Efficacy, safety, and tissue penetration of solithromycin in Japanese patients with otorhinolaryngological infections.

OBJECTIVE: To assess the efficacy, safety, and tissue penetration of solithromycin for the treatment of otorhinolaryngological infections, we conducted three studies: a tissue penetration study with patients scheduled to undergo otorhinolaryngological tissue removal, an open-label study comprising patients with otitis media, pharyngitis, laryngitis, and tonsillitis, and a non-inferiority study compared with high-dose cefcapene-pivoxil (CFPN-PI). METHODS: Tissue penetration study; 17 patients with chronic rhinosinusitis, chronic otitis media, chronic tonsillitis, or palatine tonsillar hypertrophy, who required resection or removal of their tissue, were enrolled. Solithromycin was administered orally, and otorhinolaryngological tissues were collected 3.5-6 h after drug administration; blood was collected within 15 min before and after drug administration. The collected tissues and blood concentrations were measured at a central laboratory. Open-label study; 55 patients who were diagnosed with acute otitis media, laryngopharyngitis, or tonsillitis were enrolled. Solithromycin was administered orally 800 mg on Day 1, while on days 2-7, 400 mg of the drug was administered once daily. The primary endpoint is the clinical response at Test-of-Cure (TOC: 5-10 days after completion) Non-inferiority study; 283 patients with acute rhinosinusitis or acute exacerbation of chronic rhinosinusitis were randomized into either the solithromycin group or CFPN-PI group. Solithromycin was administered 800 mg once daily on Day 1 and 400 mg once daily while on Days 2-7 in solithromycin group, and CFPN-PI was administered 150 mg three times a day while on Days 1-7 in CFPN-PI group. The primary endpoint is the clinical response at TOC. RESULTS: In the tissue penetration study, the tissue concentration ratios (tissue concentration/plasma concentration) of solithromycin were 4.19 in the sinonasal mucosa, 1.33 in the middle ear mucosa, and 6.12 in the palatine tonsil tissue. In the open-label study, the efficacy rates at the TOC were 97.0 % for acute otitis media, 100 % for laryngopharyngitis, and 81.8 % for tonsillitis. In the non-inferiority study comprising patients with rhinosinusitis, the efficacy rate at the TOC was 87.7 % for solithromycin and 89.7 % for CFPN-PI. The difference in the efficacy rate (95 % confidence interval) was -2.0 % (-9.4 % to 5.4 %), verifying the non-inferiority of solithromycin to CFPN-PI. The most common adverse events in patients administered solithromycin were diarrhea (20.7 %), nausea and nasopharyngitis (3.6 %,), pharyngitis and elevated hepatic function test results (3.1 %), and abnormal hepatic function (2.1 %). CONCLUSION: Based on the findings, it is suggested that solithromycin is useful for the treatment of otorhinolaryngological infections.

Application of phosphorylcholine derivative as mucosal adjuvant enhancing mucosal immune responses in the upper respiratory tract.

OBJECTIVE: A phosphorylcholine (PC)-derivative with high binding ability (PCDB) was intranasally administered to mice with ovalbumin (OVA), and immune responses were investigated to determine whether PCDB has antigenicity and adjuvanticity. METHODS: BALB/c mice were intranasally immunized with PCDB coupled with OVA, unbound PCDB plus OVA, cholera toxin (CT) plus OVA, OVA alone, and PCDB alone. Then, the production of OVA- and PC-specific antibodies in external secretions and serum, and the secretion of cytokines such as IL-4 and IFN-γ from splenic mononuclear cells by stimulation with PCDB and OVA were examined. Furthermore, the secretion of IL-12p40 from CD11c+ cells following stimulation with PCDB was observed to clarify the adjuvant effect of PCDB through TLR4. RESULTS: Intranasal immunization with PCDB plus OVA increased OVA- and PC-specific IgA in external secretions and OVA- and PC-specific antibodies in the serum. The analysis of IgG subclasses specific to OVA and PC showed a higher production of IgG1 than IgG2, and the secretion of both IL-4 and IFN-γ was enhanced. However, IL-12p40 secretion from CD11c+ cells was increased and OVA-specific IgE production was not promoted by PCDB stimulation. CONCLUSION: Intranasal administration of the protein antigen with PCDB enhanced immune responses specific to the mixed antigen and PC. Although PCDB acted to bias the immune response toward the Th2-type, antigen-specific IgE production did not increase. These findings suggest that PCDB has the potential to be a mucosal vaccine with both adjuvanticity and antigenicity without causing side effects due to type I allergy.

Dysphonia in Polymyositis/Dermatomyositis in Adults.

The purpose of this study was to examine clinical dysphonia in patients with polymyositis (PM)/dermatomyositis (DM). The subjects were 21 Japanese patients with PM/DM (11 females, 10 males; mean age ± SD, 61.4 ± 16.2 years) who visited our department between April 2009 and March 2020. Dysphonia was evaluated by laryngoscopy and histopathological examination. Eight (38.1%) patients were aware of dysphonia. These patients included one with PM and 7 with DM, 5 were male and 3 were female, and the mean age at diagnosis was 62.0 (range 48 to 72) years. White lesions on the vocal cords were found in 7 of the patients with dysphonia. The patient without these white lesions had regurgitation into the nasal cavity. Histopathological examination revealed inflammation of lamina propria in the laryngeal white lesions. White lesions on the vocal cords were found in patients with dysphonia in patients with polymyositis (PM)/dermatomyositis (DM). Histopathological examination revealed fiber necrosis and inflammatory cell infiltration in lamina propria of the laryngeal lesions. White lesions on the vocal cords were relieved by treatment. Level of Evidence 2b (Individual retrospective cohort study).

Executive summary: Japanese guidelines for allergic rhinitis 2020.

The Practical Guideline for the Management of Allergic Rhinitis, the fist guideline for allergic rhinitis in Japan, was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 9th edition was published in 2020 and is widely used today. The most recent collection of evidence from the literature was supplemented to the revised guideline to incorporate evidence-based medicine. The revised guideline includes updated epidemiology of allergic rhinitis in Japan, a figure representing the mechanisms of allergic rhinitis in both the onset and sensitization phases with the introduction of regulatory T cells and type 2 innate lymphoid cells, practical assessment for diagnosis, new pharmacotherapy agents such as anti-IgE mAb and a new drug delivery system for antihistamines, sublingual immunotherapy for children, dual sublingual immunotherapy for house dust mites and Japanese cedar pollen extract, new classification for surgery for allergic rhinitis, and treatment and prescriptions for older adults. An evidence-based step-by-step strategy for treatment is also described.

Induction of Mucosal IgA-Mediated Protective Immunity Against Nontypeable Haemophilus influenzae Infection by a Cationic Nanogel-Based P6 Nasal Vaccine.

Nontypeable Haemophilus influenzae (NTHi) strains form a major group of pathogenic bacteria that colonizes the nasopharynx and causes otitis media in young children. At present, there is no licensed vaccine for NTHi. Because NTHi colonizes the upper respiratory tract and forms biofilms that cause subsequent infectious events, a nasal vaccine that induces NTHi-specific secretory IgA capable of preventing biofilm formation in the respiratory tract is desirable. Here, we developed a cationic cholesteryl pullulan-based (cCHP nanogel) nasal vaccine containing the NTHi surface antigen P6 (cCHP-P6) as a universal vaccine antigen, because P6 expression is conserved among 90% of NTHi strains. Nasal immunization of mice with cCHP-P6 effectively induced P6-specific IgA in mucosal fluids, including nasal and middle ear washes. The vaccine-induced P6-specific IgA showed direct binding to the NTHi via the surface P6 proteins, resulting in the inhibition of NTHi biofilm formation. cCHP-P6 nasal vaccine thus protected mice from intranasal NTHi challenge by reducing NTHi colonization of nasal tissues and eventually eliminated the bacteria. In addition, the vaccine-induced IgA bound to different NTHi clinical isolates from patients with otitis media and inhibited NTHi attachment in a three-dimensional in vitro model of the human nasal epithelial surface. Therefore, the cCHP-P6 nanogel nasal vaccine induced effective protection in the airway mucosa, making it a strong vaccine candidate for preventing NTHi-induced infectious diseases, such as otitis media, sinusitis, and pneumonia.

Sudden death after operation, radiotherapy or chemoradiotherapy for head and neck cancer.

OBJECTIVE: The purpose of this report to determine sudden death following operation, radiotherapy (RT) or chemoradiotherapy (CRT) for head and neck cancer. STUDY DESIGN: Retrospective, observational, single-center. METHODS: Data from 729 consecutive patients diagnosed with head and neck cancer (confirmed using multiple modalities) who underwent operation, RT or CRT at Kagoshima University Hospital between April 2011, and March 2020 were analyzed. A total of 199 patients underwent operation, 223 patients underwent RT and 307 underwent CRT. 175 patients who received operation, 118 patients who received RT and 190 who received CRT had a complete response. RESULTS: There were 13 cases of sudden death reported in 10 years. 12 were male and one was female.Sudden death occurred in 3/175 patients (1.7%) who received operation, in 4/118 patients (3.4%) who had received RT and in 6/190 (3.1%) who had received CRT. CONCLUSIONS: We present the first report on cases of sudden death after operation, RT and CRT for head and neck cancer. Otolaryngologists should still follow these patients carefully after such treatment given that sudden death does occur in some patients.

The mucosal immune system of the upper respiratory tract and recent progress in mucosal vaccines.

The mucosal immune system prevents microorganism invasion through mucosal surfaces and consists of inductive and effector sites. Nasopharynx-associated lymphoid tissue (NALT) functions as an inductive site, inducing mucosal immune responses in the upper respiratory tract. It follows that intranasal vaccines may prevent upper respiratory infections. To induce and enhance the immune response by administering inactivated antigens intranasally, mucosal adjuvants have been developed, including mutant cholera toxin and cationic cholesteryl pullulan nanogel, which do not accumulate in the central nervous system. Moreover, multivalent pneumococcal polysaccharide conjugate vaccines are used to prevent invasive pneumococcal infections and otitis media, although they only provide moderate protection against acute otitis media because non-vaccine serotypes of Streptococcus pneumoniae and Haemophilus influenzae also cause this infection. To address this problem, pneumococcal surface protein A of S. pneumoniae and P6 of H. influenzae are used as broad-spectrum vaccine antigens. Alternatively, phosphorylcholine (PC) is present in the cell walls of both gram-positive and gram-negative bacteria and induces immune responses through antigenic activity. The significant effects of PC as a mucosal vaccine have been demonstrated through intranasal and sublingual immunization in mice. Furthermore, intranasal administration of PC reverses increases in IgE levels and prevents allergic rhinitis. After immunization with pneumococcal polysaccharide conjugate vaccine, intranasal immunization with PC boosts immune responses to vaccine strains and to PC itself. Thus, PC may be useful as a mucosal vaccine to prevent upper respiratory infections and allergic rhinitis, and it could be used as a booster to the currently used pneumococcal vaccine as it protects against non-vaccine strains.

Survey of nebulizer therapy for nasal inflammatory diseases in Japan before and during the COVID-19 pandemic.

OBJECTIVE: Nebulizer therapy is an effective and safe topical treatment for rhinosinusitis and is frequently used by otolaryngologists in Japan. However, treatment methods used vary among regions and according to doctors' preferences. In this study, we aimed to investigate the use of nebulizer therapy for rhinosinusitis. Administration of nebulizer therapy has been affected by the coronavirus disease 2019 (COVID-19) pandemic. Thus, we also investigated the difference in the prevalence of nebulizer use before and during the pandemic. METHODS: Between February and September 2016 and in January 2021, we administered questionnaire surveys on nebulizer treatment for rhinosinusitis to otorhinolaryngologists, who were members of the Oto-Rhino-Laryngological Society of Japan, in Aomori, Saitama, Mie, Fukui, Shiga, Okayama, and Kagoshima prefectures. RESULTS: More than 90% of the otorhinolaryngologists performed nebulizer treatment for rhinosinusitis in 2016. In April 2020 (the first wave of the COVID-19 pandemic), the use rate decreased to 20%, but in January 2021, the use rate increased to 60%. Jet nebulizers were the most frequently used type. One-third of the otolaryngologists enlarged the natural opening of the paranasal sinuses in more than half of their patients by using vasoconstrictors. Cefmenoxime and betamethasone were the most commonly used antibiotics and steroids, respectively. CONCLUSION: Because it is important to perform nasal pretreatment and strict disinfection of nebulizer equipment, it is clear that education of otorhinolaryngologists as well as paramedical personnel is required to ensure safe and effective use of nebulizer therapy in Japan.

Effectiveness of antibacterial agents against cell-invading bacteria such as Streptococcus pyogenes and Haemophilus influenzae.

BACKGROUND: Recurrent tonsillitis is one of the most common otolaryngological disorders caused by cell-invading bacteria, such as Streptococcus pyogenes (S. pyogenes) and Haemophilus influenzae. The aim of this study was to investigate the effect of antibacterial agents against cell-invading bacteria. METHODS: The intracellular invasion of Detroit 562 cells by five strains of nontypeable Haemophilus influenzae (NTHi) and four strains of S. pyogenes was investigated. The antibacterial agents used were garenoxacin (GRNX), clarithromycin (CAM), amoxicillin (AMPC), cefditoren pivoxil (CDTR-PI), and levofloxacin (LVFX). RESULTS: Both NTHi and S. pyogenes fully invaded Detroit 562 cells in 6 h and were less sensitive to CAM. GRNX, CAM, and LVFX were effective against bacteria invading the cells, but AMPC and CDTR-PI were not effective. GRNX was the most effective. CONCLUSION: GRNX was the most effective agent against bacteria invading cells.

Three cases of non-occlusive mesenteric ischemia that developed after head and neck cancer therapy.

Non-occlusive mesenteric ischemia (NOMI) causes intestinal necrosis due to irreversible ischemia of the intestinal tract despite the absence of organic obstruction in the mesenteric blood vessels. The disease has extremely poor prognosis. We report three cases of NOMI hypothesized to have developed after head and neck cancer therapy; thus, we report these cases considering the available literature. Case 1: A 74-year-old man with T2N0M0 stage Ⅱ oropharyngeal carcinoma complained of abdominal pain 5 days after chemoradiotherapy. The patient was diagnosed with NOMI, and an emergency surgery was performed. Case 2: A 69-year-old man with T2N2bM0 stage IVA hypopharyngeal carcinoma complained of abdominal pain during TPF chemotherapy. The patient was diagnosed with NOMI, and he died on the same day. Case 3: A 82-year-old man with T2N2bM0 stage IVA hypopharyngeal carcinoma complained of abdominal pain with reduced level of consciousness, 5 days after total laryngopharyngectomy. The patient was diagnosed with NOMI, and an emergency surgery was performed on the same day. We therefore suggest that ENT physicians must be aware of NOMI as a complication that can develop after head and neck cancer therapy.

Unilateral arytenoid swelling in acute epiglottitis suggests the presence of peritonsillar abscess.

OBJECTIVE: To investigate the incidence of acute epiglottitis (AE) and the clinical features of patients with AE complicated by peritonsillar abscess (PTA), considering that PTA, especially inferior-type PTA, is often a comorbidity of AE. METHODS: We retrospectively reviewed the medical records of patients who were diagnosed as having AE by otolaryngologists and referred to our hospital between January 2009 and December 2017. All the patients underwent laryngeal endoscopy and contrast-enhanced computed tomography (CT) for examination of the severity of AE and its complications by other infections, including PTA. The clinical characteristics of patients with PTA were compared with those of patients without PTA. RESULTS: A total of 139 patients were enrolled, of whom 21 (15%) were found to have PTA. Among the 21 patients, only one had a superior-type PTA and the others had an inferior-type PTA. The patients with complicated AE by an inferior Cap-type PTA frequently showed unilateral arytenoid swelling. CONCLUSION: PTA is a comorbidity of AE, and unilateral arytenoid swelling is considered to suggest the presence of inferior-type PTA.

The seventh nationwide surveillance of six otorhinolaryngological infectious diseases and the antimicrobial susceptibility patterns of the isolated pathogens in Japan.

The Japanese Three Academic Societies Joint Antimicrobial Susceptibility Surveillance Committee conducted a nationwide surveillance on six otorhinolaryngological diseases and investigated the antimicrobial susceptibility patterns and isolation rates of the causative pathogens. The surveillance program was conducted in the otorhinolaryngological departments of 12 universities, and 36 affiliated hospitals and clinics. Patients with acute otitis media (children under six years old), chronic otitis media, acute nasal sinusitis, chronic nasal sinusitis, acute tonsillitis, and peritonsillar abscess (over 20 years old) between December 2015 and June 2017 were investigated. The collected swab or incision samples were cultivated for microbial identification, and the antimicrobial susceptibility of the detected bacteria was measured at the Kitasato University Research Center for Infections and Antimicrobials. The surveillance focused on three gram-positive bacteria (Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus), three gram-negative bacteria (Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa), and three anaerobic bacteria (anaerobic gram-positive cocci, Prevotella spp., Porphyromonas spp., and Fusobacterium spp.). Bacterial susceptibility to 40 antimicrobial agents was investigated. We were unable to completely mitigate the rise in the occurrence of resistant bacteria, such as methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, penicillin-intermediate resistant S. pneumoniae, beta-lactamase non-producing ampicillin-resistant H. influenzae, and beta-lactamase producing ampicillin-resistant H. influenzae. We suggest promoting the proper usage of antimicrobial agents to prevent the spread of these bacteria. We also suggested that immunization with pneumococcal vaccines is useful for decreasing the occurrence of otorhinolaryngological infectious diseases caused by pneumococci.

Japanese guidelines for allergic rhinitis 2020.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Consensus guidance of nebulizer therapy for acute rhinosinusitis.

The guidance deals with the recommended applications, procedures, and safety management of nebulizer therapy for acute rhinosinusitis. In Japan, nebulizer therapy for sinusitis has been covered by public health insurance since 1958 and has been commonly carried out nationwide. The Japan Society for Infection and Aerosol in Otorhinolaryngology and the Oto-Rhino-Laryngological Society of Japan set up a working group to draw up a consensus guidance on nebulizer therapy for acute rhinosinusitis. The device for nebulizer therapy are classified into jet, ultrasound, and mesh types. In Japan, cefmenoxime hydrochloride (CMX) was approved for use in nebulizer therapy since 1996. The widening of the obstructed lesions such as large polyps prior to nebulizer therapy were recommended. The numbers of times of nebulizer therapy is recommended for three times in a week for at least for 2 weeks (cure rate: 68%, eradication ratio: 48%). Concerns should be pay for the changes of activity of medicine due to the mixing and bacterial contamination. Pseudomonas cepacia growing in a short even in both saline and distilled water leads to contamination at high concentrations by 2 days. Nebulizer therapy is an effective treatment based on a drug delivery system (DDS) to the nasal and paranasal cavities. The therapy effectively increases the local drug concentration by promptly and uniformly delivering drugs to a targeted local site. The therapy is safe with less systemic absorption and with few adverse reactions.

Squamous cell carcinoma at sites of old maxillary fractures.

Malignancies have been reported to occasionally arise in scar tissue following injury. One hypothesis involves prolonged overactivation of tissue repair systems due to chronic inflammation and irritation, although the pathogenesis of cancers occurring in scars is not fully understood. We describe here two cases with a history of maxillary fracture at the site where squamous cell carcinoma (SCC) subsequently developed. The first patient developed SCC 7 years after right maxillary fractures resulting from a traffic accident. He underwent chemoradiotherapy (70 Gy in 35 fractions) and maintained complete response (CR) for 10 months. The second patient developed SCC 3 years after sustaining right maxillary fractures in an ice hockey game. Radiotherapy and total maxillectomy were performed, but local recurrence arose and he has since been receiving chemotherapy.

The usefulness of abscess tonsillectomy followed by intraoral drainage for parapharyngeal abscess concomitant with peritonsillar abscess in the elderly.

Parapharyngeal abscess (PPA) may cause life-threatening complications and peritonsillar abscess (PTA) and tonsillitis frequently precede PPA. The optimal management of PPA caused by PTA has been the subject of debate with respect to the surgical approach. We present three cases of PPA concomitant with PTA in elderly patients. In two cases, the abscesses in parapharyngeal space were drained by abscess tonsillectomy followed by intraoral incision of the tonsillar bed. On the other hand, the third case did not undergo abscess tonsillectomy because of his refusal of surgery and needed extraoral drainage after the aggravation of PPA. Based on the experience of those three cases, it was suggested that abscess tonsillectomy followed by intraoral incision of the tonsillar bed might be a useful surgical approach for the drainage of PPA concomitant with PTA, especially in elderly patients.

Phosphorylcholine intranasal immunization with a 13-valent pneumococcal conjugate vaccine can boost immune response against Streptococcus pneumoniae.

OBJECTIVE: This study aimed to investigate whether systemic immunization with a 13-valent pneumococcal conjugate vaccine (PCV13) followed by intranasal (IN) immunization with phosphorylcholine (PC) can boost immune response against Streptococcus pneumoniae. MATERIALS AND METHODS: Two weeks after the intraperitoneal (IP) injection of PCV13, mice were divided into two groups (mice requiring another IP injection of PCV13 and mice requiring PC-keyhole limpet hemocyanin IN immunization in combination with cholera toxin as a mucosal adjuvant) to compare the magnitude of systemic and mucosal immune responses against S. pneumoniae and PC. RESULTS: Serum immunoglobulin (Ig) G antibody titer against the vaccine strains of S. pneumoniae was similar between the PCV13 systemic immunization group and PC IN immunization group, while the serum IgG antibody titer against PC was significantly higher in the PC IN immunization group. PC-specific IgA antibody titer in the nasal lavage and PC-specific IgA-producing cell number in the nasal mucosa were also significantly higher in the PC IN immunization group. Induction of PC-specific IgA in the PC IN immunization group enhanced the clearance of bacteria from the middle ear. CONCLUSION: Additional IN immunization with PC after PCV13 immunization, which is currently conducted under a periodic vaccination program, can produce a booster effect comparable to that achieved by additional systemic immunization as well as PC-specific mucosal immune response, thereby providing protection against S. pneumoniae serotypes not contained in PCV13.

Role of Phosphorylcholine-Specific Immunoglobulin M in Acute Upper Respiratory Tract Infections.

OBJECTIVES: The aim of this study was to clarify the role of serum phosphorylcholine (PC)-specific immunoglobulin M (IgM) as a natural antibody against infectious diseases. METHODS: The relationship between serum PC-specific IgM level and C-reactive protein level or white blood cell counts was examined in patients with severe upper respiratory tract infections (ie, acute epiglottitis and peritonsillar abscess). RESULTS: PC-specific IgM level was significantly negatively correlated with C-reactive protein level and white blood cell count. In addition, C-reactive protein level and white blood cell count was significantly lower in women than in men, whereas PC-specific IgM level was significantly higher in women. CONCLUSIONS: PC-specific IgM is suggested to have protective and suppressive effects against the progression of infectious and inflammatory reactions. Higher levels of PC-specific IgM in women might be one of the reasons why the incidence and severity of acute epiglottitis and peritonsillar abscess are lower in women.

Clinical practice guidelines for the management of olfactory dysfunction - Secondary publication.

OBJECTIVE: To provide an evidence-based recommendation for the management of olfactory dysfunction in accordance with the consensus reached by the Subcommittee of the Japanese Clinical Practice Guideline for olfactory dysfunction in the Japanese Rhinologic Society. METHODS: Seven clinical questions (CQs) regarding the management of olfactory dysfunction were formulated by the subcommittee of the Japanese Clinical Practice Guideline for olfactory dysfunction. We searched the literature published between April 1990 and September 2014 using PubMed, the Cochrane Library, and Ichushi Web databases. The main search terms were "smell disorder," "olfactory dysfunction," "olfactory loss," "olfactory disturbance," "olfactory impairments," "olfaction disorder," "smell disorder," "anosmia," "cacosmia," and "dysosmia." Based on the results of the literature review and the expert opinion of the Subcommittee, 4 levels of recommendation, from A-strongly recommended to D-not recommended, were adopted for the management of olfactory dysfunction. RESULTS: Both oral and locally administered corticosteroids have been strongly recommended for patients with olfactory dysfunction due to chronic rhinosinusitis. Nasal steroid spray and antihistamine drugs have been moderately recommended for patients with allergic rhinitis. Although no drugs have been deemed to be truly effective for post-viral olfactory dysfunction by randomized-controlled trials (RCTs) or placebo-controlled trials, olfactory training using odorants has been reported to be effective for improving olfactory function. There is considerable evidence that olfactory testing is useful for differential diagnosis, prediction of disease progression, and early detection of cognitive decline in neurodegenerative diseases. CONCLUSION: The Clinical Practice Guideline has developed recommendations for the management of various aspects of olfactory dysfunction.