Acute bacterial rhinosinusitis in children: Clinical features and diagnosis INTRODUCTION Acute rhinosinusitis is an illness that results from

m infection of one or more of the paranasal sinuses. A viral infection associated with the common cold is the most frequent etiology of acute rhinosinusitis, more properly called viral rhinosinusitis. (See "The common cold in children: Clinical features and diagnosis" and "The common cold in children: Treatment and prevention".) Uncomplicated viral rhinosinusitis usually resolves without treatment in 7 to 10 days. Although acute bacterial rhinosinusitis (ABRS) also may resolve without treatment, treatment with antibiotics hastens recovery [1,2]. It is important to distinguish between uncomplicated viral rhinosinusitis and ABRS to prevent unnecessary use of antibiotics (table 1). The clinical features and diagnosis of ABRS in children will be discussed here. The microbiology and treatment of ABRS in children and acute sinusitis and rhinosinusitis in adults are discussed separately. (See "Acute bacterial rhinosinusitis in children: Microbiology and treatment" and "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis" and "Acute sinusitis and rhinosinusitis in adults: Treatment".) ANATOMY The paranasal sinuses develop as outpouchings of the nasal cavity (figure 1) [3]. The onset and duration of development of the paranasal sinuses vary depending upon the location, as described below. Development of the paranasal sinuses may not be fully completed until 20 years of age; however, by 12 years of age, the nasal cavity and paranasal sinuses in most individuals have nearly reached adult proportions [4].

The maxillary sinuses are present at birth and expand rapidly by four years of age [4]. Ciliary activity is necessary for drainage of secretions from the maxillary sinus into the nose because the ostia are located high on the medial walls of the maxillary sinus [5]. The ethmoid sinuses are present at birth; they are comprised of a collection of tiny air cells, each with its own opening into the nose [4]. The sphenoid sinuses, which begin to develop during the first two years of life, are typically pneumatized by five years of age, and attain their permanent size by 12 years [4]. Development of the frontal sinuses is variable [3]. By six to eight years of age, the frontal sinuses can be distinguished radiographically from the ethmoid sinuses [5], but they do not complete their development for another 8 to 10 years. Between 1 and 4 percent of adults have agenesis of the frontal sinuses, 80 percent have bilateral frontal sinuses, and the remainder has unilateral frontal sinus hypoplasia [3].

DEFINITIONS Sinusitis is inflammation of the mucosal lining of one or more of the paranasal sinuses [3]. The terms sinusitis and rhinosinusitis often are used interchangeably because inflammation of the paranasal sinuses is almost always accompanied by inflammation of the nasal mucosa [6].

Inflammation of the sinuses is common during upper respiratory infection (URI) but usually resolves spontaneously. Acute bacterial rhinosinusitis (ABRS) occurs when there is secondary bacterial infection of the sinuses [3]. ABRS has been classified according to duration and recurrence as follows [7]:

Acute symptoms completely resolve in <30 days Subacute symptoms completely resolve in 30 and <90 days Recurrent acute at least three episodes of <30 days duration separated by intervals of 10 days without symptoms in a six-month period, or at least four such episodes in a 12-month period; individual episodes respond briskly to antibiotic therapy

Chronic sinusitis is defined by episodes of inflammation of the paranasal sinuses that last >90 days, during which patients have persistent symptoms (cough, rhinorrhea, nasal obstruction). Chronic rhinosinusitis may be related to noninfectious conditions such as allergy, cystic fibrosis, ciliary dyskinesia, gastroesophageal reflux, or exposure to environmental pollutants [8,9]. Chronic rhinosinusitis is discussed separately. (See "Clinical manifestations, pathophysiology, and diagnosis of chronic rhinosinusitis" and "Management of chronic rhinosinusitis" and "Microbiology and antibiotic management of chronic rhinosinusitis".) EPIDEMIOLOGY Acute bacterial rhinosinusitis (ABRS) is a common problem in children. It is estimated that approximately 5 to 7 percent of viral upper respiratory infections (URI) in children are complicated by the development of a secondary bacterial rhinosinusitis [2,10]. These proportions translate into a large number of infected individuals and substantial medical expenditures. PATHOGENESIS The paranasal sinuses are usually sterile [11-13]. However, because the membranes that line the nose are continuous with the membranes that line the sinus cavities, the paranasal sinuses may be contaminated with bacteria that colonize the nasal mucosa and nasopharynx. The contaminating bacteria are typically removed by mucociliary clearance [3]. When mucociliary clearance is altered (eg, by conditions that damage the ciliary epithelium or affect the number or function of cilia, the production or viscosity of mucous, or the patency of the ostia), the sinuses may be inoculated with large numbers of microorganisms, and infection may develop. PREDISPOSING FACTORS Viral upper respiratory infection (URI) is the most important risk factor for the development of acute bacterial rhinosinusitis (ABRS) [14]. The risk of viral URI is increased in children who attend day care [15]. Allergic rhinitis is another important risk factor for ABRS [16-18]. URI and allergic rhinitis contribute to the development of ABRS through mucosal congestion and possibly by depressing the local and systemic immune response [19-21]. The epidemiology and clinical manifestations of viral URI and allergic rhinitis are discussed separately. (See "The common cold in children: Clinical features and diagnosis" and "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis" and "Epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections".)

Less common predisposing factors to ABRS include [3]:

Anatomic obstruction (eg, nasal septal deformities; craniofacial anomalies; adenoidal hypertrophy; or nasal foreign bodies, masses, or polyps. The presence of nasal polyps should prompt evaluation for possible cystic fibrosis and allergic diatheses) [8]. (See "Etiologies of nasal symptoms: An overview" and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Sinus disease' and "Clinical manifestations, pathophysiology, and diagnosis of chronic rhinosinusitis", section on 'CRS with nasal polyposis'.) Mucosal irritants (eg, dry air, tobacco smoke, chlorinated water). Sudden changes in atmospheric pressure (eg, descent in an airplane) [20].

CLINICAL FEATURES Symptoms and signs The clinical and radiographic manifestations of acute bacterial rhinosinusitis (ABRS) in children are similar to those of viral upper respiratory infection (URI) [22]. The clinical course, particularly the persistence and severity of symptoms, helps to differentiate between uncomplicated viral URI and ABRS [6,7,23]. (See 'Clinical course' below.) In a small study in which the diagnosis of ABRS was confirmed by culture of the sinus aspirate, the frequency of clinical findings was as follows [23]:

Cough 24 of 30 (chief complaint in 8) Nasal symptoms 23 of 30 (chief complaint in 10) Fever 19 of 30 children (not a chief complaint) Headache 10 of 30 children (chief complaint in 8) Facial pain and swelling 9 of 30 children (chief complaint in 2) Sore throat - 7 of 30 children (chief complaint in 1) Halitosis 15 of 30 children (not a chief complaint)

Cough Cough (wet or dry) is an important symptom in ABRS. The cough must be present during the day, but is often described as worse at night [6,7]. Nocturnal cough as a single persistent symptom is nonspecific, and more suggestive of postnasal drip or reactive airways disease [24]. The cough becomes more prominent with increasing duration of illness [3]. Nasal symptoms Nasal symptoms of ABRS include anterior or postnasal discharge, obstruction, and/or congestion. The nasal discharge may be of any quality: watery, serous, or purulent. Postnasal discharge may cause vomiting. On examination, there may be mild erythema and swelling of the nasal turbinates with mucopurulent anterior nasal discharge. Drainage from the posterior ethmoids may lead to purulent material in the posterior pharynx.

Fever Fever is a variable symptom of ABRS and may occur in association with complications. Temperature 39C (102.2F) for at least three consecutive days is a component of the severe presentation of ABRS. Fever that occurs in uncomplicated viral URI usually resolves after two days (figure 2) [25]. (See 'Acute bacterial rhinosinusitis' below.) Other findings Complaints of headache and facial pain are also variable; they are less common in young children [23,26]. Sinus tenderness (rare in young children) may be elicited with percussion of the upper molars or percussion or application of direct pressure over the body of the frontal or maxillary sinuses [27,28]. Some children may complain of sore throat or have bad breath, but these are not usually the symptoms that lead to clinical presentation [23]. Postnasal discharge may cause vomiting. Clinical course Cough, nasal symptoms, and sore throat may occur with both uncomplicated viral upper respiratory infection (URI) and acute bacterial rhinosinusitis (ABRS). The clinical course helps to differentiate the two clinical syndromes [6,7,23]. Uncomplicated URI The course of most uncomplicated viral URIs is 7 to 10 days (figure 2) [25]. The patient may continue to have symptoms on the 10th day, but almost always the respiratory symptoms have begun to improve after peaking in severity on days three to six. Most patients with uncomplicated viral URIs are afebrile. When fever occurs, it tends to do so early in the illness, with other constitutional symptoms (eg, headache, myalgias) [25,29]. The fever and constitutional symptoms typically resolve in the first 24 to 48 hours when the respiratory symptoms become more prominent. The nasal discharge generally begins as clear and watery, but the quality may change during the course of illness. Most typically, the nasal discharge becomes thicker and more mucoid and may become purulent (thick, colored, and opaque) for several days, after which the changes reversethe purulent discharge becomes more mucoid, and then clear or simply dries. The transition from clear to purulent to clear again occurs without antimicrobial therapy. It is important to help parents of a child who has had URI symptoms for less than 10 days or has thick, opaque nasal discharge to understand the difference between an URI and acute bacterial sinusitis (table 1). It may be helpful to explain to them:

Most children with an uncomplicated viral URI get better on their own (only 5 to 7 percent of URIs are complicated by ABRS) (see 'Epidemiology' above) Antibiotics will provide no benefit for a child with an uncomplicated viral URI and may be associated with adverse effects (eg, the development of resistant pathogens, diarrhea, etc)

Acute bacterial rhinosinusitis When viral URI is complicated by ABRS, there are three potential clinical presentations [6,7,23,30-32]:

Persistent symptoms The most common clinical presentation is onset with persistent symptoms [6,7,33]. The cardinal clinical features are nasal symptoms (anterior or posterior nasal discharge, obstruction, and/or congestion), cough, or both that persist for more than 10 but less than 30 days and are not improving [7]. This last qualifier is extremely important. Some individuals with uncomplicated viral URI have residual respiratory symptoms at the 10-day mark. To be considered a sign of ABRS, these respiratory symptoms must be persistent without improvement. The nasal discharge in patients with persistent symptoms may be of any quality: thick or thin, serous, mucoid, or purulent. The cough, which may be wet or dry, must be present during the daytime, although it is often described to be worse at night [6,7]. Severe symptoms ABRS can manifest with severe symptoms at onset. In children, this presentation is defined by a combination of temperature 39C (102.2F), concurrent purulent nasal discharge for at least three to four consecutive days, and ill-appearance [6,7]. Persistent high fever for at least three to four days distinguishes this presentation from an uncomplicated viral URI (in which fever is usually low-grade and present for less than 48 hours (figure 2) [25]). Worsening symptoms ABRS also can present with worsening symptoms (ie, a biphasic illness or "double sickening") [30,34]. In this presentation, the initial illness is similar to an uncomplicated viral URI from which the patient seems to be recovering. However, on the sixth or seventh day, the patient becomes acutely and substantially worse with an increase in respiratory symptoms (exacerbation of nasal discharge or nasal congestion or daytime cough), a new onset of severe headache or fever, or a recurrence of fever if it had been present at the onset of illness.

Complications Children with untreated bacterial rhinosinusitis are at risk for serious complications, which may be the presenting manifestation. Complications may result from orbital or intracranial extension. The exact rate of complications of ABRS is unknown, but they are estimated to occur in approximately 5 percent of patients hospitalized for rhinosinusitis [35,36]. Findings that should prompt consideration of intracranial extension include [37,38]:

The combination of periorbital/orbital swelling with persistent headache and vomiting Vomiting and headache that requires hospital admission, particularly in older children Altered level of consciousness Focal neurologic deficits Signs of meningeal irritation (eg, stiff neck)

Clinical manifestations specific to orbital and intracranial complications of rhinosinusitis are listed below (table 2) [3,39-43]:

Preseptal (periorbital) cellulitis Mild complication characterized by swelling and erythema of the lids and periorbital area; there is no proptosis or limitation of eye movement (see "Preseptal cellulitis") Orbital cellulitis Pain with eye movement, conjunctival swelling (chemosis), proptosis, limitation of eye movements (ophthalmoplegia), diplopia, vision loss (see "Orbital cellulitis") Septic cavernous sinus thrombosis Bilateral ptosis, proptosis, ophthalmoplegia, periorbital edema, headache, change in mental status (see "Septic dural sinus thrombosis") Meningitis Fever, headache, nuchal rigidity, change in mental status (see "Clinical features and diagnosis of acute bacterial meningitis in children older than one month of age", section on 'Clinical features') Osteomyelitis of the frontal bone associated with a subperiosteal abscess (Pott puffy tumor) Forehead or scalp swelling and tenderness, headache, photophobia, fever, vomiting, lethargy [44] Epidural abscess Papilledema, focal neurologic signs, headache, lethargy, nausea, vomiting (see "Epidural abscess", section on 'Intracranial epidural abscess') Subdural abscess Fever, severe headache, meningeal irritation, progressive neurologic deficits, seizures, signs of increased intracranial pressure (papilledema, vomiting) [45] Brain abscess Headache, neck stiffness, changes in mental status, vomiting, focal neurologic deficits, seizures, third and sixth cranial nerve deficits, papilledema (see "Pathogenesis, clinical manifestations, and diagnosis of brain abscess")

RADIOLOGIC FEATURES Plain radiographic or computed tomography (CT) findings that are compatible with sinus inflammation include (image 1) [8,46]:

Complete opacification Mucosal thickening of at least 4 mm Air-fluid level

However, abnormal imaging studies cannot distinguish between bacterial, viral, or other causes of sinus inflammation [6,47]. Observational studies performed with plain radiographs, CT, and magnetic resonance imaging have demonstrated frequent abnormalities in the paranasal sinuses of children [48-51] and adults with uncomplicated viral upper respiratory infection [52]. Imaging studies are not usually necessary in the evaluation of children with uncomplicated acute bacterial rhinosinusitis. When imaging studies are obtained, abnormal findings should be interpreted in the context of clinical findings [48,53]. Normal imaging studies (CT or plain film) of the paranasal sinuses in children with respiratory symptoms excludes rhinosinusitis. DIAGNOSIS

Uncomplicated ABRS The diagnosis of uncomplicated acute bacterial rhinosinusitis (ABRS) in children is usually made clinically. Imaging studies are not recommended for the diagnosis of uncomplicated ABRS [7]. We suggest that both of the following criteria be met for diagnosis [6,7,23,30-32]:

Symptoms and signs compatible with sinus inflammation (daytime cough, nasal symptoms, or both) (see 'Symptoms and signs' above), and Clinical course suggestive of bacterial rather than viral infection, including (see 'Acute bacterial rhinosinusitis' above): Symptoms present without improvement for >10 and <30 days, or Severe symptoms (ill appearance, temperature 39C (102.2F), and purulent nasal discharge for 3 consecutive days), or Worsening symptoms (increase in respiratory symptoms, new onset of severe headache or fever, or recurrence of fever after initial improvement)

We have chosen these relatively strict criteria to limit the diagnosis to patients most likely to benefit from antimicrobial therapy [6]. These criteria agree with those of a multidisciplinary consensus panel and clinical guidelines developed by the American Academy of Pediatrics and the Infectious Diseases Society of America [6,7,31,32]. They are supported by a study in which 77 percent of sinus aspirate cultures in children with persistent or severe symptoms grew 104 colony forming units of pathogenic bacteria [23]. Complicated ABRS Imaging studies are usually performed in children suspected to have orbital and intracranial complications of ABRS [7,24]. (See 'Complications' above.) It is recommended that children with potential orbital or intracranial complications of ABRS undergo contrast-enhanced computed tomography (CT) imaging of the orbits, sinuses, and brain [6,7,47]. Magnetic resonance imaging (MRI) is an alternative. Advantages of CT include increased availability, lack of need for sedation, and better demonstration of the sinus anatomy including the ostiomeatal complex and bony structures [6]. Advantages of MRI include improved ability to detect intracranial complications without exposure to radiation [54-56]. Microbiologic studies Microbiologic studies usually are not necessary for children with uncomplicated ABRS who improve as expected with antimicrobial therapy. (See "Acute bacterial rhinosinusitis in children: Microbiology and treatment", section on 'Response to therapy'.) However, attempts should be made to identify the pathogen in children who are toxicappearing (eg, lethargic, poorly perfused, cardiorespiratory compromise), those with orbital or intracranial complications, immunocompromised children, children with recurrent ABRS, and children who fail to respond to antimicrobial therapy [6]. Isolation of a pathogen and antimicrobial susceptibilities permit better targeting of antimicrobial therapy.

When identification of a pathogen is necessary in children, sinus aspiration is the preferred method for obtaining samples [6,57]. Sinus aspiration should be performed by a specialist [6]. Appropriate sterilization of the area of the nose through which the trocar will pass is essential to avoid contamination from the nasal cavity [58]. Aspirated fluid should be sent for Gram stain, aerobic and anaerobic culture, and antimicrobial susceptibility testing. Sinus aspiration with a culture that yields 104 colony-forming units/mL of a significant pathogen is the gold standard for diagnosis of ABRS [6,30,59,60]. Nasopharyngeal and/or throat cultures should not be used as a surrogate for sinus aspiration in children with suspected ABRS [8]. There is a poor correlation between nasopharyngeal and throat cultures and bacteria isolated from sinus aspirates [23]. Endoscopically obtained cultures of the middle meatus are of no use in children suspected to have ABRS because the meatus is colonized with Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, even when children are asymptomatic [61]. DIFFERENTIAL DIAGNOSIS The main consideration in the differential diagnosis of acute bacterial rhinosinusitis is the distinction between viral upper respiratory infection or allergic inflammation and secondary bacterial infection of the paranasal sinuses. The clinical course, particularly the persistence and severity of illness, is helpful in making this distinction. (See 'Clinical course' above.) Other possible diagnoses in children with persistent nasal symptoms and/or cough include [3,8]:

Allergic rhinitis with or without reactive airways disease. (See "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis", section on 'Clinical manifestations'.) Nasal foreign body (usually suspected on basis of foul odor and serosanguineous nasal drainage; may be apparent by direct observation). (See "Diagnosis and management of intranasal foreign bodies", section on 'Clinical manifestations'.) Enlarged or infected adenoids (associated symptoms and signs include enlarged adenoids, mouth breathing and snoring). (See "Etiologies of nasal symptoms: An overview", section on 'Enlarged adenoids'.) Structural abnormalities (eg, mucosal cyst of the maxillary antrum) may require imaging (computed tomography or magnetic resonance imaging) for diagnosis. Pertussis, particularly in the catarrhal stage. In pertussis, nasal symptoms usually resolve after one to two weeks, after which the severity of cough increases. The cough is typically paroxysmal and sometimes followed by an inspiratory whoop. (See "Clinical features and diagnosis of Bordetella pertussis infection in infants and children", section on 'Catarrhal'.)

SUMMARY AND RECOMMENDATIONS

Rhinosinusitis is inflammation of the mucosal lining of one or more of the paranasal sinuses. Such inflammation is common during viral upper respiratory infections

(URI), but usually resolves spontaneously. Acute bacterial rhinosinusitis (ABRS) occurs when there is secondary bacterial infection of the sinuses. (See 'Definitions' above.) Viral URI and allergic rhinitis are the most frequent predisposing factors for ABRS in children. Less common predisposing factors include anatomic obstruction, mucosal irritants, and sudden changes in atmospheric pressure. (See 'Predisposing factors' above.) The clinical features of ABRS include cough, nasal symptoms, fever, headache, facial pain and swelling, sore throat, and halitosis. (See 'Symptoms and signs' above.) The clinical course, particularly the persistence and severity of symptoms, helps to differentiate between the ABRS and viral URI. (See 'Clinical course' above.) Complications of ABRS, which may be the presenting manifestation, include preseptal (periorbital) and orbital cellulitis; septic cavernous sinus thrombosis; meningitis; osteomyelitis of the frontal bone; and epidural, subdural, or brain abscess (table 2). (See 'Complications' above.) The diagnosis of uncomplicated ABRS can be made clinically in children with symptoms and signs of sinus inflammation (ie, daytime cough, nasal symptoms, or both) and one of the following presentations (see 'Uncomplicated ABRS' above): Symptoms present without improvement for >10 and <30 days, or Severe symptoms (ie, ill appearance, temperature 39C [102.2F], and purulent nasal discharge for 3 consecutive days), or Worsening symptoms (ie, increase in respiratory symptoms, new onset of severe headache or fever, or recurrence of fever after initial improvement) Imaging studies are not necessary for children with uncomplicated ABRS. It is recommended that children with potential orbital or intracranial complications of ABRS undergo contrast-enhanced computed tomography (CT) imaging of the orbits, sinuses, and brain. Magnetic resonance imaging is an alternative. (See 'Complications' above and 'Radiologic features' above.) The differential diagnosis of ABRS includes uncomplicated viral URI, allergic or non-allergic rhinitis, nasal foreign body, enlarged or infected adenoids, mucosal cyst of the maxillary antrum, and the catarrhal stage of pertussis. These conditions can usually be distinguished from ABRS with history and examination, but imaging may be necessary to exclude structural abnormalities. (See 'Differential diagnosis' above.)

Pathogenesis of allergic rhinitis (rhinosinusitis) INTRODUCTION Allergic rhinitis is associated with a symptom complex characterized by paroxysms of sneezing, rhinorrhea, nasal obstruction, and itching of the eyes, nose, and palate. It is also frequently associated with postnasal drip, cough, irritability, and fatigue [13]. The pathogenesis of allergic rhinitis is presented in this topic review. The clinical manifestations, diagnosis, and treatment of this condition are discussed separately. (See "Clinical manifestations, pathophysiology, and diagnosis of chronic rhinosinusitis" and "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis" and "Pharmacotherapy of allergic rhinitis".) MECHANISMS OF UPPER AIRWAY ALLERGIC REACTIONS Upon exposure to an allergen, atopic individuals respond by producing allergen-specific IgE. These IgE antibodies bind to IgE receptors on mast cells in the respiratory mucosa and to basophils in the peripheral blood. When the same allergen is subsequently inhaled, the IgE antibodies are bridged on the cell surface by allergen, resulting in activation of the cell. Mast cells in the nasal tissues release preformed and granule-associated chemical mediators, which cause the symptoms of allergic rhinitis. Models of nasal allergen challenge in patients with allergic rhinitis have provided information about the pathogenesis of allergic rhinitis [4,5]. In this model study system, individuals known to have allergic rhinitis on exposure to a particular allergen are exposed to incremental doses of that allergen placed in the nose. The subsequent reaction is then monitored over time with nasal biopsies or washes. This allows direct quantitation of cell types by stains and surface markers and assessment of message for transcription or direct measurement of cellular cytokines and other mediators of inflammation [6]. Rhinomanometry, the measurement of nasal airway resistance, permits measurement of both resistance and airflow following allergen provocative challenge [7]. (See "Occupational rhinitis", section on 'Rhinomanometry techniques'.) Immunogenetics The expression of allergic diseases of the upper airways reflects an autosomal dominant pattern of inheritance with incomplete penetrance. This inheritance pattern is manifested as a propensity to respond to inhalant allergen exposure by producing high levels of allergen specific immunoglobulin E (IgE). The IgE response appears to be controlled by immune response genes located within the major histocompatibility complex (MHC) on chromosome 6. (See "Major histocompatibility complex (MHC) structure and function".) The immunologic mechanisms of atopy have been studied in murine models and in humans. These mechanisms involve the expression of a repertoire of responses associated with the Th2 type of T-helper lymphocyte. There are probably multiple genetic and environmental influences that lead to overexpression of Th2 type T cell responses relative to Th1 responses (figure 1). (See "The adaptive cellular immune response".)

Th2 lymphocytes and IgE production Sensitization to allergen is necessary to elicit an IgE response (figure 2). After inhalation, the allergen must first be internalized by antigen presenting cells, which include macrophages, CD1+ dendritic cells, B-lymphocytes, and possibly epithelial cells [8]. After allergen processing, peptide fragments of the allergen are exteriorized and presented with class II (MHC) molecules of host antigen presenting cells to CD4+ T lymphocytes. (See "The adaptive cellular immune response".) Nasal provocation with allergen has been associated with increases of such HLA-DR and HLA-DQ positive cells in the lamina propria and epithelium in allergic subjects [9]. These lymphocytes have receptors specific for the particular MHC peptide complex and this interaction results in the release of cytokines by the CD4+ cell. The switch from the Th1 phenotype to the Th2 phenotype is the crucial early event in allergic sensitization and is key to the development of allergic inflammation. Allergic inflammation conceptually derives from two major Th2 mediated pathways:

One involves the secretion of interleukin-4 (IL-4) and IL-13 that results in isotypic switching of B-lymphocytes to secrete IgE [10]. The second pathway involves the secretion of the eosinophil growth factor, IL-5 [11].

Thus, the release of IL-4, IL-5, and IL-13 are cardinal features of allergic inflammation. B-lymphocytes require two signals for isotypic switch to IgE. (See "Immunoglobulin genetics" and "Normal B and T lymphocyte development".) In the first signal, IL-4 or IL13 stimulate transcription at the Ce locus, the site of exons that encode the constant region of the IgE heavy chain [10,12]. (See "The biology of IgE".) Interaction of CD40 on the B cell membrane with CD40 ligand on the surface of T lymphocytes provides the second signal that activates genetic recombination in the functional IgE heavy chain [13]. IL-4 and IL-13 also up-regulate vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells promoting adhesion of inflammatory cell populations and facilitate their migration into areas of allergic inflammation. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".) In situ hybridization and/or antibody studies have demonstrated increased numbers of cells with messenger RNA for and/or expression of IL-3, IL-4, IL-5, IL-13, eotaxin, and GMCSF within the nasal mucosa after allergen provocation (picture 1) [4,6]. Interferon-gamma (IFN-gamma), a Th1 type cytokine that inhibits B-lymphocyte activation and IgE synthesis is absent. Il-12 and IL-18, major inducers of IFN-gamma, are also absent. Thus, atopy appears to be the result of a predisposition toward Th2 type responses, which results in the formation of large quantities of allergen specific IgE [4]. Mast cell activation After IgE antibodies specific for a certain allergen are synthesized and secreted, they bind to high-affinity receptors on mast cells (and basophils). When allergen is inhaled into the nose, it cross links these allergen specific cell bound IgE antibodies on the mast cell surface in a calcium dependent process, resulting in rapid

degranulation and mediator release. The mediators stimulate blood vessels, nerves, and glands to cause the clinical manifestations of allergic rhinitis and feed back to other elements of the immune system to perpetuate the process. The superficial nasal epithelium in patients with allergic rhinitis has 50-fold more basophilic cells (mast cells and basophils) per specimen than does epithelium from nonallergic subjects. Increased concentrations of mast cells are found near post capillary venules, where they increase vascular permeability; near sensory nerves, where they initiate the sneeze reflex; and near glands, where they facilitate secretion. Nasal mast cells are predominately located in the nasal lamina propria as connective tissue mast cells, although 15 percent are epithelial and called mucosal mast cells. Mucosal mast cells express tryptase without chymase and proliferate in allergic rhinitis under the influence of Th2 cytokines. (See "Mast cells: Development, identification, and physiologic roles".) Mast cell mediators are either preformed, associated with granules, formed during degranulation, or generated after transcription [14]. (See "Mast cell derived mediators".) Histamine Histamine is the most important preformed mediator in allergic rhinitis. Histamine reproduces all of the acute symptoms of allergic rhinitis when sprayed into the noses of normal volunteers. Histamine causes mucus secretion, vasodilatation leading to nasal congestion, increased vascular permeability leading to tissue edema, and sneezing through stimulation of sensory nerve fibers. Prostaglandins and leukotrienes The cross linking of IgE antibody on mast cells activates phospholipase A2 and releases arachidonic acid from the A2 position of cell membrane phospholipids. Mast cells then metabolize arachidonic acid either via the cyclooxygenase pathway to form prostaglandin and thromboxane mediators or via the lipoxygenase pathway to form leukotrienes. Prostaglandin D2 (PGD2), the sulfidopeptide leukotrienes LTC4, LTD4, and LTE4 are thus formed during degranulation. PGD2 is synthesized by mast cells, but not basophils, and appears to be more potent than histamine in causing nasal congestion. LTB4 is the most potent chemotactic factor yet described in humans [15]. Other mediators Platelet activating factor (PAF) and bradykinin (generated by the action of tryptase) are also formed during degranulation. PAF is a potent chemotactic factor, and the bradykinins are vasoactive. Cellular infiltration Once allergic reactions begin, mast cells amplify such reactions by releasing not only vasoactive agents, but also cytokines, including GM-CSF, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), IL-1 to IL6, and IL-13 [16-18]. Tissue eosinophilia is characteristic of allergic rhinitis [19]. It appears that mast cell derived cytokines promote further IgE production, mast cell and eosinophil growth, chemotaxis, and survival. As an example, IL-5, TNF-alpha, and IL-1 promote eosinophil movement by increasing the expression of adhesion receptors on endothelium. In turn, eosinophils secrete a plethora of cytokines including IL-3, IL-4, IL-5, IL-10, and GM-CSF which favor, among

others, Th2 cell proliferation and mast cell growth. Eosinophils also serve an autocrine function in these reactions by producing the cytokines IL-3, IL-5, and GM-CSF, which are important in hematopoiesis, differentiation, and survival of eosinophils themselves [20,21]. Eosinophils release oxygen radicals and proteins including eosinophil major basic protein, eosinophil cationic protein, and eosinophil peroxidases; these have been shown to be associated with nasal epithelial injury and desquamation, subepithelial fibrosis, and hyperresponsiveness [6,22]. As a result of mast cell and eosinophil activation in the allergic response, the following events occur in succession:

Vascular endothelial cell expression of adhesion molecules Adhesion of leukocytes to vascular endothelium Transendothelial migration

Chemotaxis and increased survival of eosinophils occur within areas of allergic inflammation. In addition to the families of adhesion molecules, chemokine molecules that affect the expression and function of adhesion molecules on endothelium and leukocytes are also expressed in these reactions. Increased numbers of cells positive for chemokines, such as RANTES, eotaxins, MCP-3, and MCP-4 are present in the mucosa after allergen challenge [4,23]. These chemokines further enhance the recruitment and activation of inflammatory cells possessing their cell surface receptors in allergic reactions [6]. Nitric oxide (NO), a vasodilator, is also produced in the nasal mucosa of patients with allergic rhinitis and may play a role in the production of nasal obstruction [24]. Nitric oxide synthetase is expressed by mast cells, neutrophils, and endothelial cells, among others. IMMEDIATE AND LATE NASAL REACTIONS Exposing the nasal mucosa to ragweed in ragweed sensitive subjects (nasal challenge) provokes the immediate onset of sneezing and nasal itching associated with significantly increased concentrations of inflammatory mediators. The time course of histamine concentration, symptoms (sneezing), and increases in nasal airway resistance are closely correlated (figure 3) [25,26]. Immediate Within seconds to minutes of allergen exposure, an immediate allergic response is observed, which peaks in 15 to 30 minutes [19]. Sneezing correlates with the appearance of measurable histamine, the kininogen product tosyl-L-arginine methyl ester (TAME esterase), and PGD2 in nasal washes. Increased levels of sulfidopeptide leukotrienes C4 and B4, tryptase, kinins, albumin, eosinophil major basic protein, and platelet activating factor are also present in nasal washes after allergen challenges [27]. The presence of histamine, tryptase, and prostaglandin D2 indicate the central role of the mast cell in the early response to allergen [26]. After about 30 minutes, PGD2 and histamine levels return to baseline, whereas TAME esterase concentrations remain elevated. Biopsy specimens of the nasal mucosa at this time show an increased number of degranulated mast cells. Late A late phase nasal allergic reaction develops in approximately 50 percent of patients with seasonal rhinitis, which peaks at 6 to 12 hours after nasal allergen challenge [19]. This secondary inflammatory response is thought to be important in establishing the

chronicity of the disorder [20]. During this later phase, symptoms may recur after a second release of mast cell mediators coincident with maximum mast cell cytokine production [26]. The late phase allergic reaction is associated with elevated levels of the same mediators noted in the immediate reaction, except that PGD2 is not detected. Thus, basophils appear to be partly responsible for such late phase reactions because histamine is generated by both mast cells and basophils, whereas only mast cells can produce PGD2. In support of this concept, marked basophil influx into the nasal mucosa has been noted 3 to 11 hours after allergen challenge [28]. Large numbers of neutrophils, mononuclear cells, and eosinophils also migrate into the nasal mucosa at this time. Increases in eosinophil cationic protein and other eosinophil products also become detectable in nasal secretions. After allergen challenge, lymphocytes remain the predominant cells in the nasal mucosa. These cells actively transcribe messages for IL-3, IL-4, IL-5, and GM-CSF and have increased expression of the IL-2 receptor. IL-1 through IL-5 and GM-CSF, among others, have been recovered from nasal washes after allergen challenge. ALTERATIONS OF NASAL PHYSIOLOGY Under normal conditions, the nose accounts for one-half to two-thirds of the resistance to airflow in the airway. It is lined by pseudostratified epithelium resting upon a basement membrane that separates it from deeper submucosal layers [19]. The submucosa contains mucous, seromucous, and serous glands. The small arteries, arterioles, and arteriovenous anastomoses determine regional blood flow. Capacitance vessels consisting of veins and cavernous sinusoids determine nasal patency. The cavernous sinusoids lie beneath the capillaries and venules, are most dense in the inferior and middle turbinates, and contain smooth muscle cells controlled by the sympathetic nervous system. Withdrawal of sympathetic tone, or to a lesser degree, cholinergic stimulation, causes this sinusoidal erectile tissue to become engorged. Cholinergic stimulation causes arterial dilation and promotes the passive diffusion of plasma protein into glands and active secretion by mucous glands in cells. The role of neurotransmitters may be important in the pathogenesis of allergic rhinitis. Novel neurotransmitters, including substance P, a chemical that increases vascular permeability, calcitonin gene related peptide, and vasointestinal peptide, have been detected in nasal secretions after nasal allergen challenge of patients with allergic rhinitis [11]. Capsaicin, which depletes sensory nerves of SP and CGRP, reduces symptoms induced by nasal allergen challenge [29]. Antidromic stimulation of sensory nerve fibers in the nose can release a variety of neurotransmitters, including substance P. Neurotransmitters also produce changes in regional blood flow and glandular secretion. INVOLVEMENT OF THE PARANASAL SINUSES There are data indicating that the inflammatory response noted in the mucosa of patients with allergic rhinitis is often present in the paranasal sinuses as well [6]. There is concomitant epithelial denudation, extracellular matrix deposition, and basement membrane disruption.

Acute bacterial rhinosinusitis in children: Microbiology and treatment Author Ellen R Wald, MD Section Editors Sheldon L Kaplan, MD Glenn C Isaacson, MD, FAAP Robert A Wood, MD Deputy Editor Mary M Torchia, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2013. | This topic last updated: Jul 24, 2013. INTRODUCTION Acute rhinosinusitis is a disease that results from infection of one or more of the paranasal sinuses. A viral infection associated with the common cold is the most frequent etiology of acute rhinosinusitis, more properly called viral rhinosinusitis. (See "The common cold in children: Clinical features and diagnosis" and "The common cold in children: Treatment and prevention".) Uncomplicated viral rhinosinusitis usually resolves without treatment in 7 to 10 days. Although untreated acute bacterial rhinosinusitis (ABRS) also may resolve without treatment, treatment with antibiotics hastens recovery [1,2]. It is important to distinguish between uncomplicated viral rhinosinusitis and ABRS to prevent unnecessary use of antibiotics (table 1). The microbiology and treatment of ABRS in children will be discussed here. The clinical features and diagnosis of ABRS in children and acute sinusitis and rhinosinusitis in adults are discussed separately. (See "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis" and "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis" and "Acute sinusitis and rhinosinusitis in adults: Treatment".) CLINICAL PRESENTATIONS The clinical presentation of acute bacterial rhinosinusitis in children is characterized by [3-8]:

Persistent symptoms (nasal discharge or cough or both) for >10 days without improvement, or Severe symptoms (onset with temperature of 39C [102.2F] and purulent nasal discharge for 3 consecutive days), or Worsening symptoms (respiratory symptoms that worsen after initial improvement) or onset of new fever or severe headache

(See "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Acute bacterial rhinosinusitis'.) MICROBIOLOGY

Common pathogens Streptococcus pneumoniae, Haemophilus influenzae (nontypeable), and Moraxella catarrhalis are the predominant causes of acute bacterial rhinosinusitis (ABRS) [9-11]. Culture of material aspirated from the sinus yielding 104 colony-forming units/mL of bacteria is the standard for determining the etiology of ABRS [12]. However, sinus aspiration is an invasive procedure that is not routinely performed in children with uncomplicated ABRS. Studies of the microbiology of ABRS in which sinus aspirates were obtained from children with uncomplicated ABRS were performed before the widespread development of antibiotic resistant S. pneumoniae [5]. However, because acute otitis media (AOM) and ABRS have similar pathogenesis and microbiology, data generated from cultures of middle-ear fluid obtained by tympanocentesis from children with AOM can be used as a surrogate for cultures of the paranasal sinuses [13,14]. Before the availability of pneumococcal conjugate vaccines (2000), the relative proportion of middle ear isolates in cases of AOM was 55:35:10 for S. pneumoniae, H. influenzae and M. catarrhalis, respectively. Studies of the microbiology of pediatric AOM after the pneumococcal conjugate vaccine was introduced into the childhood immunization schedule indicate that S. pneumoniae is isolated in approximately 45 percent of episodes in which an organism is cultured, H. influenzae (predominantly nontypeable H. influenzae) in about the same, and M. catarrhalis in the remainder [15,16]. There was a brief resurgence in the recovery of S. pneumoniae when penicillin-resistant serotype 19A emerged. However, this has resolved since initiation of immunization with the 13-valent pneumococcal conjugate vaccine (in 2010), which includes serotype 19A. A study in which tympanocentesis was performed in children with AOM during 2010 and 2011 indicates that nontypeable H. influenzae is currently the most frequent isolate in cases of AOM [17]. (See "Acute otitis media in children: Epidemiology, microbiology, clinical manifestations, and complications", section on 'Microbiology'.) Several studies have reported isolation of S. aureus from sinus aspirates (obtained endoscopically) or from cultures of the middle meatus in children (most of whom had chronic sinusitis) [18-20]. However, these studies must be interpreted with caution because of methodologic limitations (eg, unknown indication for obtaining culture, lack of quantification, and possibility of contamination from the nasal cavity) and because cultures of the middle meatus have not been established as a reliable surrogate for maxillary sinus aspirates in children [21]. Antimicrobial susceptibility The proportion of isolates of S. pneumoniae that are nonsusceptible to penicillin varies from community to community. Isolates obtained from surveillance centers nationwide indicate that 10 to 15 percent of upper respiratory tract isolates of S. pneumoniae are nonsusceptible to penicillin [22,23]. However, values as high as 50 to 60 percent have been reported in some areas [24,25]. Of the organisms that are resistant, approximately one-half are highly resistant to penicillin and the remaining onehalf are intermediate in resistance [22,23,25-28]. Between 10 and 42 percent of H. influenzae [25-28] and close to 100 percent of M. catarrhalis are likely to be betalactamase positive and nonsusceptible to amoxicillin. A study of middle ear isolates obtained from children with AOM during 2010-2011 found a decreasing recovery of S.

pneumoniae (including penicillin-resistant S. pneumoniae) and increasing recovery of betalactamase producing H. influenzae [17]. Unfortunately, there are scant data, even from tympanocentesis, upon which to estimate the relative prevalence of S. pneumoniae and beta-lactamase producing H. influenzae in cases of either acute otitis media or acute bacterial sinusitis [29]. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics".) Risks for antimicrobial resistance Risks for resistant pathogens include [4,30-33]:

Living in an area with high endemic rates (ie, 10 percent) of invasive penicillin non-susceptible S. pneumoniae Age <2 years Daycare attendance Antibiotic therapy within the past month Hospitalization within the past five days

INDICATIONS FOR REFERRAL Children with uncomplicated acute bacterial rhinosinusitis (ABRS) can usually be managed by their primary care provider. Consultation with a specialist (eg, infectious disease, otolaryngology, immunology) may be warranted in the following circumstances [4,34,35]:

Intracranial or orbital complications (see "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Complications') Need for sinus aspiration (see "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Microbiologic studies') Isolation of resistant or rare pathogens from sinus aspirate Diagnosed or suspected immunodeficiency Recurrent ABRS, particularly if it exacerbates underlying pulmonary conditions (eg, asthma)

EMPIRIC ANTIBIOTIC THERAPY General principles We suggest that children with a clinical presentation that is compatible with acute bacterial rhinosinusitis (ABRS) be treated with antimicrobial therapy (see 'Clinical presentations' above) [4]. In general, empiric antibiotic therapy should be initiated promptly; prompt initiation of therapy may shorten the duration of illness. However, for children with ten days of persistent symptoms that are neither severe nor worsening, some experts suggest observation for two to three days, with initiation of antimicrobial therapy for clinical worsening or failure to improve, as an option [3]. Our recommendations for treatment are largely consistent with those of the Infectious Diseases Society of America (2012) and the American Academy of Pediatrics (2013) [3,4]. Unfortunately, there have been no randomized, placebo-controlled trials of antibiotic treatment for ABRS that have used pre- and post-treatment quantitative sinus aspirate culture as the standard for diagnosis and cure. Studies that use clinical and/or radiologic criteria for diagnosis and outcome may underestimate the benefit of antibiotic therapy

because they are likely to include at least some patients with self-limited uncomplicated viral upper respiratory tract infection. Randomized trials evaluating antibiotics versus placebo for the treatment of ABRS in children have conflicting results [1,2,36]. In a meta-analysis of three trials including a total of 310 children [1,2,36], the rate of improvement or cure was greater among children treated with antibiotics than placebo (78.5 versus 59.7 percent, odds ratio 2.52, 95% CI 1.52-4.18) [4]. In the only study that was performed after the development of widespread antibiotic-resistant S. pneumoniae, treatment with amoxicillin-clavulanate was associated with increased rates of cure (50 versus 14 percent) and decreased rates of treatment failure (14 versus 68 percent) compared with placebo [2]. Adverse events, predominantly selflimited diarrhea, were more common in the treatment group (44 versus 14 percent), but only three patients in the treatment group discontinued therapy because of adverse effects. Outpatient therapy Most children with ABRS can be treated as outpatients. Those who are toxic-appearing (eg, lethargic, poorly perfused, with cardiorespiratory compromise) or have complications or suspected complications should be admitted for parenteral therapy [11]. (See 'Inpatient therapy' below.) Antibiotics that are used to treat ABRS must provide antibacterial coverage for S. pneumoniae, H. influenzae, and M. catarrhalis (see 'Microbiology' above). Additional factors in the choice of therapy include the severity of illness, risk of complications, likelihood of infection with a resistant organism, antimicrobial spectrum, acceptability, dosing convenience, and adverse effects [4,11]. We suggest amoxicillin-clavulanate as the first-line agent for the treatment of ABRS in children because of its spectrum of activity, effectiveness, and safety [2,4,29,37]. Less comprehensive alternatives include third-generation cephalosporins (eg, cefpodoxime and cefdinir) [38]. Levofloxacin may be used when there is no other safe and effective alternative (eg, in patients who have anaphylaxis with or are intolerant of beta-lactams) [39]. Levofloxacin typically remains active against multi-drug resistant pneumococci with high level resistance to penicillin or third-generation cephalosporins and is an option for treatment when patients have failed first-line therapy. Mild/moderate disease Mild/moderate ABRS is characterized by temperature <39C (102.2F) and lack of systemic signs or a clinical severity score <8 (table 2). For children with uncomplicated mild/moderate ABRS who have no risks for antibiotic resistance, we suggest empiric antimicrobial therapy with standard dose amoxicillinclavulanate rather than other oral antibiotics (eg, amoxicillin, fluoroquinolones, macrolides, trimethoprim-sulfamethoxazole, doxycycline, or second- or third-generation cephalosporins) (table 3) (see 'Risks for antimicrobial resistance' above) [4]:

Amoxicillin-clavulanate 45 mg/kg per day of the amoxicillin component orally in 2 divided doses

For children with uncomplicated mild/moderate ABRS who have one or more risks for antibiotic resistance, we suggest treatment with high-dose rather than standard-dose amoxicillin-clavulanate (table 3) (see 'Risks for antimicrobial resistance' above)

Amoxicillin-clavulanate 90 mg/kg per day of the amoxicillin component orally in two divided doses (maximum daily dose 4 g)

We suggest amoxicillin-clavulanate rather than amoxicillin because the addition of clavulanate improves coverage for ampicillin-resistant H. influenzae and M. catarrhalis. Beta-lactamase producing nontypeable H. influenzae is an increasingly important cause of respiratory tract infection, particularly in children with acute otitis media (the microbiology of which is similar to ABRS) since introduction of immunization the 13-valent pneumococcal conjugate vaccine) [4,15,24,26,29,40-42]. However, some experts suggest that amoxicillin may be used as initial therapy for mild/moderate disease [3]. They recommend amoxicillin 45 mg/kg per day orally divided in two doses for children without risk factors for antimicrobial resistance and amoxicillin 90 mg/kg per day orally divided in two doses for children with risk factors for antimicrobial resistance. (See 'Risks for antimicrobial resistance' above.) High-dose amoxicillin-clavulanate provides better coverage for penicillin nonsusceptible S. pneumoniae and ampicillin-resistant non-beta-lactamase producing H. influenzae than standard dose amoxicillin-clavulanate [24]. However, because of the slight increase in cost and side effects, we suggest that high-dose amoxicillin-clavulanate be reserved for children with severe disease or increased or unknown risk of antibiotic resistance (either penicillinnonsusceptible S. pneumoniae or beta-lactamase producing H. influenzae) [4]. (See 'Risks for antimicrobial resistance' above.) In a meta-analysis of randomized trials, fluoroquinolones provided no advantage over betalactam antibiotics in the treatment of ABRS in adults [43]. Although fluoroquinolones have a wider spectrum of activity, they are associated with more severe side effects than amoxicillin-clavulanate. In vitro studies have demonstrated high rates of resistance among the most common ABRS pathogens to macrolides, trimethoprim-sulfamethoxazole, and variable rates of resistance (especially penicillin non-susceptible S. pneumoniae) to secondand third-generation cephalosporins [24,40,41,44-46]. Severe disease or risk for severe disease Severe disease is characterized by temperature 39C (102.2F) and other systemic signs or a clinical severity score 8 (table 2). Children with immune compromising conditions (eg, human immunodeficiency virus) are at increased risk for severe disease [4]. For children with severe ABRS or risk for severe ABRS who are treated as outpatients, we suggest treatment with high-dose amoxicillin-clavulanate (table 3) [4].

Amoxicillin-clavulanate 90 mg/kg per day of the amoxicillin component orally in two divided doses (maximum daily dose 4 g)

We suggest high-dose rather than standard-dose amoxicillin-clavulanate for children with severe ABRS to provide coverage for penicillin-nonsusceptible S. pneumoniae in addition to ampicillin-resistant H. influenzae and M. catarrhalis [4]. (See 'Microbiology' above.) Less comprehensive alternative regimens include a third-generation cephalosporin such as cefpodoxime or cefdinir. The advanced generation cephalosporins have been considered less comprehensive because they fall short in covering penicillin-resistant S. pneumoniae. However, if penicillin-resistant S. pneumoniae are diminishing as causes of acute otitis media and acute bacterial sinusitis (since the introduction of immunization with the 13valent pneumococcal conjugate vaccine) this may be less of an issue [17]. Levofloxacin, which has a comprehensive spectrum, should be reserved for cases in which there are no alternative choices:

Cefpodoxime 10 mg/kg per day orally divided every 12 hours or Cefdinir 14 mg/kg per day orally divided every 12 or 24 hours, or Levofloxacin 10 to 20 mg/kg per day orally divided every 12 to 24 hours; levofloxacin should be reserved for cases in which there is no other safe and effective alternative [39].

Penicillin allergy Alternatives to amoxicillin-clavulanate for children with an allergy to penicillin depend upon the type of allergy (table 3). (See "Allergy to penicillins" and "Penicillin-allergic patients: Use of cephalosporins, carbapenems, and monobactams".)

For children with uncomplicated ABRS who have a severe type I allergy to penicillin, we suggest levofloxacin 10 to 20 mg/kg per day orally divided every 12 or 24 hours [4,39]. For children with uncomplicated ABRS who have a non-type I allergy to penicillin, we suggest therapy with a third-generation cephalosporin (eg, cefpodoxime or cefdinir): Cefpodoxime 10 mg/kg per day orally divided every 12 hours, or Cefdinir 14 mg/kg per day orally divided every 12 or 24 hours

Vomiting A single dose of ceftriaxone 50 mg/kg per day (maximum dose 2 g/day) intravenously or intramuscularly can be used in children with uncomplicated ABRS and vomiting that precludes administration of oral antibiotics [3,4]. Therapy with an oral antibiotic should be initiated 24 hours later, provided the vomiting has resolved. Inpatient therapy Indications for hospitalization and parenteral antibiotics include toxicappearance (eg, lethargic, poorly perfused, cardiorespiratory compromise), complications or suspected complications, and treatment failure with outpatient therapy (ie, high-dose amoxicillin-clavulanate, third-generation cephalosporin, or levofloxacin) [11]. (See "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Complications' and 'Treatment failure' below.) Sinus imaging with contrast-enhanced computed tomography should be performed in patients with symptoms or signs of intracranial or orbital complications. (See "Acute

bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Complications'.) Sinus aspiration (performed by a specialist) for Gram stain, aerobic and anaerobic culture, and antimicrobial susceptibility testing should be obtained in hospitalized children with complications or outpatient failure [4,47]. Isolation of a pathogen and antimicrobial susceptibilities enable better targeting of antimicrobial therapy. For children who were initially hospitalized for toxic appearance without complications or suspected complications, sinus aspiration may be deferred pending response to intravenous therapy [3]. (See "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Microbiologic studies'.) Empiric therapy for children hospitalized with ABRS should provide coverage for highly resistant S. pneumoniae and ampicillin-resistant H. influenzae and M. catarrhalis. The regimen should be adjusted based upon clinical response and culture results. For children hospitalized with ABRS, we suggest empiric antibiotic therapy with one of the following regimens (table 3) [4]:

Ampicillin-sulbactam 200 to 400 mg/kg per day intravenously (IV) divided every six hours (maximum 8 g ampicillin component per day), or Cefotaxime 100 to 200 mg/kg per day IV divided every six hours (maximum 8 g per day), or Ceftriaxone 100 mg/kg per day IV divided every 12 hours (maximum 2 g per day), or Levofloxacin 10 to 20 mg/kg per day IV divided every 12 to 24 hours (maximum 500 mg per day); levofloxacin should be reserved for cases in which there is no other safe and effective alternative [39].

These suggestions are based on in vitro susceptibilities. There are no studies comparing intravenous antibiotic regimens for the treatment of ABRS in children. RESPONSE TO THERAPY Improvement Most patients with acute bacterial rhinosinusitis (ABRS) who are treated with an appropriate antimicrobial agent respond within 48 to 72 hours with improvement of symptoms and general well-being [1,2]. We usually continue antimicrobial therapy for total of 10 days in children whose symptoms improve within three days of initial therapy [48]. (See 'Duration' below.) Treatment failure Treatment failure is defined by worsening within three days or failure to improve after three days of antimicrobial therapy [1,2]. Causes of treatment failure may include [3,4]:

Resistant pathogen (see 'Microbiology' above)

Complication (see "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Complications') Noninfectious etiology (eg, foreign body, structural abnormality) (see "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Differential diagnosis') Initial presentation of immune deficiency [49] (see "Approach to the child with recurrent infections")

MANAGEMENT OF TREATMENT FAILURE In outpatients For children with uncomplicated acute bacterial rhinosinusitis (ABRS) who are initially treated as outpatients and whose symptoms worsen after two to three days or fail to improve after three days of initial antimicrobial treatment, we suggest broadening antimicrobial coverage or switching to a different class of antibiotic. Potential regimens depend on what was used initially and might include:

Amoxicillin-clavulanate 90 mg/kg per day of the amoxicillin component orally in two divided doses (maximum daily dose 4 g) (for patients initially treated with lowdose amoxicillin or amoxicillin-clavulanate) Ceftriaxone 50 mg/kg per day intramuscularly for one to three days, followed by amoxicillin-clavulanate 90 mg/kg per day of the amoxicillin component to complete 10 to 14 days, or Cefpodoxime 10 mg/kg per day orally divided every 12 hours or Cefdinir 14 mg/kg per day orally divided every 12 or 24 hours, or Levofloxacin 10 to 20 mg/kg per day orally divided every 12 or 24 hours; levofloxacin should be reserved for cases in which there is no other safe and effective alternative [39].

Imaging and/or sinus aspiration may be indicated to confirm the diagnosis, evaluate complications, and tailor therapy, particularly for children whose symptoms have not improved or have worsened after three days of initial antibiotics and another three days of broadened coverage. (See "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Complicated ABRS' and "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Microbiologic studies'.) Hospital admission for a trial of intravenous therapy and/or consultation with a specialist (eg, infectious disease, otolaryngology) may be warranted for children with ABRS who fail to improve after second-line therapy. (See 'Inpatient therapy' above and 'Indications for referral' above.) In hospitalized patients Failure to improve or worsening in hospitalized children who are receiving empiric antibiotic therapy warrants additional evaluation, including [4]:

Contrast-enhanced computed tomography imaging (or magnetic resonance imaging) to exclude orbital and intracranial complications (if not performed previously). Quantitative sinus aspirate cultures if they were not obtained at the time of admission.

Antimicrobial therapy should be modified according to results of sinus aspirate cultures as soon as the results are available. If sinus aspirate cultures are unavailable or if no pathogens are isolated in an ill child who has not improved despite therapy with a third-generation cephalosporin, ampicillinsulbactam, or levofloxacin, the addition of vancomycin (to cover highly resistant S. pneumoniae and S. aureus) with or without metronidazole (to cover anaerobes) may be warranted [50].

Vancomycin 60 mg/kg per day IV divided every six hours (maximum 4 g/day) Metronidazole 30 mg/kg per day IV divided every six hours (maximum 4 g/day)

Consultation with an infectious disease specialist and/or otolaryngologist is suggested. DURATION The optimal duration of therapy for patients with acute bacterial rhinosinusitis (ABRS) has not been studied systematically. We consider 10 days adequate for children whose symptoms improve within three days of initial therapy [48]. For those who improve more slowly or who have required escalation of therapy, we continue antibiotic therapy for seven days after the patient becomes free of symptoms (ie, a minimum of 10 days) [3,51]. (See 'Response to therapy' above.) Guidelines from the Infectious Diseases Society of America suggest a 10- to 14-day course for the treatment of ABRS in children [4]. SYMPTOMATIC TREATMENT Theoretic therapies to improve sinus drainage in patients with acute bacterial rhinosinusitis (ABRS), include [3,52,53]:

Saline nasal irrigation Decongestants (topical or systemic) Antihistamines Intranasal corticosteroids Sinus aspiration

There are limited data regarding the efficacy of these therapies in children with ABRS [5355]. Topical saline We suggest topical saline as an adjunctive therapy for children with ABRS. Saline nose drops, saline nasal sprays, and/or saline nasal irrigation may help in preventing crust formation and liquefying sinus secretions. In a small randomized trial, nasal saline irrigation improved symptoms, quality of life scores, and peak expiratory flow rates in children with acute sinusitis [56]. Although the potential benefits for children are not well established by this single trial, topical saline is inexpensive and unlikely to be harmful or impede recovery.

Decongestants and antihistamines We do not suggest the use of decongestants or antihistamines in children with ABRS who do not have an underlying allergic component [3,52]. Although decongestants may reduce tissue edema, improve ostial drainage, and provide symptomatic relief [52], these benefits may be offset by increased viscosity of secretions, decreased blood flow to the nasal mucosa (potentially impeding delivery of antibiotics to the sinuses), and increased irritability in children. Antihistamines also can dry secretions and impair sinus drainage. In a randomized trial in which children with presumed ABRS were treated with amoxicillin and a combination decongestant-antihistamine or amoxicillin and placebo, symptoms improved in all children within three days of initiation of antibiotics [57]. Intranasal corticosteroids We do not suggest the use of intranasal corticosteroids in children with ABRS who do not have an underlying allergic component. Although nasal corticosteroids theoretically may decrease inflammation of the mucous membranes, which contributes to obstruction of the ostia and impaired mucociliary clearance [58], the benefits in randomized trials have been marginal and the trials have methodologic limitations (eg, varying inclusion criteria, inclusion of patients with and without allergies, varying outcome criteria) [3,59-61]. Sinus aspiration Sinus aspiration may be warranted for relief of intense headache or facial pain [47]. Sinus aspiration should be performed by a specialist. SUMMARY AND RECOMMENDATIONS

Clinical presentations compatible with a diagnosis of acute bacterial rhinosinusitis (ABRS) include (see 'Clinical presentations' above): Persistent symptoms (nasal discharge or cough or both) for >10 days without improvement, or Severe symptoms (onset with temperature of 39C [102.2F] and purulent nasal discharge for 3 consecutive days), or Worsening symptoms (respiratory symptoms that worsen or onset of fever or severe headache after initial improvement) Streptococcus pneumoniae, Haemophilus influenzae (nontypeable), and Moraxella catarrhalis are the predominant causes of uncomplicated ABRS in otherwise healthy children. The proportion of S. pneumoniae isolates nonsusceptible to penicillin varies from community to community. Approximately 10 to 42 percent of H. influenzae and more than 90 percent of M. catarrhalis respiratory tract isolates are beta-lactamase producing (ie, resistant to ampicillin). (See 'Microbiology' above.) We suggest that children with a clinical presentation compatible with ABRS be treated with antimicrobial therapy (Grade 2B). Empiric antibiotic therapy should be initiated as soon as possible. (See 'General principles' above.)

Most children with ABRS can be treated as outpatients. Those who are toxicappearing (eg, lethargic, poorly perfused, with cardiorespiratory compromise) or have complications or suspected complications should be admitted for parenteral therapy. (See 'Outpatient therapy' above and 'Inpatient therapy' above.) The choice of antibiotic is based upon the degree of severity of illness, recent exposure to antibiotics, and the likelihood of infection with resistant bacteria (table 3). We suggest amoxicillin-clavulanate rather than other oral antibiotics as the initial treatment for uncomplicated ABRS in children (Grade 2B). (See 'Outpatient therapy' above.) Treatment failure is defined by worsening after two to three days or failure to improve after three days of antimicrobial therapy. Causes of treatment failure may include a resistant pathogen, complication, noninfectious etiology (eg, foreign body), or immune deficiency. (See 'Treatment failure' above.) For children with uncomplicated ABRS who are initially treated as outpatients and whose symptoms worsen after two to three days or fail to improve after three days, we broaden antimicrobial coverage or switch to a different class of antibiotic (table 3). (See 'In outpatients' above.) We continue antibiotics for 10 days in children whose symptoms improve within three days of initial therapy. For children who respond more slowly, we continue antibiotics for seven days after symptoms resolve (a minimum of 10 days). (See 'Duration' above.) We suggest saline nose drops and/or saline nasal sprays for children with ABRS (Grade 2C). We suggest not using decongestants, antihistamines, or nasal corticosteroids (Grade 2B). (See 'Symptomatic treatment' above