Prof. L.R Shostakovich-KoretskayaDep. Inf.Dis

DMA

Acute Viral Upper Respiratory Tract Infections – is a large group of infectious diseases,

which are caused by viruses, transmitted by droplet way, characterized by intoxication and catarrhal syndrome with predominant changes in mucous membranes of the upper respiratory tract.

An infection of this type is normally further classified as an upper respiratory tract infection(URI or URTI) or a lower respiratory tract infection(LRI or LRTI).

Lower respiratory infections, such as pneumonia, tend to be far more serious conditions than upper respiratory infections, such as the common cold.

  

Respiratory tract infection refers to any of a number of infectious diseases involving the respiratory tract.

•Human Parainfluenza virus - 5 types ,belong to paramyxovirus family (large RNA viruses 150-200 nm, contain hemagglutinine and neuraminidase with stable antigen structure).

• Respiratory syncitial (RS) virus, belong to paramyxovirus family (large polymorph RNA viruses 120-200 nm) doesn’t have neuraminidase and without hemagglutination

•

Adenoviruses – a stable DNA-viruses of medium size, is ubiquitous in human and animal populations, survives long periods outside a host, and is endemic throughout the year. 52 serotypes. Adenovirus is recognized as the etiologic agent of various syndromes.

It is transmitted via direct inoculation to the conjunctiva, a fecal-oral route, aerosolized droplets, or exposure to infected tissue or blood

Etiology

• Rhinoviruses, with over 100 serotypes, belong to picornavirus family (small RNA viruses 20-30 nm, instable in the environment).

• Rheoviruses – 3 serotypes RNA-viruses of medium size, 70-80 nm, stable in the environment.

• Enteroviruses

• Coronaviruses

Etiology

· A source of infection are patients with URT viral infection, and virus-carriers (Adenovirus, Rhinovirus, Rheovirus and RS-virus)

Droplet with inhalation of small or large airborne drops during coughing, sneezing, speaking, by contact with contaminated hands, toys ets.

Also fecal-oral (for Adenovirus, Rheovirus infection)

Receptivity – early age children, from 6 month and under-fives, contagiousness is high (40-80%)

Seasonality – autmn-winter or winter-spring flashes and sporadic diseases during a year

Inoculation of viruses in upper respiratory tract epitheliocytes, conjunctiva, lymph nodes

Local reproduction of virus Development of inflammatory

process in upper respiratory tract, destructive changes

Start of immune reactions

Delete of the virus

Immune factors supression

Possible viremia

Bacterial complications

Damege of organs and systems

OR

An acute viral infection is characterized by rapid onset of disease, a relatively brief period of symptoms, and resolution within days.

It is usually accompanied by early production of infectious virions and elimination of infection by the host immune system.

· Complaints: more or less severe symptoms of general intoxication, catarrhal symptoms are: sore throat (considerably rare is pharyngeal pain), dry cough.

· Moderate hyperemia, mainly palatal arch, soft palate, uvula, back pharyngeal wall with the presence of enlarged lymphoidc follicles .

Hyperemia of nasal mucosa.

Tonsils are mainly intact (except adenoviral infection).

Conjunctivitis (more or less severe, in dependence on the type of URTI).

Signs of a few parts of upper respiratory tract inflammation.

Specific clinical signs of ARVI depend on the type of infection and what parts of the respiratory tract are involved in the inflammatory process

Etiology Clinical formsSeverity

Course

Adenoviruses

Pharyngoconjunctival fever, catarrh of the Upper Respiratory Tract, keratoconjunctivitis, tonzyllopharyngitis, diarrhea (intestinal syndrome), mesadenitis, hepatosplenomegaly

Mild

Moderate

Severe

1. Without complications

Paramyxoviruses

Croup syndrome, catarrh of the Upper Respiratory Tract, tonzyllopharyngitis,

2. With complications

Etiology Clinical formsSeverity

Course

RS-viruses Acute bronchitis, bronchiolitis, Croup syndrome

Severe

Rhinoviruses

Rhinitis, pharyngitis, catarrh of URT,  Interstitial pneumonia, Croup syndrome (seldom)

Mild

Moderate

Identification of virus from nasopharyngeal smears (also feces or blood in Adenovirus infection ) by culture, immunofluorescence, or ELISA.

Serologic diagnosis to find antibodies against viruses with fourfold increasing of antibodies title in 10-14 days may be used.

In CBC, mainly leucopenia (normocytosis) with a shift to the left or relative lymphomonocytosis.

During X-ray – strengthening of the pulmonary picture

Differential diagnosis should be performed between other viral respiratory tract infections, allergic rhinitis, foreign body aspiration, epiglottitis, bacterial tracheitis, pertussis, measles, Epstein-Bar Virus infection, bacterial croup

Rhinoviral infection: with allergic rhinitis, foreign body of the nose.

RS-infection: whooping cough, chlamidiosis, mycoplasmosis.

Adenoviral infection: with infectious mononucleosis, micoplasmosis, and measles.

Parainfluenza: with true croup in diphtheria, other viral croup (i.e. in measles).

DiseaseDisease ClinicsClinics

Allergic rhinitisAllergic rhinitis 1.1. Itching and sneezing are predominatingItching and sneezing are predominating2.2. Nasal eosinophylia Nasal eosinophylia

SinusitisSinusitis 1.1. Headache, tenderness at percussion, Headache, tenderness at percussion, periorbital edemaperiorbital edema;;

2.2. Cough and/or rhinorrhea more than Cough and/or rhinorrhea more than 10-14 10-14 daysdays..

Streptococcal Streptococcal nasopharyngitis nasopharyngitis

Purulent exudate from the nose and tonsillsPurulent exudate from the nose and tonsills

Most upper respiratory tract infections (URIs) are self-diagnosed and self-treated at home.

Symptom-based therapy is the mainstay of URI treatment in immunocompetent adults , although antimicrobial or antiviral therapy is appropriate in selected patients (immunocompromised)

Treatment consists of adequate fluid intake, rest, humidified air, analgetics and antipyretics

Nasal spray( tramazoline or azelastine) for decongesting the mucosa, Saline nasal drops

Paracetamol or similar drugs to fever , Antitussive agents such as

dextromethorphan,glycodin or bromhexine , as well as preparations with plantain , thyme or ivy extract

Bronchodilator drugs with respiratory problems such as beclomethasone, theophylline or drugs with ivy extract.

Antibiotics are not needed in circumstances of Viral respiratory infections.

Good hand and respiratory hygiene. Offer influenza vaccination to

children 6 months to 18 years of age.

Encourage parents/caregivers and household contacts of children to get vaccinated.

Influenza, one of the most common infectious diseases, is a highly contagious airborne disease that occurs in seasonal epidemics and manifests as an acute febrile illness with variable degrees of systemic symptoms, ranging from mild fatigue to respiratory failure and death

There were 3 global pandemics in the last (XX)century, the worst of which occurred in 1918. Called the Spanish flu.

This pandemic killed an estimated 20-50 million persons.

The Spanish influenza pandemic of 1918 (H1N1)

The pandemic of 1957 (H2N2) The pandemic of 1968 (H3N2) Smaller outbreaks occurred in 1947,

1976, 1977, and 2009

Influenza viruses are encapsulated,, single-stranded RNA viruses of the family Orthomyxoviridae.

The core nucleoproteins are used to distinguish the 3 types of influenza viruses: A, B, and C.

Influenza A viruses cause most human and all avian influenza infections.

Influenza A is generally more pathogenic than influenza B.

Epidemics of influenza C have been reported, especially in young children.

During the 2011-2012 influenza season, H3N2 viruses predominated overall, but H1N1 and influenza B viruses also circulated widely

The RNA core consists of 8 gene segments surrounded by a coat of 10 (influenza A) or 11 (influenza B) proteins.

The most significant surface proteins include hemagglutinin (H) and neuraminidase (N).

Hemagglutinin and neuraminidase are critical for virulence, and they are major targets for the neutralizing antibodies of acquired immunity to influenza.

Hemagglutinin binds to respiratory epithelial cells, allowing cellular infection.

Neuraminidase cleaves the bond that holds newly replicated virions to the cell surface, permitting the infection to spread.

The hemagglutinin and neuraminidase variants are used to identify influenza A virus subtypes. 2. The most common subtypes of human influenza virus identified by only hemagglutinins 1, 2, and 3 and neuraminidases 1 and 2

For example, influenza A subtype H3N2 expresses hemagglutinin 3 and neuraminidase 2

Influenza A is a genetically labile virus, with mutation rates as high as 300 times that of other microbes.

Changes in its major functional and antigenic proteins occur by 2 well-described mechanisms: antigenic drift and antigenic shift.

Antigenic drift is the process by which inaccurate viral RNA polymerase frequently produces point mutations in certain regions in the genes.

These mutations are responsible for the ability of the virus to evade annually acquired immunity in humans

Drift occurs within a set subtype (eg, H2N2). For example, AH2N2 Singapore 225/99 may reappear with a slightly altered antigen coat as AH2N2 New Delhi 033/01.

Antigenic shift generates viruses with entirely novel antigens

Avian influenza (ie, human infection with avian H5N1 influenza virus) is transmitted primarily through direct contact with diseased or deceased birds infected with the virus.

Contact with excrement from infected birds or contaminated surfaces or water are also considered mechanisms of infection

The World Health Organization estimates that worldwide, annual influenza epidemics result in about 3-5 million cases of severe illness and about 250,000 to 500,000 deaths.

Influenza viruses spread from human to human via aerosols created when an infected individual coughs or sneezes.

Infection occurs after an immunologically susceptible person inhales the aerosol.

If not neutralized by secretory antibodies, the virus invades airway and respiratory tract cells.

The incubation period of influenza ranges from 1 to 4 days.

Aerosol transmission may occur 1 day before the onset of symptoms ;

It may be possible for transmission via asymptomatic persons or persons with subclinical disease

Viral shedding occurs at the onset of symptoms or just before the onset of illness (0-24 hours). Shedding continues for 5-10 days.

Young children may shed virus longer, placing others at risk for contracting infection.

In highly immunocompromised persons, shedding may persist for weeks to months

The pathogenicity of influenza A virus (IVA) depends on interactions between virus and host proteins.

HA is responsible for determining the target animal species, organs, and cell-types for IVA.

The NS1 protein of IVA inhibits IFN-I production in virus-infected cells by interfering with the RIG-I signaling pathway.

Pulmonary macrophages induce epithelial cell apoptosis( mediated by the TRAIL-DR6 interaction in the IVA-infected lung)

A model of multi-cellular interactions that regulate the inflammatory response during influenza virus infection.

Influenza virus infection induces innate immune responses mediated by the TLR7 and RIG-I signaling pathways.

RIG-I retinoic acid-inducible gene-I

TLR7- toll-like receptor

Onset of illness can occur suddenly over the course of a day, or it can progress more slowly over the course of several days.

Typical signs and symptoms include the following (not necessarily in order of prevalence):

Cough and other respiratory symptoms

Fever Sore throat Myalgias Headache Nasal discharge Weakness and severe fatigue Tachycardia Red, watery eyes

In December 2013, the CDC reported about severe respiratory illness among young and middle-aged adults, including a number who were infected with influenza A (H1N1) pdm09 (pH1N1) virus, the strain responsible for the 2009 influenza pandemic.

The virus continues to circulate widely during the 2013-14

Cough and other respiratory symptoms may be initially minimal but frequently may progress to severe form.

Patients may report nonproductive cough, cough-related pleuritic chest pain, and dyspnea.

In children, diarrhea may be a feature.

Fever may vary widely among patients, with some having low fevers and others developing fevers as high as 39°C.

Sore throat may be severe or mild and may last 3-5 days. The sore throat may be a significant reason why patients seek medical attention.

Myalgias are common and range from mild to severe. Frontal or retro-orbital headache is common and is usually severe.

Ocular symptoms develop in some patients with influenza and include photophobia, burning sensations, or pain upon motion.

Some patients with influenza develop rhinitis of varying severity.

Weakness and severe fatigue may prevent patients from performing their normal activities or work.

Patients report needing additional sleep.

High fever Myalgias Tachycardia, which

most likely results from hypoxia, fever, or both

Pharyngitis- the findings may range from minimal infection to more severe inflammation

Eyes may be red and watery

Pulmonary findings may include dry cough with clear lungs or rhonchi, as well as focal wheezing

Nasal discharge is absent in most patients

Diarrhea Nausea and vomiting Fatigue appearance

Acute encephalopathy has been associated with influenza A virus infection.

Clinical features included altered mental status, coma, seizures, and ataxia.

Most of patients had abnormal CSF, MRI, and EEG findings.

Primary influenza pneumonia is characterized by progressive cough, dyspnea, and cyanosis following the initial presentation.

Chest radiographs show bilateral diffuse infiltrative patterns, without consolidation, which can progress to a presentation similar to acute respiratory distress syndrome (ARDS).

The elderly, especially nursing home patients, and those with cardiovascular disease are usually the groups at highest risk;

however, particular influenza strains may target younger persons. For example, in the 1918-1919 epidemic, many young adults died of a viral pneumonia.

•Chronic lung diseases •Diabetes mellitus •Neurological and muscle diseases •Malignancy

Secondary bacterial pneumonia can occur from numerous pathogens (eg, Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae).

The most frequent complication is staphylococcal pneumonia, which develops 2-3 days after the initial presentation of viral pneumonia.

Patients appear severely ill, with productive bloody cough, hypoxemia, an elevated white blood cell (WBC) count, and multiple cavitary infiltrates on chest radiography

Flu H1N1

A review of avian influenza cases in 4 countries found that the clinical course progressed to ARDS and respiratory failure in 70-100% of patients.

The mean time to the development of ARDS was 6 days.

Lymphopenia at presentation is a significant predictor of the progression to ARDS and death

H5N1

•Bacterial: otitis, sinusisits, pneumonia, etc. •Acute myositis•Reye syndrome•Neurologic (encephalitis, Guilliene-Barre syndrome, myelitis) •Cardiological (myocarditis)

Influenza pneumonia must be differentiated from other forms of viral pneumonia,

bacterial pneumonia, and noninfectious causes of

respiratory distress, such as heart failure, chronic obstructive pulmonary disease, pulmonary edema, and aspiration pneumonitis.

Differential Diagnoses Acute Respiratory Distress Syndrome Adenoviruses Arenaviruses Cytomegalovirus Dengue Fever Echoviruses Hantavirus Pulmonary Syndrome HIV Disease Legionnaires Disease Parainfluenza Virus

Rapid influenza diagnostic tests that directly detect influenza A or B virus–associated antigens or enzyme in throat swabs, nasal swabs, or nasal washes.

These tests can produce results within 30 minutes

The tests tended to be more sensitive in children (67%) than in adults (54%) and better at detecting influenza A (65%) than influenza B (52%).

For viral culture, nasopharyngeal samples with swabs must be sent in appropriate viral transport media to the laboratory to be cultured in several lines of cells.

A laboratory diagnosis of influenza is established once specific cytopathic effect is observed .

Staining the infected cultured cell lines with fluorescent antibody confirms the diagnosis

Most laboratories and hospitals now offer nucleic acid (PCR)-based studies. A nasal swab is submitted in special transport media to the laboratory, and results can be available within 24 hours.

Sensitivity for influenza is greater than 90%. These tests may be offered as respiratory

panels that provide information on the presence of other viruses, such as respiratory syncytial virus (RSV) and adenovirus

Some laboratories offer direct immunofluorescent tests on fresh specimens, but these tests are labor- and personnel-intensive and are less sensitive than culture methods

Several serologic tests have become available.; Generally, 30-60 minutes are required to perform the test’s multiple steps. Test sensitivities generally range from 60-70%.

Early radiographic findings include no or minimal bilateral symmetrical interstitial infiltrates.

Later, bilateral symmetrical patch infiltrates become visible.

Focal infiltrates indicate bacterial pneumonia.

Radiographic findings

Patients with influenza generally benefit from bed rest.

Most patients with influenza recover in 3 days;

However, malaise may persist for weeks.

Patients most often require hospitalization when influenza exacerbates underlying chronic diseases.

On occasion, the direct pathologic effects of influenza may necessitate hospitalization.

Most commonly, this is influenza pneumonia

Non specific:•Oral or IV desintoxication •NSAIDs – ibuprophen, paracetamole Aspirin is contraindicated !

Specific:•Antivirals – first 48 hour, 5 days (Oseltamivir (Tamiflu), Zanamivir, Remantadin)

Four licensed prescription influenza antiviral agents are available in the : Amantadine, Rimantadine, Zanamivir, and Oseltamivir.

Zanamivir and Oseltamivir are related antiviral medications in a class of medications known as neuraminidase inhibitors.

These two medications are active against both influenza A and B viruses.

Amantadine and rimantadine are related antiviral drugs in a class of medications known as adamantanes.

These medications are active against influenza A viruses but not influenza B viruses.

In recent years, influenza A (H3N2) virus strains and 2009 H1N1 virus strains are resistant to adamantanes .

Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A virus strains.

TABLE 1. Recommended dosage and schedule of influenza antiviral medications* for treatment† and chemoprophylaxis§ Antiviral agent Age group (yrs)

1--6 7--9 10--12 13--64 ≥65Zanamivir

Treatment, influenza A and B

NA 10 mg (2 inhalations) twice daily

10 mg (2 inhalations) twice daily

10 mg (2 inhalations) twice daily

10 mg (2 inhalations) twice daily

Chemoprophylaxis, influenza A and B

NA for ages 1--4

Ages 5--910 mg (2 inhalations) once daily

10 mg (2 inhalations) once daily

10 mg (2 inhalations) once daily

10 mg (2 inhalations) once daily

Oseltamivir¶

Treatment,** influenza A and B

Dose varies by child's weight**

Dose varies by child's weight**

Dose varies by child's weight**>40 kg = adult dose

75 mg twice daily

75 mg twice daily

Chemoprophylaxis, influenza A and B

Dose varies by child's weight††

Dose varies by child's weight††

Dose varies by child's weight††

>40 kg = adult dose

75 mg once daily

75 mg once daily

Abbreviation: NA = not approved

Zanamivir is approved for treatment of persons aged ≥7 years and approved for chemoprophylaxis of persons aged ≥5 years.

Zanamivir is administered through oral inhalation by using a plastic device included in the medication package.

Zanamivir is not recommended for those persons with underlying airway disease

Oseltamivir is manufactured by Roche Pharmaceuticals (Tamiflu --- tablet). Oseltamivir is approved for treatment or chemoprophylaxis of persons aged ≥1 year.

Oseltamivir is available for oral administration in 30 mg, 45 mg, and 75 mg capsules and liquid suspension.

No antiviral medications are approved for treatment or chemoprophylaxis of influenza among children aged <1 year.

Recommended duration for antiviral treatment is 5 days. Longer treatment courses can be considered for patients who remain severely ill after 5 days of treatment.

Recommended duration is 10 days when administered after a household exposure and 7 days after the most recent known exposure in other situations.

For control of outbreaks in long-term care facilities and hospitals, CDC recommends antiviral chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the most recent known case was identified

Wash your hands often with soap and water or an alcohol-based hand rub.

Avoid touching your eyes, nose, or mouth. Germs spread this way.

Try to avoid close contact with sick people. Practice good health habits. Get plenty of sleep

and exercise, manage your stress, drink plenty of fluids, and eat healthy food.

Cover your nose and mouth with a tissue when you cough or sneeze. Throw the tissue in the trash after you use it.

If you are sick with flu-like illness, stay home for at least 24 hours after your fever is gone without the use of fever-reducing medicine.

The chemoprophylaxis dosing recommendation for oseltamivir for children aged ≥1 year who weigh ≤15 kg is 30 mg once a day.

For children who weigh >15 kg and up to 23 kg, the dose is 45 mg once a day.

For children who weigh >23 kg and up to 40 kg, the dose is 60 mg once a day.

For children who weigh >40 kg, the dose is 75 mg once a day

The injected flu vaccine contains inactivated strains of the flu virus .

The vaccine contains live, but weakened, forms of flu virus which do not cause flu in those vaccinated.

Flu nasal spray vaccination.The flu vaccine is given as an annual nasal spray to: children aged two to 18 years at risk of flu healthy children aged two and three years.

The vaccine is given as a single dose of nasal spray.

The flu shot contains killed (inactive) viruses. The flu shot is approved for people age 6 months and older.

Flu shots may be injected into the muscle or just below the skin.

Each year the seasonal (annual) flu vaccine contains three common influenza virus strains.

The flu virus changes each year this is why a new flu vaccine has to be given each year.

Last year’s seasonal flu vaccine had 3 strains of flu viruses as recommended by the World Health Organization (WHO)

The three strains are An A/California/7/2009 (H1N1)pdm09-like virus;An A(H3N2) virus antigenically like the prototype virusA/Victoria/361/2011; B/Massachusetts/2/2012-like virus