Compositae dermatitis in a Danish dermatology department in 1 year

During our first year of routine testing with Compositae allergens and extracts, contact allergy to Compositae was frequently found in eczema patients (4.5%), especially in middle-aged or elderly persons. Based on clinical patterns, patch test reactions and the long-term course of the disease, 4 groups of patients were recognized: (a) a small group with localized eczema: (b) another with classic Compositae dermatitis of exposed skin; (c) a 3rd group, the largest, with localized eczema that suddenly one summer turned into a widespread dermatitis: (d) a 4th group with a vesicular hand eczema and more-or-less widespread dermatitis with seasonal variation from the beginning, 65% of the patients had vesicular hand eczema at some time, partly reflecting the frequency of atopy (25%) and metal allergy (44%). 75% of the patients had contact allergy to 5 ≥1 compounds besides Compositae Thus, Compositae allergy may be primary, e.g., in young patients with occupational plant contact, or secondary to other contact allergies, perhaps as a result of increased individual susceptibility. The clinical patterns in the latter patients were most often a widespread dermatitis with summer exacerbation. The variability in the clinical picture makes routine patch testing with Compositae allergens recommendable.     

Patch test sensitization to Compositae mix, sesquiterpene-lactone mix, Compositae extracts, laurel leaf, Chlorophorin, Mansonone A, and dimethoxydalbergione.

BACKGROUND: Compositae mix and sesquiterpene-lactone (SL) mix are important patch test substances to show allergic contact dermatitis from various Compositae plants. OBJECTIVES: The aims of this study are to calculate the sensitization rates to Compositae mix and SL mix in an occupational dermatology clinic and to describe cases of active sensitization caused by patch testing with Compositae mix and SL mix. METHODS: Conventional patch testing was performed. SL mix (0.1%) and Compositae mix (6% in petrolatum) were tested in a modified European standard series and a plant allergen series. Testing with other appropriate patch test series was also performed. RESULTS: SL mix provoked 8 allergic patch test reactions (0.7%) in 1,076 patients, whereas Compositae mix was positive in 15 of 346 patients (4.2%). Three patients were actively sensitized to Compositae mix and 1 patient to SL mix. One patient was also sensitized to other plant allergens in a series of allergenic plant chemicals, namely to Mansonone A, an ortho-quinone; (R)-3,4-dimethoxydalbergione, a quinone; and Chlorophorin, a hydroxy stilbene. Allergic patch test reactions to laurel leaf were caused by cross-sensitization to SLs. CONCLUSION: Compositae mix seems to be a more important patch test substance than SL mix to detect allergic contact dermatitis to Compositae plants, but patch testing may sensitize. The concentration of the individual components of the Compositae mix should be adjusted so that the mix detects allergic patients but does not sensitize.     

Compositae dermatitis

Compositae dermatitis is an allergic contact dermatitis. The most important allergens in the Compositae family are sesquiterpene lactones (SL), which are present in the oleoresin fraction of leaf, stem, flower and possibly pollen. Compositae dermatitis is most frequently seen in middle-aged and elderly people in patterns reflecting airborne or direct contact with the allergens. The pattern typically starts in summer and disappears in the autumn or winter. Repeated exposure over many years may lead to a chronic and, at times, a disseminated pattern. Seasonal variation does not occur in occupational Compositae dermatitis. In addition to the classically described airborne pattern of face, 'V' of neck, hands and forearms, hand dermatitis is now recognized to be an equally common presentation. This variability of clinical features, and the frequent occurrence of atopic dermatitis and contact allergy to one or more compounds, highlights the need for routine patch testing with sesquiterpene lactone mix 0.1% (Thermal, Hamburg, Germany), combined with aimed patch testing with Compositae plants and extracts. Avoidance of the plants and plant extracts of this large family can be difficult due to its widespread occurrence in flower, herb and vegetable gardens, urban and rural weed population and native vegetation. Importantly, Compositae plant extracts are present in many cosmetics, shampoos, herbal creams and ingested herbal remedies and tonics.     

Recalcitrant atopic dermatitis due to allergy to Compositae

Atopic dermatitis is often complicated by allergic contact dermatitis, although patch testing may reveal positive reactions of uncertain relevance. We report a case of a 35-year-old woman with recalcitrant atopic dermatitis, with a positive patch-test reaction to Compositae mix (CM). Initially, sensitization appeared to be of past relevance only, due to use of calendula. However, it turned out that she followed a self-devised diet consisting largely of food products of the Compositae family. On excluding these food products her skin condition improved quickly. This case report underscores the difficulty in determining the relevance of positive patch tests, and shows that thorough analysis of positive patch tests, by both patient and physician, may reveal unexpected or less common sources of contact allergens.     

Lettuce contact allergy

Lettuce (Lactuca sativa L.) and its varieties are important vegetable crops worldwide. They are also well‐known, rarely reported, causes of contact allergy. As lettuce allergens and extracts are not commercially available, the allergy may be underdiagnosed. The aims of this article are to present new data on lettuce contact allergy and review the literature. Lettuce is weakly allergenic, and occupational cases are mainly reported. Using aimed patch testing in Compositae‐allergic patients, two recent Danish studies showed prevalence rates of positive lettuce reactions of 11% and 22%. The majority of cases are non‐occupational, and may partly be caused by cross‐reactivity. The sesquiterpene lactone mix seems to be a poor screening agent for lettuce contact allergy, as the prevalence of positive reactions is significantly higher in non‐occupationally sensitized patients. Because of the easy degradability of lettuce allergens, it is recommended to patch test with freshly cut lettuce stem and supplement this with Compositae mix. As contact urticaria and protein contact dermatitis may present as dermatitis, it is important to perform prick–to–prick tests, and possibly scratch patch tests as well. Any person who is occupationally exposed to lettuce for longer periods, especially atopics, amateur gardeners, and persons keeping lettuce‐eating pets, is potentially at risk of developing lettuce contact allergy.     

Compositae dermatitis: a survey

Compositae dermatitis in an allergic contact dermatitis, frequently chronic, triggered by plants of the Compositae family. The condition, which is seen, in particular, in middle-aged and elderly persons, typically starts in the summer months with an acute eczema either corresponding to areas exposed to light and air, or corresponding to areas of plant contact; it disappears spontaneously during the fall of the year. Repeated exposure over a number of years may cause severe intractable dermatitis affecting the patient throughout the year. The responsible allergens are sesquiterpene lactones, and investigations to date indicate that the frequency of the allergy is similar to that seen with some of the contact allergens of the standard patch test series. The diagnosis, however, is difficult, partly due to the fact that the clinical picture may be mistaken for a photodermatosis, and partly owing to the difficulty in obtaining commercially available allergens for patch testing. The diagnosis is therefore based on testing with plant extracts, which can cause pronounced local reactions and possibly active sensitization. A survey is given of the possible modes of sensitization, sex and age distribution, the relationship to photosensitivity and atopy, as well as the possible treatment. It is concluded, on the basis of the chronic nature of the disease, and the diagnostic and treatment problems, that continued intensive research into the condition is urgently needed.     

Systemic allergic dermatitis caused by sesquiterpene lactones

Patients with Compositae sensitization are routinely warned against the ingestion of vegetables, spices, teas and herbal remedies from this family of plants. The evidence for the occurrence of systemic allergic dermatitis caused by sesquiterpene lactone‐containing plants is mostly anecdotal and based on statements from patients rather than scientific data. However, a few clinical reports on accidental sensitization and exposure and oral challenge prove the existence of this kind of reaction, most convincingly for strong contact allergens such as costunolide in bay leaves, and less so for weak allergens such as those of lettuce. Other Compositae species suspected of causing systemic reactions are artichoke, mugwort, yarrow, dandelion, feverfew, and elecampane. Some Compositae vegetables and teas, such as lettuce and chamomile tea, may induce systemic reactions through both humoral and cell‐mediated mechanisms. It is difficult to disentangle the contribution of these reactions to both local and systemic symptoms of skin and mucous membranes in, for example, lettuce contact allergy. Further studies are needed to assess the prevalence of systemic allergic dermatitis caused by sesquiterpene lactones, and to clarify the pathogenesis for individual haptens.     

Patch testing for Compositae allergy

The main allergenic constituents of Compositae plants are the sesquiterpene lactones (SLs). In recent years, a mixture of three SLs, each with a different sesquiterpene skeleton (alantolactone, dehydrocostuslactone or costunolide), has been routinely used to detect Compositae allergy. The purpose of our study was to establish the value of testing with a range of Compositae extracts. Ninety-seven consecutive patients with exposure pattern dermatitis or hand eczema and gardening as a hobby or occupation were patch tested to the European standard series including SL mix 0.1% pet., Compositae extracts and other relevant allergens. Twenty-six of the 97 patients tested showed allergic reactions to SL mix or Compositae extracts. Fifteen of these showed positive reactions to both the SL mix and Compositae extracts. Eleven patients showed a negative reaction to the SL mix but positive reaction to the Compositae extracts. Dandelion elicited a positive reaction in eight of the 11 SL mix-negative patients and three patients reacted to feverfew. The SL mix failed to detect 38% of our Compositae-sensitive patients. Dandelion extract alone detected 73% of SL-negative patients. Additional testing with feverfew extract would have detected 91% of the SL mix-negative individuals. Our study highlights the importance of testing the response of SL-negative patients to additional Compositae extracts when there is a clinical suspicion of Compositae allergy.     

Sesquiterpene lactone mix patch testing supplemented with dandelion extract in patients with allergic contact dermatitis, atopic dermatitis and non-allergic chronic inflammatory skin diseases

We investigated the value of patch testing with dandelion (Compositae) extract in addition to sesquiterpene lactone (SL) mix in selected patients. After we detected a case of contact erythema multiforme after patch testing with dandelion and common chickweed (Caryophyllaceae), additional testing with common chickweed extract was performed. A total of 235 adults with a mean age of 52.3 years were tested. There were 66 men and 169 women: 53 consecutive patients with allergic contact dermatitis (ACD); 43 with atopic dermatitis (AD); 90 non-atopics suffering from non-allergic chronic inflammatory skin diseases; 49 healthy volunteers. All were tested with SL mix 0.1% petrolatum (pet.) and diethyl ether extracts from Taraxacum officinale (dandelion) 0.1 and 3.0% pet. and from Stellaria media (common chickweed) 0.1 and 3% pet. A total of 14 individuals (5.9%) showed allergic reaction (AR) to at least 1 of the plant allergens, 4 (28.6%) to common chickweed extract, and 11 (78.6%) to Compositae allergens. These 11 persons made the overall prevalence of 4.7%: 8 (3.4%) were SL-positive and 3 (1.3%) reacted to dandelion extract. 5 persons (45.5%) had AD, 2 had ACD, 2 had psoriasis and 2 were healthy controls. The Compositae allergy was relevant in 8 cases (72.7%). The highest frequency of SL mix sensitivity (9.3%) was among those with AD. Half the SL mix-sensitive individuals had AD. ARs to dandelion extract were obtained only among patients with eczema. A total of 9 irritant reactions (IRs) in 9 individuals (3.8%) were recorded, 8 to SL mix and 1 to common chickweed extract 3.0% pet. No IR was recorded to dandelion extract (P = 0.007). Among those with relevant Compositae allergy, 50.0% had AR to fragrance mix and balsam of Peru (Myroxylon pereirae resin) and colophonium. SLs were detected in dandelion but not in common chickweed. Our study confirmed the importance of 1 positive reaction for emerging, not fully established, Compositae allergy. In conclusion, the overall prevalence of 4.7% in our study represents a basal SL mix detection rate of 3.4% reinforced and safely supplemented by testing with the dandelion extract.     

Cosmetics and herbal remedies with Compositae plant extracts – are they tolerated by Compositae‐allergic patients?

Background: Compositae-sensitive patients are routinely warned against topical use of Compositae-containing cosmetics and herbal remedies. However, the risk of elicitation of dermatitis in presensitized persons is unknown.
Objectives: The main aim of this study was to assess the significance of direct plant allergen contact via Compositae-derived cosmetics and herbal remedies in Compositae-allergic patients with special reference to arnica ( Arnica montana ) and German chamomile ( Chamomilla recutita ).
Methods: 8 of 12 chamomile-sensitive patients tested positive to chamomile-containing preparations, including tea, creams, ointments, and oil. 5 of 6 arnica-sensitive persons tested positive to arnica-based products.
Results: When the group was patch tested with cosmetic and/or herbal product ingredients, plant allergens elicited positive reactions most frequently, but fragrances, emulsifiers, and preservatives tested positive as well. Plant allergens were mainly derived from Compositae, but avocado oil, and Hamamelis virginiana tincture were unexpectedly detected as sensitizers too. Chemical analyses indicated that the Compositae allergens were both sesquiterpene lactones and other naturally occurring compounds.
Conclusion: In conclusion, Compositae-allergic persons should be warned against topical use of Compositae-containing products, not only because of the plant allergens, but also because of allergenic cream constituents that may cause reactions in the group of patients who have multiple contact allergies beside the Compositae allergy.     

Active participation of eosinophils in patch test reactions to inhalant allergens in patients with atopic dermatitis

Intracutaneous testing and patch tests with house dust mite and grass pollen allergens were performed in patients with atopic dermatitis. Only patients with an immediate type skin reaction to house dust mite or grass pollen allergens showed a positive patch test reaction to these allergens 24-48 h after testing. Occasionally positive patch test reactions at 20 min, 2 h and 6 h were also observed. Patch test reactions were not found in normal controls or atopic patients without atopic dermatitis. Analysis of the cellular infiltrate demonstrated an influx of eosinophils into the dermis, starting from 2-6 h after patch testing. Immunostaining with antibodies against granular constituents of the eosinophils revealed that the infiltrating eosinophils were in an activated state and had lost part of their granular contents. At 24 h eosinophils also appeared in the epidermis. Electron microscopy showed that in the epidermis, some eosinophils were in close contact with Langerhans cells, suggesting a cell-cell interaction. Taken together, these results strongly suggest an active role for eosinophils in patch test reactions to inhalant allergens in atopic dermatitis patients.     

An 8-year experience with routine SL mix patch testing supplemented with Compositae mix in Denmark

Routine patch testing with sesquiterpene lactone (SL) mix, supplemented with Compositae mix (CM) and other Compositae extracts and allergens where appropriate, was evaluated over an 8-year period. 190 of 4386 patients tested (4.3%) were Compositae-sensitive, 143 females (mean age 51.5 years) and 47 males (mean age 55 years), and 83% of reactions considered clinically relevant. 22% were suspected of occupational sensitization/dermatitis. 62% had a contact allergy to 2 or more compounds, most often to nickel, fragrance and colophonium. SL mix detected 65%, CM 87% of Compositae-allergic patients, and the overall detection rate with both mixes was 93%. Few irritant reactions and no cases of clear-cut active sensitization were recorded with the mixes, but our results emphasize the importance of differentiating late-appearing reactivation reactions from patch test sensitization. The weakly positive CM reactions could reflect some irritancy, but as they were associated with fragrance and/or colophonium allergy to a higher degree than weakly positive SL mix reactions, they probably represented cross-reactions. In conclusion, the detection rate with SL mix was high enough to support its continued use as a screening mix and it was very well and rather safely supplemented by aimed testing with CM.     

Patch testing, tuberculin testing and sensitization with dinitrochlorobenzene and nitrosodimethylanilini of patients with atopic dermatitis.

Cell-mediated immunity was studied in patients with atopic dermatitis. 113 patients were patch tested with ten contact allergens. The frequency of positive reactions to patch testing with "common contact allergens" was found to be lower in patients with "high IgE values" than in those with IgE less than or equal to 1000 U/ml. A larger number of patients with severe dermatitis reacted negatively to PPD and were more difficult to sensitize with DNCB and NDMA as compared with the patients with mild dermatitis. The results of this investigation support the findings of earlier workers that patients with atopic dermatitis show disturbances in the cell-mediated immune system and these disturbances appear to be correlated to the degree of severity of the dermatitis.     

Patch testing in allergic contact dermatitis: is it useful to perform the cosmetic series in addition to the European standard series?

Background Cosmetics are the causative agents in 8–15% of patients suspected of having allergic contact dermatitis. Patch testing with standard series identifies 70–80% of the responsible allergens in all contact dermatitis; however, many important cosmetic‐related allergens may be missed by using standard series alone. Objective The aim of this study was to determine the value of using cosmetic series in addition to the European standard series in patients with suspected allergic contact dermatitis. Methods In this prospective study, 93 consecutive patients suspected of having allergic contact dermatitis were patch tested with the European standard series, and simultaneously with cosmetic series. Positive allergic reactions were further interpreted as clinically relevant or irrelevant. The clinically relevant reactions were subsequently stratified into three subgroups: (i) reactions only to allergen/allergens in the European standard series; (ii) reactions only to allergen/allergens in cosmetic series; and (iii) reactions both to allergen/allergens in the European standard and cosmetic series. Results A total of 74 positive reactions were observed in 93 patients. However, only 46 (62.2%) of the total positive reactions were found to be clinically relevant. Of all the clinically relevant positive reactions, 27 (58.7%) were caused by the allergens in the European standard series; 19 (41.3%) were caused by the allergens in cosmetic series. Of the 93 patients tested, 44 (47.3%) had at least one positive allergic reaction, 30 (68.2%) of whom had clinically relevance. Of the 30 patients with clinically relevant positive tests, 16 (53.3%) reacted only to allergens in the European standard series; nine (30%) reacted only to cosmetic series allergens; and five (16.7%) reacted both to the European standard and cosmetic series allergens. Among the 45 cosmetic series allergens tested, 15 (33.3%) gave positive reactions of which 14 (93.3%) of those were found to be clinically relevant. The clinically relevant cosmetic series allergens which were found to be over the critical incidence of 1% included methyldibromo glutaronitrile, Euxyl K400, and isopropyl myristate. Conclusion Patch testing with cosmetic series in addition to the European standard series increased the capability to detect the relevant allergen/allergens, particularly in patients with a suspicion of cosmetic allergy. However, it is not practical and cost‐effective to test those patients routinely with all 45 allergens in the cosmetic series. As the European baseline series which includes methyldibromo glutaronitrile is now widely used as the guideline minimum set of allergens for routine diagnostic patch test investigations, we additionally recommend Euxyl K400 and isopropyl myristate as the candidates for patch testing.     

Patch testing with constituents of Compositae mixes

Background. The development of mixes containing Compositae plant extracts has improved the diagnosis of Compositae contact allergy, but none of them has fulfilled the criteria for an ideal European plant mix. Objective. To evaluate which constituents of two commercial Compositae mixes were most useful as screening agents. Patients. These comprised 76 patients testing positive to Compositae mix 6% in petrolatum and 29 patients testing positive to Compositae mix 5% pet., all of whom were tested with constituents of the respective mixes. Results. The majority of patients tested positive to parthenolide or parthenolide‐containing extracts, followed by German chamomile, yarrow, and arnica. As German chamomile is a weak sensitizer, the results suggest cross‐reactions or reactions to unknown allergens. No one was positive to Roman chamomile. Conclusions. Even though parthenolide seems to be a suitable supplement to the baseline series, the results emphasize that it is important to patch test with extracts of native or locally grown plants, not only because of the geographical variation, but also because of the potential unknown allergens contained in short ether preparations and the variability in the individual patient's exposure and cross‐reaction patterns.     

Patch testing is a useful investigation in children with eczema

Background. Allergic contact dermatitis in children is less recognized than in adults. However, recently, allergic contact dermatitis has started to attract more interest as a cause of or contributor to eczema in children, and patch testing has been gaining in recognition as a useful diagnostic tool in this group. Objectives. The aim of this analysis was to investigate the results of patch testing of selected children with eczema of various types (mostly atopic dermatitis) attending the Sheffield Children's Hospital, and to assess potential allergens that might elicit allergic contact dermatitis. Patients and methods. We analysed retrospectively the patch test results in 110 children aged between 2 and 18 years, referred to a contact dermatitis clinic between April 2002 and December 2008. We looked at the percentages of relevant positive reactions in boys and girls, by age groups, and recorded the outcome of treatment following patch testing. Results. One or more positive allergic reactions of current or past relevance was found in 48/110 children (44%; 29 females and 19 males). There were 94 allergy‐positive patch test reactions in 110 patients: 81 had a reaction of current or past relevance, 12 had a reaction of unknown relevance, and 1 had reaction that was a cross‐reaction. The commonest allergens with present or past relevance were medicaments, plant allergens, house dust mite, nickel, Amerchol® L101 (a lanolin derivative), and 2‐bromo‐2‐nitropropane‐1,3‐diol. However, finding a positive allergen was not associated with a better clinical outcome. Conclusions. We have shown that patch testing can identify relevant allergens in 44% of children with eczema. The commonest relevant allergens were medicament allergens, plant allergens, house dust mite, nickel, Amerchol® L101, and 2‐bromo‐2‐nitropropane‐1,3‐diol. Patch testing can be performed in children as young as 2 years with the proper preparation.     

Compositae sensitivity among patients with contact dermatitis

Patch tests with 24 Compositae species were performed on 81 patients suspected of having a plant dermatitis, of whom 16 had positive reactions to various species. When Compositae were included in the standard series, 10 of 488 consecutive patients (2%) were found to be sensitive to one or more species. Most of the positive test reactions were relevant. Fourteen of 16 sensitivities could have been detected by testing with two mixtures of Compositae. Alantolactone could not serve as a screening agent, since four of seven Compositae-sensitive patients had negative reactions to it. Concomitant reactions to balsams were found in four of 10 patients with unexpected sensitivy to Compositae. The clinical pattern of Compositae dermatitis may be that of a lichenified photo dermatitis. These cases are invariably missed, unless patch tests with Compositae are performed. Another group of patients have hadn eczema and also require patch tests with Compositae for etiological diagnosis. Because positive, relevant reactions are common, inclusion of a safe and reliable Compositae screening test in the standard series is urgently required. At the present stage, however, our test materials are sometimes irritant and they have occassionally caused active sensitization.     

The detection of clinically relevant contact allergens with a standard screening tray of 28 allergens

Background. A standard method for diagnosing allergic contact dermatitis in the United States is the Thin‐layer Rapid Use Epicutaneous (TRUE) test (TRUE Test?), which consists of three panels containing 20 individual allergens and eight allergen mixes. Previous studies had raised concern regarding the adequacy of the initial two‐panel TRUE Test? system (16 individual allergens and seven allergen mixes) in fully assessing patients with possible allergic contact dermatitis. Objectives. We sought to investigate the effectiveness of the current three‐panel TRUE Test? as the sole diagnostic tool for detecting allergic contact dermatitis. Patients/materials/methods. This study was a retrospective analysis of 2088 patients who underwent patch testing between 1995 and 2010. Study groups were analysed to determine whether positive reactions were to allergens and/or mixes present in the TRUE Test? panels. Results. Of the 2088 patch‐tested patients, 1385 had at least one positive reaction. Among these 1385 patients, 27.6% were fully evaluated by use of only the TRUE Test? series, 49.9% were partially evaluated, and 22.5% did not have any of their allergens detected. On assessment for clinical relevance, similar percentages were observed. Conclusion. In our study, the current TRUE Test? series of 28 allergens would have completely identified allergens in only 27.6% of patients. Broadening the standard panel to include common allergens causing >50% of allergic contact dermatitis cases in a given geographical location and aim testing allergens on the basis of the patient's history will increase the test's sensitivity.     

Study of persistence and loss of patch test reactions to dichromate and cobalt *

Allergic contact dermatitis has been suggested as a possible cause of vulval vestibulitis, a condition of unknown aetiology characterized by burning, stinging and dyspareunia, with symptoms localised to the vestibule. To examine this relationship, 30 women with vulval vestibulitis were patch tested using a standard series of contact allergens and a special series relevant lo perianal and vulval disorders. Other potential allergens identified by the patients as causing aggravation were also included. There were 5 positive reactions, 4 to nickel and 1 to fragrance mix, though none of these reactions were considered relevant. Our results suggest that allergic contact dermatitis is unlikely to be a primary factor in the development or persistence of vulval vestibulitis. Patch testing patients with vulval vestibulitis cannot routinely be recommended.     

Occupational allergic contact dermatitis caused by decorative plants

12 cases of occupational allergic contact dermatitis caused by decorative plants were diagnosed in a 14-year period. The patients were middle-aged, and their average exposure time was 13 years. The plant families and plants causing occupational contact dermatitis were Compositae (5 patients: chrysanthemum, elecampane, gerbera, feverfew), Alstroemeriaceae (5 patients, Alstroemeria ), Liliaceae (4 patients; tulip, hyacinth). Amaryllidaceae (2 patients: narcissus) and Caryophyllaceae (2 patients; carnation, cauzeflower). The known chemical allergens causing dermatitis were tuliposide-A and sesquiterepene lactones, such as alantolactones and parthenolide, in the Liliaceae and Compositae families. 7 of the 12 patients were able to continue their work; 5 were not because of severe relapses of skin symptoms. The plant allergen and extract series currently available are of great help in the diagnosis.