In most cases spontaneous acute urticaria disappears within two to four weeks (by definition within six weeks).

Acute urticaria is considered as a classical manifestation of viral infection in general, especially in children 7 11 12 but also in adults. Recent data found infections to be the most common identified cause (37%) 13 . Accordingly, in children infections were identified in 57% of acute urticaria cases 14 , benign viral upper respiratory (nasopharnygitis) or digestive infections being the most frequent etiology.

Due to the limited duration of spontaneous acute urticaria systematic studies are rare. With regard to general inflammatory parameters leukocytosis was found in 36/57 children (63%) with acute urticaria and elevated C-reactive protein in 16/36 (44%) 15 .

Reports described acute urticaria caused by streptococcus, mycoplasma pneumoniae, parvovirus B19, norovirus, enterovirus, Hepatitis A or B (so called "yellow" urticaria), and plasmodium falciparum (Table 1). A review 16 summarized five studies and found upper respiratory viral infections to affect about half of the patients with acute urticaria. Seasonal variations of incidence have been explained by peaks of infections with influenza-, adeno-, respiratory syncytial, possibly also parainfluenza and rhinoviruses in winter and different types of coxsackie-, corona- and adenoviruses in June 17 . In addition, acute urticaria due to influenza vaccination has been reported 18 .

However, bacterial infections such as cystitis and tonsillitis can be also found in association with acute urticaria 12 19 20 . Already 1964 it has been described that antistreptolysin titres are significantly more common in acute urticaria compared to controls 21 .

20-30% of children with spontaneous acute urticaria, 91% of them caused by infection, progressed to chronic urticaria 12 .

In southern countries acute urticaria might be caused by Anisakis simplex, a seafish nematode, after eating uncooked fish 22 23 However, the role of Anisakis in recurrent acute urticaria is discussed controversially 24 25 26 . Double blind placebo-controlled oral challenges with 100 lyophilized Anisakis simplex larvae, or its equivalent in antigen, did not induce clinical symptoms in individuals with a clinical history and laboratory findings of hypersensitivity to Anisakis simplex 27 .

Whereas the prevalence of infections, bacterial, viral, parasitic or fungal, appears not to differ in spontaneous chronic urticaria compared to the general population, there is a very large amount of reports demonstrating benefit after eradication of infectious processes 7 .

Published data differ substantially with respect to study population, diagnostic tests, evaluation procedure and follow-ups, assessment of treatment and interpretation. Moreover, often the multitude of triggering factors has been oversimplified.

Regarding general inflammatory parameters elevated erythrocyte sedimentation was found in 2% of 66 patients with chronic urticaria, abnormal C-reactive protein in 16% of 88 patients, and leukocytosis in 23% of 133 patients 28 .

Most reported infections in chronic urticaria are related to the gastro-intestinal tract, but also to the dental or ENT region.

Several gastro-intestinal infections have been linked to chronic urticaria (Table 1). Best evidence exists for Helicobacter pylori infection (Table 2).

Systematically reviewing existing studies addressing the effect of antibiotic therapy for chronic urticaria patients infected with Helicobacter pylori in 2003 revealed that resolution of urticaria was more likely when antibiotic therapy was successful in eradication of Helicobacter 29 . 10 studies fulfilled the inclusion criteria and when data from these studies were combined, eradication of Helicobacter pylori was both significantly associated with remission of urticaria (odds ratio 2.9, 95% confidence interval 1.4-6.8; p = 0.005). When comparing the remission in patients with H. pylori eradication to H. pylori negative patients with chronic urticaria the odds ratio increased to 4.7 (95% CI 2.6-17.6, p = 0.001) 29 . The authors concluded that clinicians, after considering other causes of urticaria, should constitute (1) testing for Helicobacter pylori; (2) treating with appropriate antibiotics if Helicobacter pylori is present; and (3) confirming successful eradication of infection 29 . We are recommending this approach for several years 7 19 30 31 32 .

The problem of several studies, including one from 2008 33 that argue against a benefit of Helicobacter pylori eradication in chronic urticaria, is, that a control of the eradication status was missing or inadequate eradication schedules or control methods were used. This has been reviewed in detail 1 . Control of eradication success is of particular importance since the success of eradication with triple therapy has been decreasing with increasing resistance to commonly used antimicrobials. A multicenter study published in 2001 4 demonstrated significant resistance rates against metronidazole and clarithromycin in Western countries of up to 62% (Helsinki, Finland) and 27% (Chieti, Italy), respectively (for amoxicillin up to 8%) 4 . In this regard, clinicians should bear in mind that an urea breath test or a Helicobacter pylori stool antigen test can be false negative (e.g. if proton pump inhibitors are not stopped four weeks before).

After publication of the systematic review in 2003 29 several studies from different countries (Japan, Mexico, Israel, India) have confirmed a clear and statistical significant benefit of Helicobacter eradication in chronic urticaria (Table 2) 34 35 36 37 . In all these studies eradication status was proven 4-6 weeks after the treatment and only patients with proven eradication of Helicobacter pylori were evaluated regarding the outcome of their urticaria. Moreover, in two studies well-accepted objective urticaria activity scores or standardized quality of life instruments were used to demonstrate that proven eradication of Helicobacter pylori resulted in a statistically significant reduction of urticaria activity score 36 and a significant increase of quality of life (CU-Q₂ol) 37 , respectively.

Nowadays, the combination of all studies regarding Helicobacter that included patients with chronic urticaria, excluded other causes of urticaria by appropriate testing, and controlled success of eradication treatment resulted in the identification of 13 studies (including a total of 322 eradicated patients) pro a benefit of Helicobacter eradication for chronic urticaria (Table 2) and 9 studies (including 164 eradicated patients) contra a benefit (Table 3). In the studies that apply for a benefit 84% of patients demonstrated significant improvement or complete remission of chronic urticaria after eradication of Helicobacter, in contrast to 45% of untreated Helicobacter positive, and 29% of untreated Helicobacter negative patients with chronic urticaria (Table 2). Looking at the treatment schedules it is interesting that most pro studies (69%) used a triple treatment consisting of a proton pump inhibitor plus amoxicillin plus clarithromycin, the two newer studies by Magen 36 and Yadav 37 even for two weeks, in contrast to only 44% of contra studies. Thus, future studies should clarify whether the type of treatment schedule has an impact on the urticaria remission rate.

Taken all studies (pro and contra) together (Table 4), the rate of remission of urticaria when Helicobacter pylori was eradicated was 61.5% (275/447) compared with 33.6% (43/128) when Helicobacter pylori was not eradicated; the background remission rate among control subjects without H pylori infection was 29.7% (36/121). To account for the clustering of observations, a chi-square test was used. Compared to the review published in 2003, the difference is much clearer in favour of a benefit of Helicobacter eradication (p < 0.001) (Table 4). The remission/improvement rate is nearly doubled when Helicobacter pylori is eradicated.

Concerning other gastro-intestinal infections, two studies described abnormal serology for yersinia (abnormal anti-yersinia-IgA and several bands in the immunoblot) consistent with persistent yersiniosis in 39% (36/93 chronic urticaria patients) and 31% (46/145 patients), respectively 38 . In several cases remission of urticaria after adequate antibiotic treatment (quinolones or TMP/SMX) was observed. In addition, a more recent study found specific antibodies for yersinia (IgG) in 31/74 (42%) of chronic urticaria patients 19 33 .

Looking at viral gastrointestinal infections there is one report that linked chronic urticaria to infection with Norovirus 39 . In contrast, a review regarding a link between hepatitis viruses and chronic urticaria concluded that no convincing argument exists to suggest causality 40 .

Regarding parasites there is evidence for a role of infestation with Blastocystis hominis and Giardia lamblia 41 42 . A study from Switzerland found parasites in stool in 35% of 46 patients with chronic urticaria, most of them with Blastocystis hominis 28 . More rarely, other parasites such as trichinella, trichomonas vaginalis, toxocara canis have been described (Table 1). However, occult parasitosis is not a likely cause in Western populations, and peripheral blood eosinophilia nearly always indicates infestations.

Regarding fungi, recent data found no evidence for an association of Candida spp. with chronic urticaria 43 . Intestinal and oral colonization of Candida spp. and serological evidence (ELISA anti-Candida-IgG/-IgM/-IgA) of Candida infections were not significantly different between patients with chronic urticaria (n = 38) and controls (n = 42) 43 . In contrast, anti-Candida-IgE was found in another study 44 . The meaning is unclear, particularly because the findings were associated with elevated total IgE and could therefore be non-specific. Actually, candidiasis is regarded not to play a significant role for chronic urticaria although it should be treated if the colonization is extensively 45 .

A study published in 1964 found that roentgenographic examinations found sinusitis in 32% of 59 chronic urticaria, and dental focal infections in 29% of 45 patients 20 . At least 8 cases with complete remission of chronic urticaria after elimination of dental focal infections have been described 46 47 48 49 50 51 52 . However, two studies did not find a significant association between chronic urticaria and dental infections 53 54 .

A recent study identified tonsillitis or sinusitis in almost 50% of analyzed patients 55 . Anti-streptococcal antibodies have been described in 10-42% of patients with chronic urticaria, and antistaphylolysin antibodies in 1-10% of patients (reviewed in 7 ).

Recent data found high nasal carriage of Staphylococcus aureus in patients with chronic urticaria compared to controls suggesting that nasal carriage functions as focus 56 . Moreover, a sub-population of patients with chronic urticaria was demonstrated to have serum IgE antibodies to SEA, SEB, and TSST 57 .

In a study published in 1967 it was described that the outstanding historical feature in 15 of 16 children with chronic urticaria was recurrent upper respiratory infection, pharyngitis, tonsillitis, sinusitis, otitis, often by streptococci or staphylococci 58 . Remission of urticaria was frequently noted following antibiotic therapy 58 . This fits with our clinical experience in children 7 59 .

Nevertheless, systematic antibiotic treatment studies of dental or ENT focal infections are lacking although benefit after oral cephalosporin or amoxicillin treatment has been described 7 .

Angioedema is a self-limited nonpitting edema generally affecting the deeper layers of the skin and mucous membranes. It is the result of increased vascular permeability causing the leakage of fluid into the skin in response to potent vasodilators released by immunologic mediators. Two main pathways are thought to be implicated in angioedema. The most common is the mast cell pathway in which preformed mediators, such as histamine, leukotrienes and prostaglandins, are released from mast cells through IgE or direct activation. The second pathway is the kinin pathway, most notably affected by angiotensin converting enzyme (ACE) inhibitors and hereditary forms of angioedema with C1-esterase inhibitor defects, which ultimately results in the formation of bradykinin, a potent vasodilator.

Studies focusing on the role of infections in isolated recurrent angioedema are sparse. Regarding mast-cell mediated recurrent angioedema a recent study found 27 of 776 cases to be of infectious origin (e. g. dental granuloma, sinusitis, urinary tract infection) 60 . However, in this study in 41% (n = 315) the etiology remained unclear. Regarding infectious triggers the following investigations were performed routinely: blood cell count, erythrocyte sedimentation rate, C-reactive protein, hepatic enzymes, sinus and dental radiographs, stool examinations for ova and parasites and urine analyses, pharyngeal and urine samples were cultured 60 . This means that infections with Helicobacter pylori, streptococci, staphylococci, and yersinia could have been overlooked.

Among children, infection is regarded to be a common cause of angioedema 61 . Viral infections such as herpes simplex, coxsackie A and B, hepatitis B, Epstein-Barr, and other viral illnesses such as upper respiratory tract infections have been described. Bacterial infections associated with angioedema among children include otitis media, sinusitis, tonsillitis, upper respiratory tract infections, and urinary tract infections. Parasitic infections are considered to be less common, but may be possible with strongyloides, toxocara, and filarial 61 .

An exacerbating role of Helicobacter pylori infection in hereditary angioedema is well established 62 63 64 . These authors stated that, whatever the mechanism of the association between H. pylori infection and HAE attacks, screening for H. pylori infection and eradication of this pathogen from infected patients with frequently recurring abdominal symptoms both seem warranted.

In addition, two cases with acquired C1-Esterase-Inhibitor deficiency due to autoantibodies have been associated with Helicobacter pylori infection 65 66 .

Physical urticaria accounts for about 15% of urticaria cases and is triggered by exogenous mechanical stimuli that by both, immunologic and non-immunologic mechanisms - cause mast cell activation. Often these physical urticaria subtypes persist for average 3-5 years and may interfere with ability to work. Recent data demonstrated that also in children physical urticaria is long-persisting: only 38% were symptom-free 5 years post-onset 67 .

Physical urticaria is divided into several subtypes with dermatographic urticaria (urticaria factitia) being the commonest form, followed by cold urticaria and delayed pressure urticaria whereas heat urticaria, solar and vibratory urticaria are very rare. In physical urticaria the routine diagnosis is mainly limited to identify the subtype by appropriate standardized challenge tests 68 .

The association of physical urticaria to infections has been poorly studied. Most physical urticarias are regarded not to be associated with infection but systematic studies are lacking and often no investigations regarding infections have been performed.

There are no reports of infections in dermographic urticaria (urticaria factitia) although it is generally accepted that dermographism can start after infections and/or drug intake (e. g. penicillin).

The vast majority of cold urticaria is idiopathic but up to 5% of cold urticaria is regarded to be associated with infections (syphilis, borreliosis, measles, varicella, hepatitis, mononucleosis, HIV). However, a recent analysis of 62 patients with cold urticaria did not find relevant underlying infections (investigating hepatitis profile, serology for EBV, syphilis, and stool analysis for parasitosis) 69 . Nevertheless, in an open study 20-50% of patients responded to antibiotic treatment pointing to the possibility of unrecognized bacterial infections 70 . One case of acquired cold urticaria was cured after eradication of Helicobacter pylori 71 .

Cholinergic urticaria caused by increased body temperature after physical exercise and/or emotional stress is common in young adults. The long presumed hypothesis that it may be caused by sensitization to sweat antigens is under investigation 72 .

There are no reports dealing with infections in cholinergic urticaria.

The pathogenesis of aquagenic urticaria remains unclear, although there is evidence to suggest that it is histamine-mediated. A single case of aquagenic urticaria associated with HIV infection has been described 73 .

The pathogenetic mechanisms by which infections may induce urticaria are far from being clear. Several hypotheses have been developed, particularly regarding the link with Helicobacter pylori. There is increasing evidence for systemic effects of gastric Helicobacter pylori infection, which may be involved in extra-gastrointestinal disorders such as vascular, autoimmune and skin diseases.

Interestingly enough, actually, in patients with chronic idiopathic thrombocytopenic purpura (ITP) and Helicobacter pylori infection eradication is suggested by the European Helicobacter Study Group consensus 2007 74 .

In chronic urticaria several studies have described specific immune responses to Helicobacter pylori infection.

For example, the prevalence of IgA- and IgG-antibodies to Helicobacter pylori-associated lpp20 antibodies was significantly higher in Helicobacter pylori-infected chronic urticaria compared to the control group of patients with severe H. pylori-associated gastritis without urticaria (93.9 vs. 21.2%, P < 0.0001 for IgG, and 46.1 vs. 6.3%, P < 0.0029 for IgA) 75 .

In single cases specific IgE antibodies to Helicobacter antigens have been described. For example, an IgE antibody to a 44 K antigen was found in 2/2 patients with chronic urticaria and complete remission after Helicobacter eradication 76 . In a similar case Gala-Ortiz et al. 77 demonstrated IgE binding to a Helicobacter pylori antigen by immunoblotting. Moreover, Mini et al. demonstrated a specific IgA- and IgE-mediated immune response against antioxidative bacterial proteins in chronic urticaria patients but not in Helicobacter-infected dyspeptic patients without urticaria 78 .

Host factors like the presence in gastric mucosa of Lewis b antigen, a receptor for Helicobacter pylori, could be an individual susceptibility factor for infection and indirectly for development of other symptoms related to the antimicrobial immune response. It is tempting to speculate that structural components like adhesins or products of Helicobacter pylori such as urease, protease, phospholipase or cytotoxins may be released and may trigger complement activation.

Significantly increased gastric juice ECP (eosinophil cationic protein) and gastric eosinophil infiltration were described in Helicobacter pylori-infected chronic urticaria compared to both uninfected chronic urticaria patients and normal controls 79 . Moreover, Helicobacter pylori eradication resulted in a significant decrease in gastric juice ECP and gastric eosinophil infiltration only in chronic urticaria patients.

The expression of two H. pylori proteins, cytotoxin associated protein (cag A) and vacuolization cytotoxin (vac A) is considered to be related with pathogenicity of the bacterium. Infection with cag A+ strains is more common in patients with acne rosacea, stroke and coronary heart disease. Only few studies investigated cag A or vac A status in Helicobacter-infected chronic urticaria patients: Shiotani et al. did not find any distinctive features investigating the seroprevalence of IgG and IgE antibody against cag A and vac A 76 . Fukuda et al. found the cag A gene in all Helicobacter pylori strains isolated from the gastric mucosa of 13 patients with chronic urticaria, but this was comparable to Helicobacter-positive controls without urticaria 34 .

Spontaneous chronic urticaria is associated with autoreactivity/autoimmunity in at least one third of patients. Details of the autoimmune pathogenesis of chronic urticaria have been reviewed elsewhere 80 81 82 .

Particularly autoantibodies to thyroid and histamine releasing autoantibodies to the high affinity IgE receptor (FcεRI) or to IgE are found. Moreover, the serum of patients with positive autologous serum skin test contains undefined immunoglobulin-independent stimulators of mast cell/basophil activation resulting not only in histamine release, but also in cysteinyl leukotrienes production and basophil activation (CD63 surface expression) 83 . In this regard, complement mediated augmentation of mast cell/basophil degranulation or activation may play a major role but does not explain all the functional effects 84 85 86 .

In addition, the association of certain HLA class II alleles supports an autoimmune pathogenesis in a subset of patients with chronic urticaria 87 88 89 .

Autoreactivity occurs when the immune system recognizes host tissue and infectious pathogens such as bacteria are thought to play a major role in its development 90 . Mechanisms by which pathogens might cause autoimmunity include (a) molecular mimicry (pathogen-derived epitopes cross-react with self-derived epitopes); (b) epitope spreading (the persisting pathogen causes damage to self-tissue by inducing direct lysis or immune response), (c) bystander activation (non-specific activation of various parts of the immune system), or (d) cryptic antigens (subdominant cryptic antigens appear after inflammatory reactions) 90 .

Regarding the pathogens that have been described in spontaneous chronic urticaria some of these mechanisms have been described for persistent infections with Helicobacter pylori infection, streptococci, staphylococci, and yersinia 7 91 .

In autoimmune type-B gastritis molecular mimicry between Helicobacter pylori and lipopolysaccharide (LPS) and anti-Lewis antibodies has been described 92 93 . In this regard, positivity of autologous serum skin test has been associated with Helicobacter pylori infection in chronic urticaria 94 95 . Interestingly, in some but not all patients with chronic urticaria autologous serum skin test became negative after Helicobacter eradication (own unpublished observation). Moreover, recent data found a significant difference in the prevalence of Helicobacter pylori infection between autoimmune urticaria with and without thyroid autoimmunity (90.9% vs. 46.7%; P = 0.02). Autoimmune thyroiditis was associated with cag A+ Helicobacter pylori strains 96 . Thus, in immunologically predisposed individuals, infection with Helicobacter pylori may result in the manifestation of a latent autoimmune pathomechanism.

Regarding molecular mimicry for other pathogens, it may be of note that infection with yersinia is linked to autoimmune thyroiditis 97 . Accordingly, persistence of streptococcal infection has been associated with autoimmunity 98 99 . An example for this phenomenon is the molecular mimicry between haemolytic streptococcus group A antigens and host proteins, which has been studied in detailed and lead to autoimmune reactions both humoral and cell mediated causing rheumatic fever and rheumatic heart disease 100 .