[Guidelines for the diagnosis and treatment of hereditary angioedema]. / Smjernice za dijagnostiku i lijecenje hereditarnog angioedema.

Hereditary angioedema (HAE) is a rare but potentially fatal genetic disorder with nonpitting, nonerythematous, and not pruritic swelling which can affect the hands, feet, face, genitals and visceral mucosa. The type, frequency, and severity of the attacks vary between patients, and over the lifetime of an individual patient. Efforts in Croatian counties have identified approximately 100 patients (but there must be more undiagnosed patients). The first global guideline for the management of HAE was developed by the World Allergy Organization HAE International Alliance and published in 2012. Based on that document the Working group of Croatian experts was assigned to propose guideline for HAE management in Croatia. HAE is is most often related to decreased or dysfunctional C1 inh with autoactivation of C1 and bradykinin accumulation leading to localized dilatation and increased permeability of blood vessels resulting in tissue swelling. A diagnosis of HAE can be confirmed by measuring complement and C1 inh quantitative and functional levels.Three HAE types could be differentiated: HAE type 1 (C1 inh level is low), HAE type 2 (C1 inh level is normal but dysfunctional), and HAE type 3 (normal level and function of C1 inh). All patients suspected to have HAE-1/2 should be assessed for blood levels of C4, C1 inh protein, and C1 inh function. All attacks that result in debilitation/dysfunction and/or involve the face, the neck, or the abdomen should be considered for on-demand treatment. It is recommended that attacks are treated as early as possible. HAE attacks are treated with C1 inh, ecallantide, or icatibant.If these drugs are not available, attacks should be treated with solvent detergent-treated plasma (SDP). If SDP is not available, then attacks should be treated with frozen plasma.Intubation or tracheotomy should be considered early in progressive upper airway edema. Patients with attacks could receive adjuvant therapy when indicated (pain management, intravenous fluids). All patients should have on-demand treatment for two attacks and carry their on-demand treatment at all times. The administration of short-term prophylaxis should be considered before surgeries (dental/intraoral surgery, where endotracheal intubation is required), where upper airway or pharynx is manipulated, and before bronchoscopy or endoscopy. Long-term prophylaxis should be considered in all severely symptomatic HAE-1/2 patients. C1 inh concentrate or androgens can be used. Screening children for HAE-1/2 should be deferred until the age of 12 months, and all offspring of an affected parent should be tested.

[Correlation between pholcodine and perioperative anaphylaxis]. / Povezanost folkodina i perioperativne anafilaksije.

A large number of individuals experiencing anaphylactic reaction to neuromuscular blocking agents have not previously been in contact with them. The search for a substance inducing sensitization to muscle relaxants has led Norwegian and Swedish scientists to pholcodine, a cough suppressant, which is widely used in Europe and worldwide. Ammonium ion is an epitope common to pholcodine and neuromuscular blocking agents and it is the basis of their cross-reactivity. Based on the results of published studies that pointed to a connection of the use of pholcodine and perioperative anaphylactic reaction, pholcodine was withdrawn from the Norwegian market and subsequent research revealed a reduction of anaphylactic reactions in that country. In its latest report, the European Medicines Agency made a decision not to withdraw pholcodine mixtures from the market but it urged further research with the aim to clarify the cross-reactivity between pholcodine and neuromuscular blocking agents.

[Ankle-brachial pressure index as a predictor of future cardiovascular outcomes]. / Omjer tlaka nad gleznjem i nadlakticom-metoda procjene kardiovaskularnog rizika.

Peripheral arterial occlusive disease is very common in the general population and it is mostly of atherosclerotic origin. About 50%-75% of patients are asymptomatic. Many studies have shown the ankle-brachial pressure index (ABPI) to be a simple and reliable test with high sensitivity (90%) and specificity (98%) in the diagnosis of hemodynamically relevant stenosis of an arterial segment and also in detection of asymptomatic patients. The values of ABPI < 0.90 suggest widespread atherosclerosis, while the ABPI > 1.40 is associated with arterial calcification and wall stiffening. This test is highly specific (92.7%) in predicting future cardiovascular and cerebrovascular risk and could provide a tool for more focused prevention strategies.

[House dust mite allergy--living with the invisible roommates]. / Alergija na grinje kucne prasine--zivot s nevidljivim sustanarima.

House dust mites are the most common sources of allergic sensitization, primarily responsible for the occurrence of various clinical forms of respiratory and skin allergies, but also of certain forms of food allergy. There are many various mite species, of which only a small number are constantly or occasionally found in house dust samples. Mites from Pyroglyphidae family, Dermatophagoides pteronyssinus and Dermatophagoides farinae are most frequently responsible for sensitization of susceptible persons. Other less commonly found species may represent individual primary sources of sensitization, or may cause disease symptoms due to cross-reactivity. The exposure to various mite species within different geographical regions accounts for the generation of various sensitization profiles. Knowing these profiles is important for planning rational specific immunotherapy, which greatly determines its efficacy. The aims of this paper are to review the environment conditions that influence mite incidence and the ways their changes can control allergen amounts in patient homes, to review the allergenic content and the significance of cross-reactivity among mite allergens, and finally, to explain the factors that enable the generation of various sensitization profiles.

[House dust mite allergy--how to win?]. / Alergija na grinje kucne prasine--kako pobijediti?

Manifestations of house dust mite allergy include perennial allergic rhinitis often accompanied by ocular symptoms, allergic asthma, and somewhat rarer atopic dermatitis. Sensitization to mite tropomyosin may lead to hypersensitivity to certain foodstuffs. Allergic sensitization and development of the disease are connected to the level of allergen exposure, indicating that the patients' home exposure to mite allergens is a useful indicator of their risk. Since the possibility of allergen avoidance is limited, and available pharmacological treatments have just symptomatic effects, the only causative treatment for mite allergy is specific immunotherapy. Its well-documented clinical effects include reduction of symptoms, prevention of the disease severity progression, and prevention of sensitization to new allergens. Immunological parameters show characteristic dynamics during treatment, which is also reflected in gradual reduction of the skin reactivity towards the allergen. Despite ample evidence and a hundred-year use in clinical practice, the efficacy of specific immunotherapy is sometimes still questioned. The aim of this paper is to show that, when properly indicated with due consideration of the person's sensitization profile, it is a very successful treatment method.

[Asthma phenotypes and disorder of the immune system homeostasis]. / Fenotipovi astme i poremecaj homeostaze imunoloskog sustava.

Many regulatory pathways involved in the pre- and post-IgE synthesis signaling have been elucidated and effects of numerous mediators included in allergic cascade understood; however, asthma remains a clinical and scientific problem. Immune system is being confused by modern civilization, producing complex interaction among epigenetic regulation, variable extrinsic factors and various combinations of paired effects, i.e. genes, antigens and life periods. It is therefore necessary to answer the question of how to ensure an adequate level of necessary immune stimuli at the time of intensive immune system development until age 6. Advances in immunology have enabled full asthma control but not cure in a great proportion of patients. Therefore, researchers have focused on particular features of specific inflammatory asthma subtypes, i.e. eosinophilic, neutrophilic, mixed and asthma without inflammatory cells. Therapeutic response to inhalant and systemic corticosteroids in a particular subtype is also investigated. The Global Initiative for Asthma Guidelines, developed by the group of experts and regularly updated with new scientific concepts, are available in clinical routine. The guidelines provide a useful framework for the choice of drugs and dosage, but they cannot replace clinician's evaluation in individual approach to patient. However, current conditions still cannot ensure personalized asthma therapy.

[Increasing incidence of angioedema without urticaria--clinical features]. / Trend povecane incidencije angioedema bez urtikarije--klinicke osobitosti.

The causes of angioedema (AE), a self-limited, localized swelling of subcutaneous tissue or mucosa unaccompanied by urticaria, are diverse. The commonly applied label of "allergic" is frequently wrong and standard anti-allergic therapy can be ineffective. Types of AE could be categorized according to mediators which mediate vascular leakage: bradykinin AE (hereditary, acquired, angiotensin-converting enzyme inhibitor (ACEi)-related), histamine AE (allergic etiology), and various mediators mediated AE (pseudoallergic reaction to non-steroidal anti-inflammatory drugs). Idiopathic AE is a poorly understood syndrome. The growing relevance of AE without urticaria has been highlighted; angioedema is the most common cause of hospital admission among all acute allergic diseases. The diagnosis of AE is based on the presence of family history (hereditary), absence of family history with the onset during or after the fourth decade of life (acquired C1lnh deficiency), and treatment with ACEi (ACEi-related angioedema). About 0.1%-0.7% of patients taking ACEi develop angioedema as a well-documented but still frequently unrecognized side effect of drugs. Laboratory diagnosis is enabled by measuring serum levels of C1lnh antigen or C1lnh function. Type 1 (hereditary angioedema (HAE) was diagnosed when both antigenic and functional levels of C1lnh were below 50% of normal, and type 2 when functional levels of C1lnh were low, along with antigenic levels normal or higher. ACEi-related AE is diagnosed when AE recurs during therapy and disappears upon withdrawal. Symptoms may appear several years after therapy introduction. Severe acute attacks should be treated with C1lnh concentrate and icatibant, a selective and specific antagonist of bradykinin B2 receptors. Prophylaxis with attenuated androgens (danazol, stanazolol, oxandrolone) is effective in preventing symptom development.

[Chronologic annotation on the development of allergology and clinical immunology in Croatia]. / Kronoloski osvrt na razvoj alergologije i klinicke imunologije u Hrvatskoj.

This issue of Acta Medica Croatica is dedicated to historical development and role of allergology and clinical immunology in Croatia. Also listed are the names of experts who have historically marked allergology and contributed to its development. Understanding the origin of allergies as immune phenomena occurred in Croatia simultaneously to many other European countries. The origin and development of institutions established in the early 1920s constituted the backbone of a solid vertical line, crucial for the development of allergology and immunology in Croatia during the past century. Interest of allergology experts from various medical specialties has resulted in the establishment of Allergy Section at the Croatian Medical Association in 1952, now Croatian Society of Allergology and Clinical Immunology of the Croatian Medical Association. It turned out that the work of institutions and physicians, as well as cooperation with the Croatian Immunological Society and other scientific institutions during the second half of the 20th century provided solid foundation for contemporary research, design and development of allergy subspecialty centers and units at various medical institutions all over Croatia. Members of the Croatian Society of Allergology and Clinical Immunology have played an important role in educating new generations of physicians and in the organization of numerous research projects, symposia, congresses and seminars. Continuous, scientific and professional work has resulted in active Society membership in the European Academy of Clinical Immunology and Allergology.

[Pathophysiological mechanisms of allergic disease occurrence and treatment]. / Patofizioloski mehanizmi u nastanku i lijecenju alergijskih bolesti.

Why the exposure to the harmless and ubiquitous environmental substances causes inappropriately strong reactions of the immune system clinically manifested as allergies in some people, and how repeated exposures to the same substances during the specific immunotherapy divert immunologic reactivity, are so far only partially answered questions. The events that occur during the allergic inflammatory response are relatively well-known, as are the major operative mechanisms through which the specific immunotherapy, the only causative treatment method, changes that response. Nevertheless, everyday new findings are completing the puzzle and our understanding of these complex processes. The aim of this paper was to review the up-to-date known mechanisms of allergic disease occurrence and treatment, with regard to the key role of T cells in these processes.

[The high-affinity IgE-receptor signaling pathway in the treatment of allergies]. / Signalni put visokoafinitetnog IgE-receptora u lijecenju alergijskih bolesti.

The rise in a prevalence of allergic diseases observed in industrialized countries over many years, and generally a rising number of the patients, require constant searching for newer and better ways of treatment. The central event in the formation of the allergic inflammation, the activation of mast cells and basophils, is mediated by signaling through the high-affinity IgE receptor, FcepsilonRI. The signaling starts by cross-linking of receptor-bound IgE with an allergen. This initiates a cascade of signaling events that activates the cell and ultimately causes the release of mediators responsible for allergic responses. The major flaw of medications traditionally used for the treatment of allergies is their orientation to single mediators, and not to the whole sequence of complex events leading to the onset of early and late symptoms. The aim of this paper was to review a complex sequence of events from the allergen binding to the onset of symptoms, highlighting the importance of the IgE-receptor signaling pathway in searching for new therapeutic modalities.

Serum levels of VEGF and bFGF in hypoxic patients with exacerbated COPD.

Hypoxia frequently complicates the course of chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are the two most potent angiogenic factors and may play a role in adaptation to hypoxia. The aims of the study were to assess the serum levels of VEGF and bFGF and to evaluate their mutual relationship in hypoxic patients with exacerbated COPD. The study group consisted of 50 hypoxic (PaO(2) 53 mmHg) patients with exacerbated COPD. Control groups were 30 stable COPD patients with PaO(2) 70 mmHg, and 30 healthy blood donors. The serum concentrations of VEGF and bFGF were measured using commercial enzyme-linked immunoassay kits. Patients with exacerbated COPD had significantly higher serum VEGF levels (1,089.16 +/- 1,128.03 pg/mL) compared to those with stable COPD (197.68 +/- 178.06 pg/mL) (p < 0.0001) and healthy blood donor group (257.69 +/- 170.4 pg/mL) (p < 0.0001). Serum bFGF levels were significantly higher in the exacerbated COPD group (6.15 +/- 2.56 pg/mL) compared to control groups (p = 0.0001). Basic FGF was undetectable in the stable COPD and blood donor groups. Since VEGF and bFGF correlated significantly with the majority of factors investigated in COPD patients, multivariate analysis was performed. According to the step-wise regression analysis, VEGF was best determined by PaO(2), WBC and IL-6. Basic FGF was best determined by PaO(2) and pH. The highly significant, simple correlation between VEGF and bFGF was lost in multivariate analysis. This suggests that their correlation is not independent, but due to factors that remain in the model after step-wise regression. These are essentially linked to the level of hypoxia. Results of our study suggest that VEGF and bFGF production is stimulated in hypoxic patients with exacerbated COPD. Elevated levels of VEGF and bFGF may activate the process of neoangiogenesis, which may lead to increased perfusion and an improvement in tissue oxygenation in this group of patients.