Upper Respiratory Tract Infections Dr Meral Sönmezoğlu Yeditepe University Hospital Infectious Diseases

Major sites of community-acquired respiratory tract infections Frontal sinus Sinusitis Maxillary sinus Pharyngitis Respiratory infections are divided according to whether they affect the upper or lower respiratory tract. Infections of the upper respiratory tract are among the most common human health problems. It is, therefore, not surprising that infection of the upper respiratory tract is one of the most frequent reasons for patients consulting their primary care physician, and one of the major causes of absence from school or work. The most common upper respiratory tract infections are acute pharyngitis/tonsillitis, sinusitis and otitis media, which occur predominantly in children. Although such infections are non- life-threatening and are usually mild, they cause significant discomfort and lost productivity. Furthermore, some, such as streptococcal pharyngitis, can have serious sequelae. Infections of the lower respiratory tract occur less frequently but are associated with significant morbidity and mortality. They are a major cause of death globally and the leading cause of death from infectious diseases in the US (Bartlett et al. 1998). The two major bacterial infections of the lower respiratory tract are pneumonia and acute exacerbations of chronic bronchitis. Bartlett et al. Clin Infect Dis 1998;26:811–38. Pneumonia Bronchitis

Upper Respiratory Infections Common Cold Pharyngitis Acute laryngitis Acute laryngotracheobronchitis (Croup) Otitis media, otitis externa, mastoitidis

Respiratory tract infections — a major cause of mortality Death from respiratory infections in the developed world in 1990 Age (years) 0–4 5–14 15–29 30–44 45–59 The World Health Organization report on global mortality up to 1990 estimated that respiratory tract infections are responsible for approximately 4.3 million deaths each year, of which 4.0 million occur in developing countries (Murray & Lopez. 1994). In the developed world, infections of the respiratory tract account for 3% of total mortality. Patients aged 60 years and above are at greatest risk of death. In contrast, in developing countries, fatality from respiratory tract infections is highest in infants aged 4 years and under. This difference in epidemiology is most probably due to the high peri- and neonatal mortality associated with poor socioeconomic conditions in developing countries, coupled with a longer life expectancy in the developed world (Bariffi et al. 1995). Bariffi et al. J Chemother 1995;7:263–76. Murray & Lopez. Bull World Health Organ 1994;72:44780. 60–69 70+ 50 100 150 200 250 300 Estimated deaths (x 103) Murray & Lopez. Bull World Health Organ 1994;72:447–80

Cases per 1000 population/year Incidence of community-acquired lower respiratory tract infection increases with age Age (years) 16–19 20–29 30–39 40–49 50–59 In developed countries, lower respiratory tract infections occur more frequently and with greater severity in the elderly than in young adults (MacFarlane et al. 1993; Bartlett et al. 1998). There are several age-related reasons for this, including: decline in respiratory function; deterioration in immune competence; increase in incidence of chronic obstructive airway diseases. As the population continues to age, infections of the lower respiratory tract are likely to pose an even greater financial and clinical burden on society. MacFarlane et al. Lancet 1993;341:511–14. Bartlett et al. Clin Infect Dis 1998;26:811–38. 60–69 70–79 20 40 60 80 100 120 140 Cases per 1000 population/year MacFarlane et al. Lancet 1993;341:511–14

Impact of URIs Recognized for the last century as the most common infectious illness in humans Terminology has varied Common respiratory infection Common cold Rhinosinusitis Rhinoviruses (RVs) cause a majority of these infections VRIs, also called “the common cold” or rhinosinusitis, are recognized as the most common infectious illness in humans and a major cause of acute morbidity in individuals of all ages worldwide.1 Viral pathogens associated with these infections include the picornaviruses, influenza viruses, parainfluenza viruses, respiratory syncytial virus (RSV), adenoviruses, and coronaviruses. The ability to detect these viruses with advanced techniques such as reverse-transcription polymerase chain reaction (RT-PCR) assays has allowed the laboratory identification of specific viruses that cause various respiratory syndromes. Rhinoviruses (RVs, one of the genera of the picornavirus family) are the most common cause of VRI symptoms. Picornaviruses have been isolated in up to 82% of persons with self-reported cold symptoms during the peak fall season.2 Most picornaviruses identified were RVs; some were enteroviruses. Those not identified were assumed to be RV. In this study, picornavirus RNA was detected in 46% of the culture-negative nasal wash specimens. From 70% to 88% of human RV infections result in symptomatic respiratory episodes characterized by rhinorrhea, nasal obstruction, sore throat, cough, and hoarseness, without systemic symptoms such as fever.1,3 1. Monto AS, Fendrick AM, Sarnes MW. Respiratory illness caused by picornavirus infection: a review of clinical outcomes. Clin Ther. 2001;23:1615-1627. 2. Arruda E, Pitkäranta A, Witek T Jr, Doyle CA, Hayden FG. Frequency and natural history of rhinovirus infections in adults during autumn. J Clin Microbiol. 1997;35:2864-2868. 3. Gwaltney JM Jr. Rhinovirus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000:1940- 1948. Monto AS et al. Clin Ther. 2001;1615.

Parainfluenza viruses Respiratory syncytial virus (RSV) Seasonality of Respiratory Agents: Proportion Isolated in Each Calendar Month During 6 Years of Tecumseh, Michigan, Study 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;16:351-373. 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;35:2864-2868. 3. Monto AS, Sullivan KM. Acute respiratory illness in the community: frequency of illness and the agents involved. Epidemiol Infect. 1993;110:145-160. Percent Jan Apr Sep Oct Nov Dec Feb Mar May Jun Jan Apr Sep Oct Nov Dec Jan Feb Mar Apr May Jun Reprinted from Br J Prev Soc Med, 1977;31:101-108, with permission from the BMJ Publishing Group.

Transmission of Respiratory Viruses Transmission of viruses differs Influenza Airborne transmission1 Widespread outbreaks RVs Closer contact required Aerosol and direct2,3 Households and schools are sites of transmission4 Prevention of the spread of VRIs requires an understanding of how these viruses are transmitted. Influenza virus transmission is via aerosol droplets.1 The principal route of transmission of RVs is a subject of debate. Studies suggest that the principal route is by direct contact and autoinoculation.2 These studies have shown, for example, that RV transmission could be interrupted by treating contaminated surfaces with a virucidal agent.2,3 Another study showed that applying iodine to mothers’ fingers reduced their incidence of secondary respiratory infections.4 One study has established that airborne spread also occurs,5 but most experts agree that direct contact is the most efficient means of transmission.6 A major site for RV transmission is the home, with schoolchildren the most frequent introducers of infection.7 1. Goldmann DA. Transmission of viral respiratory infections in the home. Pediatr Infect Dis J. 2000;19(10 suppl):S97-S102. 2. Gwaltney JM Jr, Hendley JO. Transmission of experimental rhinovirus infection by contaminated surfaces. Am J Epidemiol. 1982;116:828-833. 3. Hendley JO, Wenzel RP, Gwaltney JM Jr. Transmission of rhinovirus colds by self- inoculation. N Engl J Med. 1973;288:1361-1364. 4. Hendley JO, Gwaltney JM Jr. Mechanisms of transmission of rhinovirus infections. Epidemiol Rev. 1988;10:242-258. 5. Dick EC, Jennings LC, Mink KA, Wartgow CD, Inhorn SL. Aerosol transmission of rhinovirus colds. J Infect Dis. 1987;156:442-448. 6. Turner RB. The common cold. Pediatr Ann. 1998;27:790-795. 7. Gwaltney JM Jr. Rhinovirus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000:1940-1948. 1. Goldman DA. Pediatr Infect Dis J. 2000;19(10 suppl):S97. 2. Gwaltney JM Jr, Hendley JO. Am J Epidemiol. 1982;116:828. 3. Dick EC et al. J Infect Dis. 1987;156:442. 4. Gwaltney JM Jr. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000:1940.

Mucosal invasion of pathogens

Clinical Features and Duration of Illness in Adults with RV Colds (n=276, RV confirmed by PCR or culture) Clinical feature 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 In a more recent study, Arruda and others also characterized the natural history and frequency of RV infection in adults with self-reported colds confirmed by RT-PCR or culture. An important clue to the etiology was the finding that sore throat was the initial symptom recognized in 39%. Runny nose was the most bothersome symptom in 36% of these adults. Runny and stuffy nose were also the most persistent symptoms. These researchers found that the median duration of colds in adults was 9.5 to 11 days. Colds interfered with people’s daily activities for 7 days and disturbed their sleep for 4 nights. 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;35:2864-2868. Adapted with permission from Arruda E et al. J Clin Microbiol. 1997;35:2864.

Differentials Symptoms Allergy URI Influenza Itchy, watery eyes Common Rare (conjunctivitis may occur with adenovirus) Soreness behind eyes, sometimes conjunctivitis Nasal discharge Nasal congestion Sometimes Sneezing Very common Sore throat Sometimes (postnasal drip) Cough Common (mild to moderate, hacking) Common (dry cough, can be severe) Headache Uncommon Rare Fever Never Rare in adults, possible in children Very common (100-102°F (or higher in young children), lasting 3–4 days; may have chills) Malaise Fatigue, weakness Very common, can last for weeks, extreme exhaustion early in course Muscle pain Slight Very common, often severe

Bacterial causes of URIs Streptococcus pyogenes (group A ßhemolytic) Group C streptococci Haemophylus influenza Moraxella catarrhalis Staphylococcus aureus Klebsiella pneumoniae Haemophylus parainfluenzae Mycoplasma pneumoniae Chlamydia pneumoniae

Viral causes of URIs Rhinovirus (100 types and 1 subtype) Coronavirus (>3 types) Parainfluenza virus Respiratory syncytial virus İnfluenza virus Adenovirus (type 3,4,7,14,21) Coxsackievirus A (type 2,4-6,8,10) Epstein Barr virus Cytomegalovirus HIV-1

Childhood etiology of URTI A respiratory virus was found in 62% (RSV 29%, rhinovirus 24%, parainfluenza viruses 10%, adenovirus 7%, influenza viruses 4%, other viruses 8%) Bacterial agent in 53% (Streptococcus pneumoniae, 37%, Haemophilus influenzae 9%, Mycoplasma pneumoniae, 7%, Moraxella catarrhalis 4%, Chlamydia pneumoniae 3%, other bacteria 2%). In 30% of cases there was evidence of a mixed viral/bacterial infection, viral infection alone was detected in 32% and bacterial infection alone in 22% of patients Thorax 2002;57:438–441

Etiology of common cold JCM Feb. 1998, p. 539–542

Clinical characteristics of “common cold” Incubation period 12-72 hrs Cardinal symptoms: Nasal discharges Nasal obstuctions Sneezing Sore and scratchy throat Cough Slight fever Duration 1 week, self limited

Diagnosis Typical and easy Differential diagnosis; -hay fever -vasomotor rhinitis Major challenge is to distinguish the uncomplicated cold from secondary bacterial sinusitis and otitismedia

Treatment First generation antihistaminics Nonsteroidal anti-inflammatory drugs Sore throat reliefs with warm saline gargles and topical anesthetics Oseltamivir?

Prevention Isolation of the patients for first days Influenza vaccines

Sinusitis — facts and figures Definition: – infection of frontal, ethmoidal or maxillary sinuses Symptoms: – facial pain, headache, nasal discharge, fever Prevalence: – 31.2 million cases per year in the USA – 16 million outpatient visits Complications: – permanent mucosal damage and chronic sinusitis – rarely, optic neuritis, subdural abscess and meningitis Acute sinusitis is an infection of the maxillary, frontal or ethmoidal sinuses, which often occurs as a complication of a common cold or other upper respiratory tract infection. Patients typically present with facial pain, purulent nasal discharge and headache. In some individuals, nasal obstruction, disorders of smell and a nasal tone to the voice are also present. Sinusitis is a common condition which affects approximately 31 million people per year in the USA and accounts for 16 million outpatient visits per year (Schwartz. 1994). Sinusitis can be divided into three main syndromes: acute, subacute and chronic. In young adults, acute sinusitis is responsible for 4.6% of physician consultations (Willet et al. 1994). If left untreated, acute sinusitis can lead to permanent mucosal damage and chronic sinusitis. In rare cases, the infection can spread leading to osteomyelitis, optic neurosis, subdural abscess and meningitis. Schwartz. Nurse Pract 1994;19:58–63. Willet et al. J Gen Intern Med 1994;9:38–45. Schwartz. Nurse Pract 1994;19:58–63

Figure 1. The dynamics and changes over time in the microbiology of bacterial sinusitis. Proc Am Thorac Soc, http://www.atsjournals.org/doi/abs/10.1513/pats.201006-038RN Published in: Itzhak Brook; Proc Am Thorac Soc  2011, 8, 90-100. © 2011 The American Thoracic Society

Figure 2. Dynamics of sinusitis Figure 2. Dynamics of sinusitis. Amox = amoxicillin; Cipro = ciprofloxacin; clinda = clindamycin; NG = no growth. Reprinted by permission from Reference 87. Proc Am Thorac Soc, http://www.atsjournals.org/doi/abs/10.1513/pats.201006-038RN Published in: Itzhak Brook; Proc Am Thorac Soc  2011, 8, 90-100. © 2011 The American Thoracic Society

Etiologic agents Viral illness is the most common cause for upper respiratory tract infections, including sinusitis. Rhinovirus, influenza virus, and parainfluenza virus are the most common causes of sinusitis. The most common bacteria isolated from pediatric and adult patients with community-acquired acute purulent sinusitis are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes. Staphylococcus aureus and anaerobic bacteria (Prevotella and Porphyromonas, Fusobacterium and Peptostreptococcus spp.) are the main isolates in chronic sinusitis.

Etiology of acute sinusitis Streptococci 8% S. aureus 6% Staphylococci 7% M. catarrhalis 1% Anaerobes 7% Other bacteria 5% S. pneumoniae 34% Acute sinusitis is a bacterial infection caused primarily by S. pneumoniae and H. influenzae. Together, these two pathogens account for about 70% of such infections (Willett et al. 1994). M. catarrhalis and other streptococci are implicated in 1% and 8% of cases of acute sinusitis, respectively. Willett et al. J Gen Intern Med 1994;9:38–45. H. influenzae 35% Total percentages greater than 100% because of multiple organisms Willett et al. J Gen Intern Med 1994;9:38–45

RV in Acute Sinusitis Sinusitis is an extremely common part of the common cold syndrome RV has been detected in 50% of adult patients with sinusitis by RT-PCR of maxillary sinus brushings or nasal swabs1 Frequency of association of RV infection with sinusitis suggests the common cold could be considered a rhinosinusitis2 Sinusitis is an extremely common part of the common cold syndrome. Sinus abnormalities have been detected by computed tomography (CT) in approximately 87% of patients with a common cold.1 Only a small proportion of cases (0.5%–2%) of viral rhinosinusitis are complicated by bacterial infection.2 The high frequency of sinusitis occurring with documented RV infection suggests that RVs play a role in acute sinusitis. The common cold can almost be considered a rhinosinusitis.2 The use of RT-PCR has clarified the role of RVs in sinusitis. In a study of 20 adults who had acute community-acquired sinusitis, RV was detected in 50% of patients by RT-PCR of maxillary sinus brushings or nasal swabs.3 Personal behaviors during a cold may be responsible for a viral sinusitis. Gwaltney and colleagues reported that the intranasal pressure created by nose-blowing, sneezing, and coughing is great enough to propel nasal secretions into the sinuses.4 Because RVs are present in nasal secretions, nose-blowing may be an important factor in introducing RVs into the sinuses during colds. 1. Gwaltney JM Jr, Phillips CD, Miller RD, Riker DK. Computed tomographic study of the common cold. N Engl J Med. 1994;330:25-30. 2. Gwaltney JM Jr. Acute community-acquired sinusitis. Clin Infect Dis. 1996;23:1209-1225. 3. Pitkäranta A, Arruda E, Malmberg H, Hayden FG. Detection of rhinovirus in sinus brushings of patients with acute community-acquired sinusitis by reverse transcription-PCR. J Clin Microbiol. 1997;35:1791-1793. 4. Gwaltney JM Jr, Hendley JO, Phillips CD, Bass CR, Mygind N, Winther B. Nose blowing propels nasal fluid into the paranasal sinuses. Clin Infect Dis. 2000;30:387-391. Pitkäranta A et al. J Clin Microbial. 1997;35:1791. Gwaltney JM Jr. Clin Infect Dis. 1996;23:1209.

Sinusitis Acute sinusitis ; into three main syndromes: subacute chronic In young adults, acute sinusitis is responsible for 4.6% of physician consultations

Diagnosis Clinical signs Radiology Purulent nasal secretions Purulent posterior pharyngeal secretions Mucosal erythema Periorbital edema Tenderness overlying sinuses Facial erythema Radiology Air-fluid levels on transillumination of the sinuses (60% reproducibility rate for assessing maxillary sinus disease) A third criterion added to the updated guideline is URI with worsening symptoms such as nasal discharge, cough, and fever after initial improvement.

X-ray of Sinuses The 2015 guidelines recommend that clinicians should not obtain radiographic imaging in patients who meet diagnostic criteria for acute sinusitis unless a complication or alternative diagnosis is suspected. X ray may demonstrate demonstrate mucosal thickening, air-fluid levels Waters view (occipitofrontal) - Primarily useful for evaluation of maxillary and frontal sinuses Caldwell view (angled posteroanterior) - Only view that visualizes the ethmoid air cells Lateral view - Primarily for adenoid and/or nasopharyngeal size and sphenoid disease

Treatment The primary goals of management of acute sinusitis are to eradicate the infection, decrease the severity and duration of symptoms, and prevent complications.. Analgesics, topical intranasal steroids, and/or nasal saline irrigation for symptomatic relief of viral rhinosinusitis First-line therapy is amoxicillin with or without clavulanate. Imagining or cultures are not needed in uncomplicated cases.

Acute pharyngitis/tonsillitis — facts and figures Definition: – inflammation of the pharynx or tonsils Symptoms: – pharyngeal pain, dysphagia and fever Epidemiology: – 1% physician visits/year – most common childhood bacterial infectiona Complications: – acute rheumatic fever and glomerulonephritisa Pharyngitis is an inflammation of the oropharynx leading to pharyngeal pain, dysphagia and, in some cases, fever. It is one of the most common human infections and is responsible for approximately 1% of physician visits each year (Garau et al. 1998). Pharyngitis is often caused by viral infection, in which case antimicrobial therapy will not be beneficial. However, many cases are caused by Group A b-hemolytic streptococci. The etiology of pharyngitis varies with age. For example, b-hemolytic streptococcal infection is particularly prevalent in children, and is the main etiology in approximately 50% of childhood cases of pharyngitis (Gwaltney. 1990). Streptococcal infections are of particular concern because they can progress to serious complications such as rheumatic fever and glomerulonephritis. Antimicrobial therapy of these infections is therefore warranted. Garau et al. Clin Microbiol Infect. 1998;4(Suppl. 2);S51–8. Gwaltney. In: Principles and Practices of Infectious Disease 1990;43:493–8. Gwaltney. In: Principles and Practices of Infectious Disease 1990;43:493–8 aStreptococcal pharyngitis

Strep Throat Fever Tonsillitis Enlarged lymph nodes Middle-ear infection

Acute streptococcal pharyngitis /tonsillitis

Etiology of pharyngitis Coronavirus (5%) Rhinovirus (20%) Adenovirus (5%) Other bacteria/viruses (7%) S. pyogenes (15–30%) In adults, pharyngitis is primarily viral in etiology. Viruses most frequently implicated are the rhinovirus, coronavirus and adenovirus, which together account for approximately 30% of cases of pharyngitis (Gwaltney. 1990). The bacterial pathogen Streptococcus pyogenes is responsible for a similar number of cases, overall. However, in children the relative importance of this pathogen increases, with streptococcal pharyngitis being the most common childhood infection. Gwaltney. In: Principles and Practices of Infectious Disease 1990;43:493–8. Unknown (40%) Gwaltney. In: Principles and Practices of Infectious Disease 1990;43:493–8

Pharyngitis Diagnosis B-Haemolytic colonies of Group A Streptococcus from a throat swab Bacitracin disk

Acute otitis media — facts and figures Definition: – infection of the middle ear leading to accumulation of fluid and inflammation of the tympanic membrane Symptoms: – cough, fever, irritability, earache Epidemiology: – 24.5 million physician visits per year – majority of cases occur in children <2 years – most frequent indication for antimicrobial treatment in children in the USA Complications: – loss of hearing Acute otitis media is one of the commonest infections among children. It is defined by the presence of fluid in the middle ear and inflammation of the tympanic membrane. Associated symptoms include fever, cough, irritability and, in approximately half of cases, earache (Garau et al. 1998). The majority of cases of acute otitis media occur in children <2 years old (Garau et al. 1998). In 1990, it accounted for 24.5 million visits to the primary care physician by children (Klein 1994), and it is now thought to be the most frequent cause of antimicrobial prescriptions for children. Antimicrobial treatment for otitis media is generally empiric. Failure to eradicate the infection can lead to serious sequelae in the middle ear, including cholesteatoma and loss of hearing. Garau et al. Clin Microbiol Infect 1998;4:51–8. Klein. Clin Infect Dis 1994;19:823–33. Garau et al. Clin Microbiol Infect 1998;4:51–8 Klein. Clin Infect Dis 1994;19:823–33

Symptoms Signs of inflammation in the tympanic membrane Bulging in the posterior quadrants of the tympanic membrane may bulge; scalded appearance of the superficial epithelial layer Perforated tympanic membrane (most frequently in posterior or inferior quadrants) Presence of an opaque serumlike exudate oozing through the entire tympanic membrane Pain with/without pulsation of the otorrhea Fever

Infected Middle Ear (otitis media)

Acute otitis media — etiology M. catarrhalis 14% H. influenzae 23% S. pneumoniae 35% Unknown 16% The majority of cases of acute otitis media appear to be of bacterial rather than viral origin. Microbial analysis of middle-ear effusions obtained by tympanocentesis shows a similar etiology to acute sinusitis with S. pneumoniae, H. influenzae and M. catarrhalis being the most likely causative pathogens (Bluestone et al. 1992). Other bacteria such as S. pyogenes, S. aureus and P. aeruginosa also account for a small number of cases. Bluestone et al. Paediatr Infect Dis J 1992;11:7–11. S. pyogenes 3% S. aureus 1% Others 32% 2807 effusions from patients in the USA 1980–1989 Total percentages greater than 100% because of multiple organisms Bluestone et al. Paediatr Infect Dis J 1992;11:7–11

Etiologic agents S pneumoniae is the most common etiologic agent responsible for AOM and for invasive bacterial infections in children of all age groups. Pneumococcal infections are probably responsible for at least 50% of AOM episodes. H influenzae is the second most frequently isolated bacterium and is responsible for approximately 20% of episodes in preschool children

Treatment Analgesics and antipyretics have a definite role in symptomatic management. Amoxicillin (or erythromycin-sulfisoxazole, in patients who are allergic to penicillin) remains the initial treatment of choice in children with AOM. Or broad-spectrum beta-lactamase–resistant cephalosporin or a combined formulation such as amoxicillin-clavulanate or trimethoprim-sulfamethoxazole

Epiglottis Definition:Inflammination of the epiglottis due to infection Epidemiology:usually occurs in the winter months Causative Organisms:H.Influenzae( now rare), S.pyogenes, Pneumococcus, Staphylococcus aureus

Epiglottis Clinical Presentation In children because of the small airway may obstruct breathing and symptoms of adults In adults fever, pain on swallowing, sore throat, cough sometimes with purulent secretions

Epiglottis Diagnosis Clinical presentation Lateral X-ray Blood Cultures/Respiratory Secretions for Culture

Epiglottis Clinical Management Maintain airway in children may require tracheostomy ( trachestomy set should be at bedside) Cefotaxime I/V

Haemophilus Influenzae Culture

Influenza Virus An enveloped RNA virus Structure

‘H’ and ‘N’ Flu Glycoproteins H – Hemagglutinin  Specific parts bind to host cells of the respiratory mucosa Different parts are recognized by the host antibodies Subject to changes N - Neuraminidase Breaks down protective mucous coating Assist in viral release

Influenza Epidemics and pandemics, mostly in winter Upper respiratory tract infection – epithelial cells Multivalent killed virus vaccine with strains from the previous year (Grown in embryonated eggs) Bird flu (H5N1) pandemic in birds

H1N1 2009 (Swine Flu)

Influenza A/California/7/2009 (H1N1)

Influenza Disease Burden in an Average Year Deaths 25,000 - 72,000 Hospitalizations 114,000 - 257,500 Physician visits ~ 25 million Influenza Disease Burden to U.S. Society in an Average Year  A recent study by Thompson et al concluded that the number of influenza-related deaths has increased significantly in the past 2 decades [Thompson 2003]. The number of pneumonia and influenza deaths rose by 83% from the 1976-1977 through 1997-1998 influenza seasons. For the 1990-1991 through 1998-1999 seasons, the greatest average numbers of deaths were associated with influenza A (H3N2) viruses, followed by influenza B, and influenza A (H1N1). Influenza viruses were associated with annual averages of 8,097 underlying pneumonia and influenza deaths, 36,155 underlying respiratory and circulatory deaths, and 51,203 all-cause deaths. The authors attributed the increase in influenza-related deaths during the past 2 decades at least partially to the aging of the population. They noted that people aged 85 years of age and older are 32 times more likely to die from an influenza-associated underlying pneumonia and influenza death than people between 65 and 69 years old. Because it is a highly contagious, acute respiratory disease, influenza is responsible for an average of 50 to 60 million infections annually, resulting in 25 million health care visits [Couch 2000]. An estimated 114,000 to 142,000 excess hospitalizations occur each year secondary to influenza [ACIP 2004], although others suggest it may be over 0.25 million [Couch 2000]. The annual direct medical costs of influenza are estimated at between $1 and $3 billion [Patriarca 1999]. Economic losses are likely higher: $3 to $5 billion [Patriarca 1999]. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-186. Couch RB. Influenza: prospects for control. Ann Intern Med. 2000;133:992-998. Advisory Committee on Immunization Practices. Prevention and control of influenza. MMWR. 2004;53(RR06):1-40. Patriarca PA. New options for prevention and control of influenza. JAMA. 1999;282:75-77. Infections and illnesses 50 - 60 million Thompson WW et al. JAMA. 2003;289:179-86. Couch RB. Ann Intern Med. 2000;133:992-8. Patriarca PA. JAMA. 1999;282:75-7. ACIP. MMWR. 2004;53(RR06):1-40.

INFLUENZA: BIOLOGY & IMPACT Single-stranded, enveloped, RNA virus (orthomyxoviridae family) Influenza A Potentially severe illness; epidemic and pandemics Rapidly changing Influenza B Usually less severe illness; may cause epidemics More uniform Influenza C Usually mild or asymptomatic illness

INFLUENZA: BIOLOGY & IMPACT 25-50 million people contract influenza annually representing and attack rate of 10-20%. ~115,000 hospitalizations per year ~35,000 (20,000 – 40,000) deaths per year Causes respiratory tract disease Sudden onset More severe pneumonia during pregnancy No carrier state (but inapparent illness may occur)

INFLUENZA: EPIDEMIOLOGY Geographic distribution – global Reservoir: Humans, swine, birds Incubation - 1 to 5 days; usually 2 days Transmission Droplet (airborne?) route Direct contact Communicability 1 to 2 days before onset of symptoms to 4 to 5 days post-onset Attack rates: Up to 60% 1.

Influenza Activity Can Peak From December Through May Month of peak influenza activity during influenza seasons in the United States, 1976–2002 11 6 4 Influenza Activity Can Peak From December Through May  The occurrence of influenza infection is recognized to be highly seasonal. The CDC monitors the incidence of influenza throughout the U.S. each year with epidemics usually appearing during the winter months. For the last several decades (1976-2002), the majority of cases were reported during the fall and winter months, with peak incidence typically appearing in February, followed by January. Influenza epidemic peaks can vary (regional differences, etc.).   www.cdc.gov/nip/publications/pink/flu.pdf 3 1 1 www.cdc.gov/nip/publications/pink/flu.pdf.

Pandemi

Structure of the Influenza Virus Hemagglutinin (HA) Neuraminidase (NA) M2 Nucleoprotein (NP) Structure of the Influenza Virus Influenza is a single-stranded, helically shaped RNA virus of the orthomyxoviridae family. Three types of influenza virus have been classified (A, B, and C) based on antigenic differences. The glycoprotein hemagglutinin (HA) is the principal antigen on the surface of the influenza virus and is cleaved by proteases in host epithelial cells. HA undergoes proteolytic cleavage to HA1 and HA2 moieties. HA1 facilitates viral entry into cell principal viral neutralization epitopes. HA2 is important in viral attachment and entry into host cells - fusion activity. The enzyme neuraminidase (NA), also on the influenza virus surface, cleaves sialic acid residues from the host cell receptor for the virus, freeing virus particles and enabling them to spread through secretions. NA also plays a secondary role in viral neutralization. The M2 envelope protein is an ion channel through which hydrogen ions pass to acidify the endosomes, facilitating viral uncoating. Note that the M2 proteins of influenza A and B viruses differ. Within each nucleocapsid is a single segment of RNA that is associated with the viral nucleoprotein (NP), with 3 polymerase proteins (PP) bound to 1 end. These internal viral proteins are important targets for cytotoxic T lymphocytes. Two nonstructural proteins (PB and PA) are also found within the nucleocapsid; they participate in viral replication.   Hayden FG, Palese P. Clinical Virology. 1997: 911-942. M1 Polymerase (P) Proteins Adapted from: Hayden FG et al. Clin Virol. 1997:911-42.

Type of Nuclear Material Viral Nomenclature Type of Nuclear Material Hemagglutinin Neuraminidase A / Sydney / 184 / 93 (H3N2) Virus type Geographic origin Strain number Year of isolation Virus subtype 1. CDC. Atkinson W, et al. Chapter 13: Influenza. In: Epidemiology and Prevention of Vaccine-Preventable Diseases, 4th ed. Department of Health and Human Services, Public Health Service, 1998, 220

Pathogenesis of Influenza Influenza can be transmitted through small or large particle aerosols or through contact with contaminated surfaces If not neutralized by mucosal antibodies, virus attacks respiratory tract epithelium Infection of respiratory epithelial cells leads to cellular dysfunction, viral replication, and release of viral progeny Pathogenesis of Influenza  Influenza can be transmitted via 3 routes: Large particle aerosols (droplets). Small particle aerosols (droplet nuclei). Direct contact with contaminated surfaces. Following transmission, influenza virus can infect both the upper and lower airways. Influenza is thought to spread primarily by small particle aerosols or airborne transmission and may thus be more likely to infect the lower respiratory tract than some other respiratory viruses, like rhinovirus, that tend to be transmitted largely by direct contact followed by self-inoculation. Sneezing, coughing, and even talking can produce droplets of varying sizes, which can lead to spread of virus. If influenza virus is not neutralized by mucosal antibodies, an assault on the respiratory epithelium occurs. Invasion of the respiratory epithelium leads to cellular dysfunction, viral replication, and further spread of virus. The release of inflammatory mediators subsequently leads to manifestations of systemic illness. Bridges CB, Kuehnert MJ, Hall CB. Transmission of influenza: Implications for control in health care settings. Clin Infect Dis. 2003;37:1094-101. Heikkinen T, Jarvinen A. The common cold. Lancet. 2003;361:51-9. Release of inflammatory mediators contributes to systemic manifestations of disease Bridges CB et al. Clin Infect Dis. 2003;37:1094-101. Heikkinen T et al. Lancet. 2003;361:51-9.

Clinical Features of Influenza Sudden onset of symptoms, persist for 7+ days Incubation period: 1-4 days, average 2 days Infectious period of wild type virus: Adults shed virus typically from 1 day before through 5 days after onset of symptoms Children shed higher titers for a longer duration than adults Clinical Features of Influenza  Influenza is characterized by the sudden onset of symptoms after an incubation period of 1 to 4 days (average 2 days). Patients will shed the virus from approximately 1 day prior to the appearance of symptoms. Shedding of virus continues for about 4 to 5 days after symptoms appear, but may occur for a longer period in children. Children may be infectious for more than 10 days, and young children may shed virus for less than 6 days prior to appearance of symptoms. Frank c.s. cultured various respiratory viruses weekly or biweekly and during acute respiratory illness as part of the Houston Family Study. Influenza A was proven in 41 children and Influenza B in 14. Influenza A cultures were positive from 6 days prior to onset of symptoms through day 14 after onset of symptoms. 3 Children produced positive cultures in week 2 after onset of symptoms (a 10% shedding frequency early in week 2). Influenza B cultures were positive from the day of onset of symptoms though day 14 after onset of symptoms (shedding frequency of 45% early in week 2 and 23% later that week) [Frank 1981]. While most symptoms last for only 3 or 4 days, some symptoms, such as cough and malaise, may persist for a week or longer. Type A and type B influenza infections manifest similar symptoms, which makes it difficult to distinguish between the 2 types. The placebo group in the Hayden c.s. study on oseltamivir (n=13 healthy adults 18-40) mean duration of shedding was 107 h (83-131) [Hayden FG 1999]. Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza. MMWR. 2004;53(RR06):1-40. Kavet J. A perspective on the significance of pandemic influenza. Am J Public Health. 1977;67:1063-70. Frank AL, Taber LH, Wells CR et al. Patterns of shedding myxoviruses and paramyxoviruses in children. J Infect Dis 1981;144:433-41. Hayden FG, Treanor JJ, Scott Fritz R et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza. JAMA 1999;282:1240-6. ACIP. MMWR. 2004,53(RR06)1-40. Kavet J. Am J Public Health. 1977;67:1063-70. Frank AL et al. J Infect Dis. 1981;144:433-441. Hayden FG et al. JAMA. 1999;282:1240-6.

Clinical Manifestations by Age Group Influenza Sign/Symptom Children Adults Elderly Cough (nonproductive) ++ ++++ +++ Fever + Myalgia Headache Malaise Sore throat Rhinitis/nasal congestion Abdominal pain/diarrhea – Nausea/vomiting Clinical Manifestations by Age Group In general, influenza may include these symptoms [http://www.cdc.gov/flu/protect/sick.htm; http://www.cdc.gov/nip/flu_or_flulike.htm]: High fever Headache Tiredness/weakness (can be extreme) Nonproductive cough Sore throat Runny nose Body or muscle aches Diarrhea and vomiting also can occur, but are more common in children Common physical signs of influenza infection include the appearance of being ill, skin that is hot and moist to the touch, flushed face, hyperemic mucus membranes, and clear nasal discharge [Cox 1999]. This slide identifies the symptoms that occur most or least frequently in persons of varying age with influenza and, therefore, that have the more or less value in diagnosing influenza infection in specific age groups. Monto et al reported that, in patients aged 12 years and older, the best multivariate predictors of influenza during confirmed community influenza outbreaks are cough and fever, with a significant positive predictive value of 79% (P<.001) [Monto 2000]. In children, gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea are frequently observed [Cox 1999]. Febrile convulsions are the initial sign of influenza infection in many children [Cox 1999]. Adults and adolescents may have abrupt onset of fever and chills with headache, sore throat, myalgia, malaise, anorexia, and a dry cough [Cox 1999]. Elderly patients may not develop a low-grade fever, thereby its absence does not rule out the flu. However, shortness of breath is a common presenting symptoms in elderly persons [Cox 1999]. www.cdc.gov/flu/protect/sick.htm www.cdc.gov/nip/flu_or_flulike.htm Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting influenza infection Arch Intern Med. 2000;160:3243-3247. Cox NJ, Subbarao K. Influenza. Lancet. 1999;354:1277-1282. Monto AS et al. Arch Intern Med. 2000;160:3243-47. Cox NJ et al. Lancet. 1999;354:1277-82. ++++ Most frequent sign/symptom; + Least frequent; – Infrequent

Influenza Manifestations & Complications Children Adults Frequent Sinusitis, bronchitis, bronchiolitis, pneumonia, croup, acute otitis media Primary viral pneumonia, secondary bacterial pneumonia, sinusitis, bronchitis Rare Encephalopathy, myositis, rhabdomyolysis, myocarditis, pericarditis, Reye syndrome, sepsis-like syndrome Myositis, rhabdomyolysis, myocarditis, pericarditis Exacerbations of underlying disease Cardiovascular, diabetes, asthma, cystic fibrosis Cardiovascular, diabetes, asthma, COPD Influenza Manifestations & Complications Loughlin J, Napalkov P, Wegmueller Y et al. A study of influenza and influenza-related complications among children in a large US health insurance plan database. Pharmacoeconomics 2003;21:273-83. Treanor JJ. Influenza virus. In: mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennetts Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill Livingstone; 2000:1823-49. ACIP. MMWR 2004;53(RR06):1-40. Loughlin J et al. Pharmocoeconomics. 2003;21:273-283. Treanor JJ. Influenza virus. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill Livingstone; 2000:1823-1849. ACIP. MMWR 2004;53 (RR06):1-40.

Patient Groups at Risk for Complications Increased risk of influenza complications among: Children <2 years Children and adolescents receiving long-term aspirin therapy Children and adults with chronic conditions Chronic pulmonary, metabolic, or CV disorders Renal dysfunction Hemoglobinopathies Immunosuppression, including HIV infection Pregnant women Residents of chronic care facilities Persons 65 years old Patient Groups at Risk for Complications  Per the CDC, persons at highest risk for influenza complications includes: Adults aged 65 years and older. Adults and children who are residents of nursing homes or other chronic care facilities because of chronic medical conditions. Adults and children with chronic pulmonary or cardiovascular disorders, including asthma. Adults and children with chronic metabolic disorders, including diabetes mellitus, renal dysfunction, and hemoglobinopathies, or immunosuppression (from medications or HIV infection). Women who will be in the second or third trimester of pregnancy during the influenza season because of the increased incidence of cardiopulmonary complications among pregnant women. Children/adolescents (6 months to 18 years) who are receiving chronic aspirin therapy and therefore are at risk for developed Reye’s syndrome following influenza infection. Children aged 6 months to 23 months because they are at increased risk for influenza-related hospitalization. These groups of patients are the primary targets to receive influenza immunization each year. Note that in the 2004 recommendations, healthy children 6 to 23 months of age are added as a group recommended for influenza vaccination.   Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza. MMWR. 2004;53(RR06):1-40. ACIP. MMWR. 2004;53(RR06):1-40.

Complications Non-Pulmonary: Pulmonary: Myositis Cardiac complications Toxic shock syndrome Guillain-Barré syndrome Transverse myelitis Encephalitis Reye syndrome Pulmonary: Primary influenza viral pneumonia Secondary bacterial pneumonia Croup Asthma, COPD,* bronchitis, cystic fibrosis exacerbation Increased severity of influenza in HIV patients * Chronic obstructive pulmonary disease

Influenza Diagnostic Testing Rapid Antigen (EIA) NP aspirates and swabs only Detects Influenza A/B nucleoproteins 1 hour TAT, batched on the hour Viral Culture (Shell Vial) Upper and lower respiratory specimens Detects Influenza A/B, Parainfluenza 1/2/3, Adenovirus and RSV 24-72 hour TAT Real-time RT-PCR Detects Influenza A matrix gene Influenza B validation in progress 24 hour TAT Increase in Sensitivity

INFLUENZA VACCINE: INDICATIONS Healthcare providers Persons >65 years of age Residents of extended care facilities of any age Adults and children with chronic cardio-respiratory illnesses Adults and children with chronic metabolic disorders, immune deficiencies, or immunosuppression Children (6 mo–18 yr) receiving aspirin (risk for Reye syndrome) Out-of-home caregivers and household contacts of children <6 mo Women who will be pregnant during influenza season Children aged 6-23 months People who want to avoid influenza

INFLUENZA VACCINE (Inactivated): CONTRAINDICATIONS Hypersensitivity to eggs or vaccine components Acute febrile illness (postpone vaccine) Active neurologic disorder characterized by changing neurologic findings. Previous Guillain-Barre or other neurologic illnesses related to previously administered vaccine Pregnancy or breastfeeding NOT a contraindication

Avrupa Birliği e-cdc

e- cdc Türkiye

Sağlık Bakanlığı Açıklaması Aralık son haftasından 12.01.2016 a kadar 2905 solunum semptomu olan hastadan alınan örneklerden 463’ünde İnfluenza A H1N1 virüsü tespit edildi 1261 örnekte bir solunum yolu virüsü tespit edilmiştir. Bunlardan 595’inde Rhino, RSV gibi diğer solunum yolu virüsleri, 463’ünde İnfluenza A H1N1, 134’ünde İnfluenza A H3N2 ve 38’inde İnfluenza B

REPORTING

2015-2016 Mevsimsel Grip Sezonu Verileri

14 Aralık 2009 Ülkemizde pandemik influenzadan 415 kişi öldü. 27’si gebe/lohusa

Pandemik  Gribe bağlı ölümlerin haftalara göre dağılımı, 19 Ekim-6 Aralık 2009, Türkiye (n = 320)

2010-2011 Aşılaması Ağustos 2010 da başlandı A (H3N2) B İçerik Pandemic H1N1 aşısı Mevsimsel Influenza aşısı İçerik A (H1N1) 2009 A (H3N2) B İlk dalga 2. dalga Olası salgın 2009 2010 H1N1 H3N2 B H1N1

TUS 2012 Ülkemizde bildirimi zorunlu olan bulaşıcı hastalıklardan bazıları sadece seçilmiş sağlık merkezlerinden bildirilmektedir. Aşağıdakilerden hangisi bu grupta yer alan hastalıklardan biridir? A) Sıtma B) Difteri C) Tifüs D) Tüberküloz E) İnfluenza

TUS 2012 Ülkemizde bildirimi zorunlu olan bulaşıcı hastalıklardan bazıları sadece seçilmiş sağlık merkezlerinden bildirilmektedir. Aşağıdakilerden hangisi bu grupta yer alan hastalıklardan biridir? A) Sıtma B) Difteri C) Tifüs D) Tüberküloz E) İnfluenza

TUS 2012 I. 38°C’den fazla ateş II. 3 yaşından küçük hasta III. Ağrısız servikal lenfadenopati IV. Konjunktivit V.  Eksüdatif tonsillofarenjit Akut tonsillofarenjiti olan bir hastada yukarıdaki bulgulardan hangisinin varlığı, etkenin A grubu beta-hemolitik streptokok olma olasılığını güçlendirir? A) | ve III   B) l ve V C) I, ll ve lll   D) II, IIl ve lV E) II. IIl ve V

TUS 2012 I. 38°C’den fazla ateş II. 3 yaşından küçük hasta III. Ağrısız servikal lenfadenopati IV. Konjunktivit V.  Eksüdatif tonsillofarenjit Akut tonsillofarenjiti olan bir hastada yukarıdaki bulgulardan hangisinin varlığı, etkenin A grubu beta-hemolitik streptokok olma olasılığını güçlendirir? A) | ve III   B) l ve V C) I, ll ve lll   D) II, IIl ve lV E) II. IIl ve V

TUS 2014 Tonsillofarenjit sonrası tortikollis,ateş? – retrofaringeal apse