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These include 1 increasing the allergen-induced ratio of Th1 cytokines to Th2 cytokines, 2 induction of epitope-specific T-cell anergy that can be blocked by neutralization of IL, 3 generation of allergen-specific Treg cells that can suppress the responses of effector T cells following delivery of either whole allergen extracts or synthetic peptides that contain or consist of a T-cell epitope, and 4 increasing the production of cytokines with regulatory activity.

IgG isotypes could compete with IgE for the same epitopes, resulting in the binding of allergen and were therefore termed blocking antibodies. SPT is the preferred method of testing for specific IgE antibodies. Patients using beta-blockers are also contraindicated to AIT because these agents can amplify the severity of the reaction and make the treatment of systemic reactions more difficult.

Generally, AIT is not initiated in pregnant women; however, it can be safely continued in women who have been on treatment prior to becoming pregnant. Other populations needing special consideration include the elderly who have comorbid medical conditions that may increase the risk of experiencing immunotherapy-associated adverse events, patients with autoimmune disorders, those with immunodeficiency syndromes and those with malignant disease Table Standardized extracts should be utilized whenever possible, since the efficacy and safety of AIT depend on the quality of the allergen extracts.

During a cluster schedule, multiple injections usually 2—3 are administered per visit once a week, reaching maintenance in several weeks, e. In a rush protocol, multiple injections are administered on consecutive days, generally reaching maintenance within 1 week. It has been documented that there is no increase in systemic reactions SRs and more rapid achievement of symptomatic improvement for the cluster schedule.

After that, many patients experience a prolonged, protective effect, and consideration can therefore be given to stopping therapy. Allergen specific IgG4 and ILsecreting type I Treg cells have been measured in some studies and found to be increased gradually. The most severe reaction is anaphylaxis, although fatal anaphylactic reactions are rare. Children 4—14 years old are maintained with the No.

Patients are instructed to keep the drops under the tongue for 1—3 minutes before swallowing. The whole treatment period is 3—5 years. Meta-analyses confirm its efficacy in reducing both symptoms and medication scores. The most common adverse effects are minor local reactions in the mouth and the gastrointestinal tract, with few cases of anaphylaxis, but no fatality. Adherence is more favorable for SLIT, since it is safe, non-invasive and easily taken at home, which is especially well suited for children.

SCIT-related SRs can range in severity from mild rhinitis or urticaria symptoms to life-threatening anaphylaxis. The percentage of SR in conventional schedules is approximately 0. Uncontrolled asthma is the most important risk factor therein, thus making assessment of asthma severity especially important for the prevention of anaphylaxis. Oral antihistamines have been demonstrated to be effective in preventing LRs in cluster and rush regimens, whereas leukotriene antagonists have been shown to be effective in rush protocols.

Most of the SCIT-related SRs appear within 30 minutes after injection, although some SRs are biphasic and could occur during 2—48 hours after the injection is administered. Prompt administration of epinephrine is vital when severe SRs occur as a lot of anaphylaxis-related fatalities are due to the delay of epinephrine use.

The specific management of adverse events is shown below Table The effectiveness of surgical treatment for refractory AR has been demonstrated in several studies. Enlargement of the inferior turbinate is the main cause of nasal obstruction in intractable AR. Septalplasty may be used for patients with severe nasal septum deviation. The mechanism underlying neuronal-immune modulation is related to the symptoms of AR. Resection of the posterior nasal nerve lowers the hypersensitivity of nasal mucosa and reduces secretion, and alleviates inflammatory reaction.

Acupuncture therapy is the safe and has no apparent adverse reactions. A systematic review has recently indicated acupoint application for AR as follows: acupoints in lung and bladder meridians are mainly selected to assist exterior and resist the pathogenic Qi, and points in spleen and kidney meridians can treat AR fundamentally by joint use.

In recent years, some acupuncturists have penetrated the needle at one special acupoint to reach the sphenopalatine ganglion SPG and get a definite effect Fig. Two recent studies have also indicated that stimulation of the SPG by acupuncture can improve nasal symptoms and quality of life in nasal inflammatory diseases.

However, compared to acupoint plaster therapy, triple-strong stimulation therapy at Dazhui GV 14 has been shown to achieve a superior effect on the prevention and treatment of AR in children, and has a good long-term effect in preventing recurrence. To sum up, an increasing body of evidence indicates that acupuncture is a safe treatment option, and most of the acupuncture methods employed can improve AR symptoms of nasal itching, sneezing, rhinorrhea, and especially nasal stuffiness.

Acupuncture at either general or special acupoints needs to be continued over several weeks to observe significant beneficial and stable effects on symptom improvement. Dog days plaster and acupoint catgut embedding therapy can provide long-term regulation for AR patients. SPG puncturing method is a new and unusual technique, with great potential for development. Regrettably, apart from data from a few animal experiments and investigations of some other diseases, there is relatively little information on the use of probiotics in the treatment of allergic disease in China.

A recent meta-analysis has shown that the use of multistrain probiotics appeared to be most effective for eczema prevention, although no cogent evidence of its preventive effect has been shown for other allergic manifestations. There are still needs strong evidence based on adequately powered, well-designed, randomized, controlled trials and a more standardized approaches to support their use before final clinical recommendations on specific strains, dosage and timing can be given.

The assessments are mainly composed of subjective assessments, 11 which include symptom scores, medication scores and QOL questionnaire of the patients. Four-point scale or VAS is used to quantify the above assessments. The assessment should also be reported on a daily basis and scored per day as follows:. When the AR patient also suffers from asthma, the score should also be calculated per day as follows:. The education must be carried out based on good communication between physicians and patients.

Patients need to know not only what to do, but also why and how to do towards the disease at the outset. Generally, a stepwise education would help patients realize the characterization of AR and its detrimental effects on QOL, understand the related treatment strategy, and complete physical and emotional preparation for accepting a long-lasting treatment. In this sense, active participation of patients can be helpful in reducing occurrence of adverse reactions and concomitance, save financial cost, and improve QOL.

The implementation of individualized education is as important as personalized treatment. Except for distinct symptoms, results of the examinations, outcomes of the treatment, economic status and life circumstances of each patient still need to be taken into account. More patience and attention need to be offered to patients who cannot understand the therapeutic strategy or those who find it hard to fulfil self-management.

Although these patients might have poor educational attainment, heavy economic burden or other reasons, their desirability of relieving symptoms is very strong. Therefore, relevant dissemination requires covering patients' family members in order to get sufficient support and cooperation. Moreover, it is notable that children with AR are likely to present symptoms with the involvement of the lungs, throat and ears. Meanwhile, QOL impairment often leads to poor- quality sleep and consequent fatigue.

More seriously, poor concentration and school performance in children should be given extra concern. On the other hand, popular science knowledge of AR could be disseminated by using traditional and novel media in an easy-to-understand fashion. AR education might be easily acceptable to patients who live in relatively developed cities. Relatively powerful education for both patients and physicians are extremely urgent in rural and poor regions.

Practicable and available methods should be applied according to local conditions such as network education as well as public assistance and government support. Moreover, better communication and close follow-up are important for patients' confidence building and will consequently improve the compliance and outcomes of the therapy.

The diagnosis and treatment system suitable for the Chinese national condition have been established. However, more work is needed in the future. In the aspect of epidemiology of AR in China, the data we have now obtained are mainly from the big cities. The extensive epidemiologic characteristic of AR for the whole population in China is unknown.

With the rapid development of our economy, not only the lifestyle of the Chinese people, but also the degree of industrialization has seen dramatic changes; the distribution of allergens and the prevalence of AR are also in flux. Thus, we need more longitudinal studies about the regional prevalence of AR.

On the other hand, studies about regional distribution of allergens should be continued to be performed, with the aim of determining specific allergens in certain regions. We have made remarkable progress in the process of uncovering the mechanisms of AR and allergy, but there are still many challenging fields, which deserve further studies. TCM, including herbal TCM and acupuncture, is a precious wealth passed down by ancient physicians and has shown to have a significant clinical effect in the treatment of AR.

In spite of this, the Western therapy system occupies a primary position in the treatment of AR in China. New drugs such as specific agonists, antagonists and biologics represent a new field in AR therapy. However, basic and clinical research about biologic agents is relatively backward in our country. For AIT, only the standardized dust mite allergen is currently used in China. Production and application of other allergen vaccines are hysteretic for the complicated procedure of approval and registration, and some allergen vaccines for immunotherapy, such as pollen, can only be used in a city like Beijing.

Thus, the application and registration of new standardized allergen vaccines for the diagnosis and treatment of AR need to be promoted as soon as possible. Genetically engineered vaccines, which are expected to improve the efficacy of immunotherapy and shorten the course of treatment, have recently been investigated by researchers and some of these are at the clinical trials stage.

Li and colleagues constructed a recombinant vaccine containing T-cell epitopes derived from Der p1 and Der p2 and showed that it effectively alleviated the allergic inflammation of the airways and lungs in experimental mice. The traditional Chinese therapy should be encouraged for the treatment of AR, but faces challenges.

Natural herbal medicines have complicated chemical compositions, and the effective constituents are difficult to separate accurately and standardize quantitatively. Further studies are needed to elaborate the effective components of herbal medicine and the mechanism underlying the drug's benefit. Acupuncture also suffers severely from the absence of high-quality clinical research.

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The State Administration of Traditional Chinese medicine. Standards for diagnosis and curative effect of Chinese medical symptom. Nanjing University Press; Shizhen W. Chinese otorhinolaryngology. Several important issues of ear nasal allergy and immunity. Chinese J Otorhinolaryngol. All patients should be provided with drugs for on-demand therapy and ideally be able to use these themselves.

Early administration of on-demand medication promotes early-stage resolution of swelling. Prophylaxis has the advantage that the majority of and in the ideal case all attacks can be prevented. Since attacks can occur despite prophylactic measures, all patients should be provided with on-demand medication. The option, advantages, and risks of self-administration should be elucidated. On-demand therapy for acute attacks is considered particularly appropriate in patients with rare attacks.

It has the advantage that the patient is able to manage with less medication compared to long-term prophylactic treatment. The severity of attacks ranges from mild to life-threatening. It is not always possible to predict how severe an attack will be from the initial symptoms. Mild swelling of the hands and feet do not necessarily require treatment if it affects only one finger or the back of the hand. In general, swelling of the hands or feet can lead to massive occupational impairment and disability, depending on the type of occupation.

This should be borne in mind when establishing the indication for treatment. Irrespective of the selected on-demand therapy, it has been shown that early administration of the on-demand medication reduces the severity and duration of attacks more effectively compared to administration of on-demand medication at a later time [ 31 , 32 , 33 ]. It is advisable to avoid, by means of timely treatment, extensive or functionally restrictive swelling, e.

The majority of abdominal attacks are so painful that drug treatment with the on-demand medication is necessary. Patients with pharyngeal or laryngeal angioedema always constitute an emergency due to the imminent danger of asphyxiation and should be immediately treated and monitored in the nearest hospital.

Patients should be informed about the advantages, as well as the potential risks, of on-demand therapy. Appropriate medication should be recommended. This should be based on a joint decision taken by the physician and the patient. In the case of life-threatening respiratory distress, immediate intubation should be carried out, including the use of fiber optics, or in extreme emergencies, cricothyrotomy or tracheotomy should be performed. Whatever the case may be, immediate treatment with C1-INH concentrate or icatibant is the drug therapy of first choice.

Patient information on how to respond to, and on the treatment of, laryngeal edema should be provided as a matter of urgency. The administration of C1-INH concentrate, i. Human C1-INH concentrate has proven to be highly effective in the treatment of acute attacks. A series of non-placebo-controlled studies demonstrated its efficacy in the treatment of laryngeal edema [ 16 , 35 ], abdominal attacks [ 31 ], and skin swelling [ 36 ] in HAE-C1-INH.

One should strive to initiate treatment as early as possible, i. What is termed as a rebound phenomenon, i. This study outcome contrasts with previous practical and published results with C1-INH concentrate in numerous patients and thousands of attacks. Why the results of the RCT study contradict all previous results is ultimately unclear. In the case of non-life-threatening swelling, i. Anaphylactic reactions have been observed in extremely rare cases.

An unexpected increase in disease activity has been reported in the case of frequent administration of C1-INH concentrate in the long-term treatment in a few patients [ 40 , 41 ]. Virus transmission has not been observed. As in all patients receiving or who could receive plasma derivatives, hepatitis B immunization active immunization is advised. Early injection is recommended in acute attacks. Some patients in Germany and many other countries now inject themselves with one of the C1-INH preparations, or let a close family member or employee of a commercial home-care company perform the injection.

The advantages for the patient of self-treatment at home are enormous, particularly for patients that suffer regular attacks. Self-treatment at home enables early injection, i. The selection of patients for self-treatment at home with intravenous injections is based on the following criteria: proven C1-INH deficiency, motivation and compliance regarding home self-treatment, written consent, access to a telephone during self-treatment, suitable venous access, presence of a partner during self-treatment at home.

Patients require appropriate prior training for self-administration—where necessary, in the presence of family members. The training is comprehensive and covers information on: the basics of anatomy, compliance with hygiene measures, preparing the injection solution, intravenous injection technique, how to respond in the case of complications or inadequate effect, and documentation according to the German Transfusion Law, among many other points.

Relevant online material is available on the websites of the pharmaceutical companies that offer the products. This type of training program can be provided by physicians or medically supervised assistants, as well as by a commercial home-care service. Success needs to be determined by a physician and regularly monitored [ 42 ]. The treating physician is not permitted to delegate the responsibility for home self-treatment.

Icatibant is a synthetic decapeptide with a structure similar to that of bradykinin. Icatibant is injected subcutaneously. The primary endpoint was not achieved in the FAST-1 study; the significance in abdominal attacks was insufficient.

Icatibant was also shown to be effective in laryngeal edema. Dosage is weight-adjusted for children. According to experience to date, the safety profile of icatibant is highly favorable. It is common for erythema, wheal formation, and burning pain to occur at the injection site. Systemic side effects include, e. Attack duration is significantly shorter and milder in the case of early injection compared to later injection of icatibant [ 33 ].

Icatibant has been approved for self-injection by patients since March The responsibility for home self-treatment by the patient must remain with the treating physician. Differences in posttranslational glycosylation result in a distinctly shortened half-life compared to C1-INH in human plasma. It is injected intravenously. However, in addition to coagulation factors, FFP also contains kallikrein-kinin system proteins, meaning that more bradykinin may be produced by these, potentially leading to a worsening of acute attacks [ 49 ].

FFP is not virus-inactivated. All are highly effective. Head-to-head comparative studies are not available to date. The advantages and disadvantages of the drugs are discussed above. Androgens and tranexamic acid see below are not suitable for the treatment of acute attacks due to their delayed onset of action. Sufficient experience with its use in humans is not available as yet, despite several case studies [ 50 , 51 , 52 ]. Use during pregnancy or lactation is not recommended, unless the treating physician deems the benefit to be greater than the possible risks.

Children receive the same weight-adjusted dosage as adults. If it is not possible to achieve adequate symptom control despite appropriate on-demand therapy, long-term prophylaxis should be considered. This would be the case if, e. Patients should be informed about the option of prophylaxis. Prophylaxis should not be initiated until such time as on-demand therapy for attacks is no longer sufficiently effective.

C1-INH concentrate can be used not only for acute treatment, but also for long-term prophylaxis. Further studies demonstrated good results with respect to efficacy and safety [ 41 , 55 , 56 ]. The severity and duration of remaining attacks were significantly decreased [ 57 ]. Its good efficacy is documented in case reports and patient series [ 58 ].

Prior to treatment, Regular follow-up checks are also required, at least once a year. These are designed to review efficacy on the one hand, and, on the other, assess whether it is necessary to continue long-term prophylaxis or whether the switch to on-demand therapy can be made. Attenuated androgens have been used for long-term prophylaxis since ; as such, there is plenty of data on their efficacy and safety.

Danazol and oxandrolone are used; stanozolol is no longer available. The efficacy of androgens is high. The attacks during danazol treatment were significantly milder compared to before or after treatment. Not all patients respond to androgen treatment.

Efficacy can decline in some patients after several years [ 61 ]. Possible side effects include, e. Isolated cases of hepatocellular adenoma have been reported [ 64 , 65 ], as well as hepatocellular carcinoma in a small number of patients.

Every 12 months: alpha-fetoprotein and ultrasound scan of the liver [ 60 ]. Attenuated androgens are not approved in Germany and need to be obtained via an international pharmacy. Anyone performing androgen treatment in HAE-C1-INH patients is also responsible for ensuring that the necessary monitoring of adverse side effects is carried out. For all these reasons, and since androgens have often been used in the past on the basis of an incorrect indication and at excessively high doses with the resultant sequelae, it is advisable for this form of treatment—if considered at all—to be carried out at an HAE treatment center see below.

The number of patients treated with danazol has declined significantly in Germany. Individual dose adjustment until the lowest possible dose at which symptoms are suppressed is reached. Pregnancy virilization of the female fetus is possible , lactation, childhood, prostate cancer, porphyria, severe heart, liver, and renal failure, active thrombosis or thromboembolic events, even in the patient history, and androgen-dependent tumor.

Interactions are numerous and must be taken into account prior to prescription carbamazepine, phenytoin, barbiturates, oral anticoagulants, sex hormones, antihypertensive drugs, antidiabetic agents, cyclosporine, tacrolimus, ethyl alcohol, alphacalcidol, statins. Another placebo-controlled cross-over study with tranexamic acid showed a marked improvement in HAE-C1-INH in the majority of patients [ 67 ].

The daily dose should then be titrated down to the lowest effective dose. Pregnancy, renal insufficiency, and acute thrombosis or thromboembolic events. Its use is highly limited in the case of a positive family history of thrombophilia or active thromboembolic events.

Possible side effects include gastrointestinal symptoms, myalgia involving elevated creatinine kinase and at least on the basis of theoretical considerations thrombosis. Patients predisposed to thrombosis should not be treated with tranexamic acid. Since impaired sense of color can also develop, regular ocular fundus examinations are necessary in the case of long-term treatment. Although they are not approved and there are no RCT on their use, there are reports on treatment success in case series [ 69 , 70 ].

Desogestrel is a progestin-only pill POP. Approximately two thirds of women reported symptom improvement on progestin. Dosage is the same as recommended for contraception. Weight gain and intermenstrual bleeding, among others, are possible side effects. Progestin treatment should not be combined with androgen treatment or tranexamic acid treatment. In general, the beneficial effects of progestin treatment are significantly more modest compared to prophylaxis with a C1-INH concentrate or attenuated androgens.

Work is underway to develop new treatment options in order to achieve the goal whereby HAE-C1-INH patients can lead as normal a life as possible. These potential new developments primarily relate to drugs intended for long-term prophylaxis. Developments are at various stages. Two developments are already well advanced:. The subcutaneous administration of C1-INH concentrate [ 72 ]. Subcutaneous or oral treatment with novel kallikrein inhibitors [ 73 , 74 ].

Particularly in the case of long-term prophylaxis in hereditary angioedema, i. Mortality due to HAE-C1-INH has diminished in recent years, not least due to numerous patient-information campaigns, transparent communication methods, and worldwide activity by patient organizations. It was particularly high in the past due to a lack of suitable diagnostic and therapeutic options.

The cause of death is virtually always asphyxiation due to laryngeal edema. This disease can still cause death today, albeit rarely [ 18 , 20 ]. Undiagnosed patients that develop edema of the upper respiratory tract in a manner that is unexpected both for themselves and those around them are at greatest risk. If the diagnosis and thus the risk it poses are known, suitable preventive measures can be taken, particularly in the form of detailed information on the disease and especially on the initial symptoms of edema, trigger factors, and emergency measures.

Irrespective of mortality, patients with HAE-C1-INH are often also affected by severe impairments in their daily and professional lives [ 75 , 76 , 77 ]. These can be significantly improved by means of adequate and effective treatment of symptoms or prophylactic treatment.

ID cards of this kind multilingual are available from the treatment centers and the German self-help group listed below. The patient and their disease should be known to the nearest hospital. All patients should have sufficient drugs for at least two attacks available at home and when traveling. In the case of schoolchildren, teachers should be informed about the fact that attacks may occur, how these manifest, and what action needs to be taken.

This information should be provided in written form. Treatment centers with particular experience in this field and which can be consulted by colleagues include:. In Germany, there is a specialist medical society that focuses specifically on hereditary and acquired angioedema:. Konrad Bork, in charge; Prof. Petra Staubach. Murat Bas. Tilo Biedermann, Prof.

Karin Hartmann, Prof. Bettina Wedi. Markus Magerl, Prof. Marcus Maurer. Inmaculada Martinez-Saguer. Hagen Ott. Canadian hereditary angioedema guideline. Allergy Asthma Clin Immunol. Article Google Scholar. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group.

CAS Google Scholar. International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency. Bork K. Immunol Allergy Clin North Am. Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies.

Orphanet J Rare Dis. Cytogenet Genome Res. Mutation screening of C1 inhibitor gene in unrelated families with hereditary angioedema: functional and structural correlates. Mol Immunol. Germenis AE, Speletas M. Genetics of hereditary angioedema revisited. Clin Rev Allergy Immunol. Plasma bradykinin in angio-oedema. Local bradykinin generation in hereditary angioedema.

J Allergy Clin Immunol. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist Icatibant. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency.

Am J Gastroenterol. Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Intern Med. Bork K, Ressel N. Sudden upper airway obstruction in patients with hereditary angioedema. Transfus Apher Sci. Asphyxiation by laryngeal edema in patients with hereditary angioedema.

Mayo Clin Proc. Bork K, Barnstedt SE. Laryngeal edema and death from asphyxiation after tooth extraction in four patients with hereditary angioedema. J Am Dent Assoc. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. Hereditary angioedema: new findings concerning symptoms, affected organs, and course.

Am J Med. The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey. Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate.

Am J Obstet Gynecol. Google Scholar. Risk of laryngeal edema and facial swellings after tooth extraction in patients with hereditary angioedema with and without prophylaxis with C1 inhibitor concentrate: a retrospective study. Dtsch Med Wochenschr. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Hereditary angioedema with a mutation in the plasminogen gene.

Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema. Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks. Ann Allergy Asthma Immunol. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. Pasteurized C1 inhibitor concentrate in hereditary angioedema: pharmacology, safety, efficacy and future directions.

Expert Rev Clin Immunol. Treatment of episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Treatment of skin swellings with C1-inhibitor concentrate in patients with hereditary angio-oedema. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks.

C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. Bork K, Hardt J.

Hereditary angioedema: increased number of attacks after frequent treatments with C1 inhibitor concentrate.

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