James R. Bonner

Objective Allergic rhinitis (AR) is one of the most common diseases affecting adults. It is the most common chronic disease in children in the United States today and the fifth most common chronic disease in the United States overall. AR is estimated to affect nearly 1 in every 6 Americans and generates $2 to $5 billion in direct health expenditures annually. It can impair quality of life and, through loss of work and school attendance, is responsible for as much as $2 to $4 billion in lost productivity annually. Not surprisingly, myriad diagnostic tests and treatments are used in managing this disorder, yet there is considerable variation in their use. This clinical practice guideline was undertaken to optimize the care of patients with AR by addressing quality improvement opportunities through an evaluation of the available evidence and an assessment of the harm‐benefit balance of various diagnostic and management options. Purpose The primary purpose of this guideline is to address quality improvement opportunities for all clinicians, in any setting, who are likely to manage patients with AR as well as to optimize patient care, promote effective diagnosis and therapy, and reduce harmful or unnecessary variations in care. The guideline is intended to be applicable for both pediatric and adult patients with AR. Children under the age of 2 years were excluded from the clinical practice guideline because rhinitis in this population may be different than in older patients and is not informed by the same evidence base. The guideline is intended to focus on a limited number of quality improvement opportunities deemed most important by the working group and is not intended to be a comprehensive reference for diagnosing and managing AR. The recommendations outlined in the guideline are not intended to represent the standard of care for patient management, nor are the recommendations intended to limit treatment or care provided to individual patients. Action Statements The development group made a strong recommendation that clinicians recommend intranasal steroids for patients with a clinical diagnosis of AR whose symptoms affect their quality of life. The development group also made a strong recommendation that clinicians recommend oral second‐generation/less sedating antihistamines for patients with AR and primary complaints of sneezing and itching. The panel made the following recommendations : (1) Clinicians should make the clinical diagnosis of AR when patients present with a history and physical examination consistent with an allergic cause and 1 or more of the following symptoms: nasal congestion, runny nose, itchy nose, or sneezing. Findings of AR consistent with an allergic cause include, but are not limited to, clear rhinorrhea, nasal congestion, pale discoloration of the nasal mucosa, and red and watery eyes. (2) Clinicians should perform and interpret, or refer to a clinician who can perform and interpret, specific IgE (skin or blood) allergy testing for patients with a clinical diagnosis of AR who do not respond to empiric treatment, or when the diagnosis is uncertain, or when knowledge of the specific causative allergen is needed to target therapy. (3) Clinicians should assess patients with a clinical diagnosis of AR for, and document in the medical record, the presence of associated conditions such as asthma, atopic dermatitis, sleep‐disordered breathing, conjunctivitis, rhinosinusitis, and otitis media. (4) Clinicians should offer, or refer to a clinician who can offer, immunotherapy (sublingual or subcutaneous) for patients with AR who have inadequate response to symptoms with pharmacologic therapy with or without environmental controls. The panel recommended against (1) clinicians routinely performing sinonasal imaging in patients presenting with symptoms consistent with a diagnosis of AR and (2) clinicians offering oral leukotriene receptor antagonists as primary therapy for patients with AR. The panel group made the following options: (1) Clinicians may advise avoidance of known allergens or may advise environmental controls (ie, removal of pets; the use of air filtration systems, bed covers, and acaricides [chemical agents formulated to kill dust mites]) in patients with AR who have identified allergens that correlate with clinical symptoms. (2) Clinicians may offer intranasal antihistamines for patients with seasonal, perennial, or episodic AR. (3) Clinicians may offer combination pharmacologic therapy in patients with AR who have inadequate response to pharmacologic monotherapy. (4) Clinicians may offer, or refer to a surgeon who can offer, inferior turbinate reduction in patients with AR with nasal airway obstruction and enlarged inferior turbinates who have failed medical management. (5) Clinicians may offer acupuncture, or refer to a clinician who can offer acupuncture, for patients with AR who are interested in nonpharmacologic therapy. The development group provided no recommendation regarding the use of herbal therapy for patients with AR.

Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks.We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used.Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo.In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

The American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Allergic Rhinitis. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 recommendations developed address the evaluation of patients with allergic rhinitis, including performing and interpretation of diagnostic testing and assessment and documentation of chronic conditions and comorbidities. It will then focus on the recommendations to guide the evaluation and treatment of patients with allergic rhinitis, to determine the most appropriate interventions to improve symptoms and quality of life for patients with allergic rhinitis.

Fc alpha receptors (Fc alpha R), detected by the binding of IgA and by anti-Fc alpha R antibodies, were found to be differentially expressed on eosinophils and neutrophils. Neutrophils were the major granulocyte population expressing Fc alpha R, and they expressed much higher levels of Fc alpha R than eosinophils. The expression of Fc alpha R by eosinophils could be upregulated approximately threefold by Ca2+ ionophore treatment in a dose- and time-dependent manner. This effect, which was blocked by a chelating agent, was not duplicated by other cellular stimuli. Eosinophils in allergic individuals displayed enhanced Fc alpha R expression, whereas neutrophils did not. The Fc alpha R on eosinophils had a higher molecular mass (70-100 kD) than those identified on neutrophils (55-75 kD). However, removal of N-linked carbohydrates from Fc alpha R of eosinophils and neutrophils revealed a major protein core of 32 kD for both cell types. The data indicate that expression of Fc alpha R molecules with a characteristic glycosylation pattern is upregulated on eosinophils in allergic individuals.

Quantitative bacteriology was performed on specimens collected by protected catheter fiberoptic bronchoscopy from 172 patients. Of the patients who had pneumonia, 75 of 78 (96%) had one or more species present at greater than or equal to 10(3) CFU/ml, whereas 2 of 35 (6%) control patients had organisms present in that quantity. In addition, 66% of the control specimens yielded no isolates by this technique. All of the 11 patients with bronchitis had greater than or equal to 10(3) CFU/ml. Quantitative bacteriology revealed high levels of colonization in patients without infection and endobronchial structural disease. The data suggest that bacterial counts of greater than or equal to 10(3) CFU/ml in suspended secretions collected with a protected catheter brush were diagnostic of the bacteriological etiology of lower respiratory tract infections in patients without endobronchial structural abnormalities.

• The ongoing epidemic of acquired immune deficiency syndrome (AIDS) has affected homosexual men, intravenous (IV) drug abusers, Haitians, hemophiliacs, and others. Defects in cell-mediated immunity place these patients at risk for opportunistic infections. We recently saw three men from Alabama with disseminated infection due to<i>Histoplasma capsulatum</i>. Two of these men were homosexual and the other was an IV drug abuser. These three patients had evidence of depressed cellular immunity consistent with a diagnosis of AIDS. Infection caused by organisms indigenous to certain geographic areas of the United States may become more common in patients with AIDS as the epidemic continues. (<i>Arch Intern Med</i>1984;144:2178-2181)

Fever in a transplant recipient is an important sign of graft rejection or infection. Rarely, fever may result from an immunosuppressive agent used to prevent graft rejection. A case of fever, rigors, arthralgias, and myalgias is reported in a cardiac transplant recipient in whom azathioprine therapy was recently begun. These findings resolved on discontinuation of the azathioprine, recurred on rechallenge, and were most consistent with a hypersensitivity reaction. The clinical spectrum of reported azathioprine hypersensitivity reactions is reviewed.

Medically and economically asthma is an extremely important disease that affects about 4 per cent of the United States population every year. Most cases require treatment and many individuals are forced to limit their activities. Asthma is most prevalent in childhood and among older adults and the disease can begin or remit at any age. There is an unexplained predominance of boys among childhood asthmatics. Studies involving skin tests, bronchial challenges, aerometric sampling, and clinical examination have established allergy as important in the etiology of both adult-onset and childhood-onset asthma. Allergen sensitivity is particularly important in childhood-onset disease. The efficacy of allergy immunotherapy in the treatment of asthma is not well established. Seasonal excerbations of asthma suggest sensitivity to pollens, molds, or dusts but may also occur in individuals with nonallergic asthma and may be related to climatic conditions or outbreaks of respiratory infection. Asthma patients often have a history of allergic rhinitis or eczema and these conditions are also frequent in the families of asthmatics. These atopic diseases usually occur at the same time and allergic rhinitis in children should not be considered a harbinger of asthma. Asthmatic attacks are frequently initiated by viral infections, and asthmatic patients appear to have an increased susceptibility to viruses. Bacterial infections are not frequently associated with asthmatic attacks, and the routine use of antibiotics for such episodes is not warranted. Breast-feeding of infants appears to reduce the incidence of atopic disease and infections. Infants from allergy-prone families should be breastfed for 6 weeks to 6 months, and highly allergic foods, such as eggs, soy, and cow’s milk, should probably be excluded from infant and maternal diets during this period. Parental smoking is associated with an increased risk of childhood asthma. Most childhood asthmatics will have complete remission of their disease but this is less likely if the asthma is very severe or accompanied by chronic sinusitis, nasal polyps, or infantile eczema. Remission in childhood may be due to increasing airway caliber with growth or loss of allergen sensitivity. A significant number of adult asthmatics will also have spontaneous remission of their disease. The natural history of asthma should be considered when evaluating claims for therapeutic interventions.

Infections of deep soft tissues with the dimorphic fungus Sporothrix schenckii are uncommon in humans, and therapy has often required toxic drugs. We report our experience in treating 11 patients who had deep-seated sporotrichosis with ketoconazole, a well-tolerated, orally absorbed antifungal agent. Eight infections involved one or more joints, and three involved thoracic, cervical, and widespread cutaneous sites, respectively. For eight patients all evidence of infection resolved during therapy. Sustained remissions (6 months to 5 years) were noted for six patients after the discontinuation of all therapy and for an additional patient 4 years after the initiation of ketoconazole treatment. Durable responses were associated with prolonged treatment with 400-800 mg of ketoconazole daily. Our favorable experience suggests that oral therapy with ketoconazole may benefit other patients with systemic sporotrichosis.

We prospectively compared the usefulness of a bronchoscopic protected catheter technique with the results from sputum cultures in the evaluation of moxalactam, a new beta-lactam antibiotic. The significance of a given isolate on protected catheter culture was determined by quantitative bacteriology. 32 patients with community-acquired pneumonia were enrolled in the study and 31 grew common lower respiratory tract pathogens from their protected catheter specimen. The most common single pathogens recovered were Streptococcus pneumoniae (11 patients) and Haemophilus influenzae (2). Mixed flora, predominantly anaerobes, were isolated from 15 patients, and 3 patients had mixed aerobic infections. All seven bacteremic cases had the identical organism isolated from the protected catheter specimen, confirming the accuracy of the technique. Comparisons with sputum cultures showed that the predominant organism on sputum culture was the same as that obtained from the protected catheter culture in only 13% of the cases. Sputum cultures revealed either no pathogen or a different pathogen in 23 cases, and no sputum could be obtained in 4. Compared to cultures of expectorated sputum, we found the protected catheter bronchoscopic culture technique to have the following advantages in the bacteriologic evaluation of moxalactam: 1) greater accuracy and sensitivity in bacteremic patients; 2) accurate delineation of the bacteriology of infections; and 3) a higher percentage of patients with evaluable bacteriology leading to greater efficiency during the investigation.

A 37-year-old woman presented to her allergist’s office after 6 months of dry cough. Before her appointment, she was treated sporadically with inhaled corticosteroids, albuterol, and antibiotics but showed no improvement. On evaluation, aeroallergen skin prick test results were negative; a complete blood cell count was normal, with 4% eosinophils; and her chest radiograph showed only peribronchial thickening. She was empirically administered montelukast for possible cough variant asthma. Within 1 month, her cough began to worsen, and she developed dyspnea that required 2 pulse corticosteroid treatments for relief. Inhaled salmeterol and budesonide were added. Chest computed tomography revealed a left-sided suprahilar opacity. The patient was referred to a pulmonologist for bronchoscopy. At that visit, a repeated chest radiograph showed infiltrates in the left upper lobe and lingula, and lavage fluid from the bronchoscopy showed predominant eosinophilia. Shortly thereafter, the patient developed a vesicular rash on her head and arms, fever, myalgias, hemoptysis, pleuritic chest pain, and worsening dyspnea. On examination, she had distended neck veins with bilateral infiltrates and cardiomegaly on her chest radiograph. On admission to the hospital, her echocardiogram showed a depressed left ventricular ejection fraction of 42% with a pericardial effusion. Pericardiocentesis yielded fluid with a differential count significant for eosinophilia of 42%. She also had peripheral eosinophilia of 24%. A biopsy specimen of the hand revealed necrobiotic collagen with granulomas and an eosinophilic infiltrate (Fig 1). The patient improved with administration of intravenous inotropes, diuretics, and corticosteroids. Montelukast use was discontinued. During the next year, she was weaned off oral corticosteroids, and she now has intermittent asthma that is controlled by daily inhaled mometasone therapy. She also developed nasal polyps that were treated successfully with surgery. Figure 1 Perivascular eosinophils and granuloma formation in a skin Churg-Strauss vasculitis (CSV) is a small- to medium-sized vessel vasculitis associated with asthma and peripheral eosinophilia. This patient had 4 of the 6 American College of Rheumatology criteria for a CSV diagnosis (asthma, peripheral eosinophilia, pulmonary infiltrates, and extravascular eosinophils), biopsy sample, findings consistent with Churg-Strauss vasculitis. and she later developed a fifth (nasal polyps). In patients with CSV, indicators of poor prognosis include cardiac and gastrointestinal involvement.1 In a study by Guillevin et al,1 96 patients with CSV were followed up to evaluate outcomes. This study showed 39% mortality with myocardial disease, and most of these patients died during the acute phase of their illness. Corticosteroids are the first-line treatment for CSV, and remission rates are 80% to 90% with this therapy. In the past decade, there seems to be an increase in the diagnosis of CSV with the introduction of leukotriene modifiers, such as montelukast. Wechsler et al2 published a 6-patient case series in 2000 that concluded that the relationship is coincidental. The authors postulated that the vasculitic component of CSV is suppressed by corticosteroids and that the addition of montelukast allows for the withdrawal of corticosteroids, thus allowing the vasculitis to be “unmasked.” Lofdahl et al3 showed in a double-blind, placebo-controlled trial that montelukast can allow for tapering of inhaled corticosteroids, but this may not be the case in all patients. Other case reports have shown a diagnosis of CSV in association with montelukast while inhaled corticosteroids were not being weaned. Sabio et al4 described a 49-year-old patient who developed rash and duodenal necrotizing vasculitis 5 months after switching from salmeterol to montelukast. Villena et al5 described a patient who developed rash, eosinophilia, and bilateral pulmonary infiltrates 4 months after beginning montelukast treatment while taking inhaled corticosteroids and bronchodilators only. Solans et al6 described an asthmatic patient who had never received oral corticosteroids who developed CSV 4 months after initiating montelukast treatment. In summary, this patient developed corticosteroid-dependent asthma and biopsy-proven CSV with a poor prognostic indicator of cardiac involvement after starting montelukast treatment. She survived with cessation of montelukast treatment, and currently her asthma is controlled with mometasone only. Although there is strong circumstantial evidence of a relationship in this patient, Weller et al7 showed in an extensive summary that no evidence exists to support the causation of CSV by leukotriene receptor antagonists. As cases continue to be reported, there should be further investigation to determine whether a true relationship exists

In the cystic fibrosis (CF) population, use of colistin is increasingly common due to emergence of multi-drug resistant (MDR) gram negative infections; largely with Pseudomonas aeruginosa. Although immediate-type hypersensitivity to this medication is rare, in the CF population it may be more prevalent. We found only one case of a patient who was desensitized to intravenous (IV) colistin using a conservative protocol. Here we present a patient who completed a more rapid protocol for induction of temporary drug tolerance to colistimethate. Skin prick at 75mg/mL and intradermal testing at 0.25mg/mL was performed. To desensitize, we started with a 1:15,000 dilution of the therapeutic dose of 150mg (0.01mg), and doubled the dose of IV colistimethate every 15 minutes until the cumulative dose approximated the therapeutic dose. Our patient is a 42 year old male with CF who recently underwent a bilateral lung transplant. Post transplant, he was found to have a MDR P. aeruginosa only susceptible to colistin. Twenty years prior, he developed diffuse hives 20 minutes into an infusion with IV colistin. Skin testing was negative, however given his history, we proceeded with desensitization. He completed the protocol without evidence of cutaneous or systemic symptoms. Using a more aggressive protocol we were able to desensitize our patient in 3.5 hours compared to 5 hours in the previously published protocol. As the average life expectancy of CF patients increases, the likelihood of MDR infections requiring colistin will increase making a more aggressive desensitization protocol useful in allergic patients.

Urticaria consists of discrete areas of skin edema that are usually pruritic. Angioedema, which involves the deeper dermis and subcutaneous tissue, presents as localized areas of soft tissue swelling. Urticarial lesions are initially erythematous but often progress with central clearing to give a typical wheal and flare appearance. These lesions can vary from a few millimeters to several centimeters in diameter and may have serpiginous or polycyclic borders. Although most commonly involving the trunk and proximal extremities, the lesions can occur anywhere and are particularly common in areas of tight-fitting clothing. The lesions of angioedema are seldom pruritic but can produce an uncomfortable burning sensation and sometimes pain. Angioedema is most common in the loose tissues around the eyes and mouth. Urticaria and angioedema occur together in 49% of patients, urticaria is seen alone in 40%, and angioedema occurs alone in 11% of cases.Urticaria is defined as chronic when lesions occur continuously or intermittently for longer than 6 weeks; although somewhat arbitrary, this definition of chronicity is clinically useful. Lesions of chronic urticaria usually last several hours and disappear in one area only to reappear in another.