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Home , Laryngitis

The growing problem of viral respiratory infections

5th ESCMID School of Clinical Microbiology and Infectious Diseases Santander, Spain, 10 - 16 June 2006 Núria Rabella

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

Majority trivial colds and sore throats

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

Influenzavirus 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 Frequency: higher in children under 4 years Major reservoir it declines in teenagers schoolchildren rises again in parents lowest in the elderly Epidemiology (1) • Transmission: respiratory route • Shedding: sneezing, coughing or talking • sneeze:

– 106 droplets < 10mm ê evaporation ê smaller- suspended in the air for several minutes – larger droplets fall to the ground

• Spreading: • inhalation • direct contact Epidemiology (2) * Sneezing: 1.940.000 viral particles * To begin an infection: Adenovirus: 7 A virus: 3 Enterovirus: 6

* Some viruses remain infectious for prolonged periods Direct contact transmission Viral persistence

Respiratory syncytial virus: porous surfaces for 30’ non-porous 6h Parainfluenzavirus: porous surfaces for 4h non-porous 10h Influenza A virus: porous surfaces for 8-12h non-porous 24-48h In the hands 5 minutes Nosocomial infection

If health care workers do not wash hands between patients they can easily transmit the infection from one patient to another Epidemiology (3)

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0 1 11 21 31 41 51 9 19 29 39 49 7 17 27 37 47 5 15 25 35 45 2 12 22 32 42 52 10 20 30 40 50 7 17 27 37 47 5 15 25 35 45 1997 1998 1999 2000 2001 2002 2003 2004

RSV FLUAV FLUBV CRV TOTAL Epidemiology (4)

Winter incidence:

• Not attributable to cold or wet “per se” • Predilection for shutting ourselves in ill- ventilated centrally-heated buildings • Ex: tropics, during the wet season people spend more time indoors in crowded conditions Respiratory viruses

Influenza A, B, C virus Respiratory syncytial virus Parainfluenzavirus 1-4 Metapneumovirus

Adenovirus

Enterovirus

Coronavirus 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 mm Ø are trapped in turbinates of the nose

•Inhaled droplets 5 -10mm Ø often reach the and bronchioles Clinical features

•Above the URTI

Described according to the anatomical site of maximal involvement

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

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

Abnormalities observed in the sinus cavity in these patients appear to result from the entrapment of secretions and resolve 2 to 3 weeks later. 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 Genus Species HCoV-229E HCoV-OC43 HCoV-NL63 HCoV-HKU1 SARS-CoV

• Responsible for about 10-20% of common colds

•re-infection is common •infections year-round, most prevalent in fall and spring •incubation period about 2 to 5 days SARS Coronavirus

•SARS: Severe Respiratory Syndrome Respiratory infection was caused by a coronavirus named SARS-CoV. •Disease extended to more than 24 countries in North-America, South-America, Europe and Asia. •8,098 persons presented the disease and 774 died. 21% health workers • sore throat is the prominent symptom • • 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 and adenovirus, enterovirus and influenza virus. Adenovirus

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

51 serotypes

Pharyngo-conjunctival fever sporadical or epidemic outbreaks association with swimming pools Epidemic acute in military recruits in 10-20% Pneumonia in immunocompromised pts BMT recipients: mortality 60% Nosocomial transmission: epidemic keratoconjunctivitis Genus Enterovirus

• Great variety of clinical syndromes including respiratory manifestations • Numerous serotypes related to respiratory illness • Pharyngits is a common manifestation concomitant with other respiratory clinical findings that could be more prominent.

Laryngitis and croup : laryngeal obstruction • varying degrees of inspiratory • cough, hoarseness • initially cold with fever •symptoms last 3 to 7 days •children < 4 years and boys > girls Important:

must be differentiated from Laryngitis Croup

In our experience: Parainfluenzavirus are responsible for about 46% of cases of laryngitis and 20% of cases of croup. Parainfluenzavirus

The major cause of LRTI in young children and URTI in older children and adults There are 4 types named 1-4 Distinct seasonal pattern: type 1 and 2: fall, every other year type 3: endemic Parainfluenzavirus

• More severe disease between 6 months and 3 years One third of children with primary infection during the first 2 years of age had involvement of the LRT • PIV 1, 2 - related to croup. PIV 3 - or pneumonia PIV 4 - very mild illness • Re-infections are frequent at any age, usually mild

Cough, severe or prolonged, fever, upper respiratory tract involvement Inflammatory disease of the larger air passages • Direct viral damage of the mucosa • Release of inflammatory mediators • Stimulation of airway irritant receptors

Any of the respiratory viruses Influenzavirus

• There are 3 influenza viruses: A, B, C • Depending on the internal protein • Winter . Sporadic and epidemic • Highly contagious •Period transmission: 7 days or throughout duration of symptoms Influenza A virus

Neuraminidase (9) Hemagglutinin (16)

• RNA fragmented genome: 8 • Drift: point mutation = variant could evade immunity • Shift: reassortment of two viruses = new virus Influenzavirus. Clinical features

NO SYMPTOMS

MILD DISEASE

UPPER RESPIRATORY TRACT INVOLVEMENT

INFLUENZA: abrupt onset, headache, chills, dry cough, high fever, , malaise, anorexia Influenzavirus Complications

Benign: Sinusitis, otitis media, and bronchitis

Severe: Viral or Exacerbation of underlying illnesses Nosocomial infection Influenza A virus

Brots epidèmics intrahospitalaris (Grip A). Nº 5 S. Microbiologia. Hospital de la Santa Creu i Sant Pau.

140 VRS VGA Mostres

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4 relatives 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 1999 2000

Clinical manifestations : light/moderate RD, URTI 10, LRTI 4, digestive symptoms 4, high fever 5, 2 died. Bronchiolitis

Expiratory wheezing with tachypnea, air trapping, and costal retractions

Narrowing of air passages: destruction of epithelium mononuclear infiltration necrosis + infiltrates accumulation mucus and debris

Multiple : image of

Peak incidence: 2 to 10 months Respiratory syncytial virus

• Major cause of RTI among children • From inapparent to severe (bronchiolitis) • 50% develop RSV infection by 12 months of age • Regularly produces epidemic outbreaks each winter

Adults: URTI (previously healthy) to LRTI (elderly, immunocompromised)

40% children hospitalized for more than 7 days in winter 50% of health workers Metapneumovirus

• Spectrum of diseases and epidemiology resembling that of RSV • Peak incidence between 4 and 6 months • Frequent coinfection with RSV •Assymptomatic or mild illness much more common

HMPV infection in 22 patients (nº 251) 9 (41%) LRTI, 3 (33%) died Nosocomial infection RSV and HMPV

* 432 hematological patients followed at HSCSP. October 1999 - May 2003 735 NPA, 170 BAL 304 episodes / 156 positive (51%).

RSV infection: 38% (total 24) nosocomial HMPV infection: 45% (total 22) nosocomial Pneumonia

Viruses are the most frequent cause in children in adults is not uncommon (FLUAV, RSV, PIV)

Immunocompromised patients 44+ (26%) /170 BAL 432 p/7y

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4% 1% 10%

Influenza A virus Respiratory syncytial virus Enterovirus Adenovirus Parainfluenzavirus Influenza B virus Rhinovirus

Respiratory viruses in bronchoalveolar lavages Community-acquired pneumonia and respiratory viruses

Period 1999 2000 2001 Total: Nº of patients 27 148 75 250 Diagnosis 19 65 24 108 43% Microorganisms: Bacteria 8 15 16 39 36%

Virus 7 34 4 45 42%

Mixed 4 16 4 24 22%

69 infections (64%) with an associated virus

74 viruses: 59 FLUAV, 5 HPIV, 5 RSV, 4 FLUBV, 1 AdV. 4 mixed with 2 viruses 160

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1997 1998 1999 2000 2001 VGA VGB Muestras Virologic diagnosis

Isolation in cell culture

Antigen detection

Nucleic acid detection

Serology Virologic diagnosis

• Isolation: gold standard. • Antigen detection: rapid, variable sensitivity Interpretation of the results: Respiratory viruses can only be recovered from the respiratory tract during acute infection

•Nucleic acid detection: sensitive and expensive •Serology: two specimens (late, lack of sensitivity) Methods for viral detection Sensitivity

Nº IF EIA IC CC

RSV 270 99% 60% 76% 59%

FLUAV 206 79% 64% 78% 39%

FLUBV 67 46% 84%

PIV 74 74% 53%

ADV 156 33% 96%

2000-2001 Treatment Influenza A, B, C virus Amantadine and Rimantadine oral administration effective for the prevention of infection and illness resistance in 30% to 80% patients after a few days of treatment Zanamivir and oseltamivir inhaled and oral administration effective for the prevention of infection and illness Treatment

Respiratory syncytial virus Parainfluenzavirus 1-4 Metapneumovirus

Ribavirin

RSV: may be considered in infants and young children at risk of severe RSV disease recommended in high-risk patients (BMT) PIV: reduction of PIV shedding and clinical improvement

MPV: reduction of PIV shedding and clinical improvement Treatment

Respiratory syncytial virus

Immunoprophylactic agents for prevention:

RespiGam Intravenous polyclonal immune globulin Enriched in neutralizing Ab against RSV Requires large volume infusion Availability limited

Palivizumab Monoclonal Ab (95% human, 5% murine) Against RSV fusion protein During RSV season for premature babies Treatment

Adenovirus

There are no approved therapeutic agents against ADV infection. Some broad spectrum antivirals have been used:

Ribavirin Most reports are anecdotal or small series of cases Cidofovir Has shown some efficacy 2 of 3 patients recovered compared 3 of 13 patients treated with ribavirin Treatment

Enterovirus Rhinovirus Coronavirus

There are no approved therapeutic agents against these viruses Conclusions

1. The clinical picture caused by a specific virus is indistinguishable from that of any other virus 2. Community-acquired pneumonia are often related to viral infection 3. Rapid etiologic diagnosis is possible 4. Nosocomial infection is common