affect patient satisfaction, which was more often correlated with the time a physician spent with the patient discussing the treatment approach.1,3 In addition, parents who expected an antibiotic but were given a contingency plan instead (the possibility of an antibiotic if the child didn’t improve) expressed greater satisfaction with the visit than those who did not receive a contingency plan.4 Furthermore, a cross-sectional telephone survey of adults in a group-model HMO found that 55% believed antibiotics were beneficial for viral respiratory illness; only 21% believed they were beneficial for bacterial but not viral illness. Only 28% of respondents reported ever having been told that antibiotics were not needed for a respiratory illness.5 These findings emphasize the necessity for continued patient education. 1. Hamm RM, Hicks RJ, Bemben DA. Antibiotics and respiratory infections: are patients more satisfied when expectations are met? J Fam Pract. 1996;43:56-62. 2. Bauchner H, Pelton SI, Klein JO. Parents, physicians, and antibiotic use. Pediatrics ;103: 3. Mangione-Smith R, McGlynn EA, Elliott MN, Krogstad P, Brook RH. The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behavior. Pediatrics ;103: 4. Mangione-Smith R, McGlynn EA, Elliott MN, McDonald L, Franz CE, Kravitz RL. Parent expectations for antibiotics, physician-parent communication, and satisfaction. Arch Pediatr Adolesc Med. 2001;155: 5. Wilson AA, Crane LA, Barrett PH Jr, Gonzales R. Public beliefs and use of antibiotics for acute respiratory illness. J Gen Intern Med. 1999;14:

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 !”

Summary 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.

LRTI in 60% in elderly persons common in young children
Rhinitis Copious watery nasal discharge, congestion, sneezing, and a mild sore throat or cough. Little or no fever 50% last longer than 1 week and 25% last up two weeks LRTI in 60% in elderly persons common in young children

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

Responsible for about 50% of common colds
Genus Rhinovirus Species 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 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 Adults with RV Colds
RV % positive First symptom (% of subjects) Sore throat Stuffy nose Runny nose Sneezing 39 17 8 Most bothersome symptom (% of subjects) Malaise 36 20 19 10 Median duration of symptoms (days) Cold episode Sleep disturbance Interference with daily activities 11 4 7

RV Infection in the Elderly
In persons 60–90 years of age with RV infection, median duration of illness was 16 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 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 days, due to an 80% chance of a secondary infection occurring

Sinusitis 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

Sinusitis Diagnosis 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

Sinusitis Management/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

Adenoviruses Immunity correlates with the presence of type- specific
51 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

Adenovirus Pharyngo-conjunctival fever sporadic or epidemic
51 serotypes Pharyngo-conjunctival fever sporadic or epidemic association with swimming pools Epidemic acute respiratory disease in military recruits pneumonia in 10-20% Pneumonia in immunocompromised patients BMT recipients: mortality 60% Nosocomial transmission: epidemic keratoconjunctivitis

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 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 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 This results in inflammation and tissue damage
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.

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

If illness progresses cough/wheezing Air hunger RR, intercostal /subcostal retractions Chest hyperexpansion Restlessness Peripheral cyanosis

Severe life-threatening illness Central cyanosis Tachypnea > 70 breaths/min Listlessness Apneic spells Chest hyperexpanded Little to no breath sounds

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

respiratory manifestations Numerous serotypes related to respiratory
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 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 Distribution n=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).

Viral Infections of the Respiratory Tract

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Viral Infections of the Respiratory Tract

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