Severe adverse cutaneous reaction to insulin due to cresol sensitivity

We present the case of an 80-year-old lady known to be sensitive to chlorocresol (4-chloro-3-methyl phenol) who developed severe erythrodermic exfoliative dermatitis with atypical features 2 weeks after commencing subcutaneous insulin. All medications except insulin were stopped, without major improvement. It was noted that the insulin contained m-cresol (m-methyl phenol) so a parabens-based insulin was substituted. There was a significant improvement in her clinical condition within 72 hr. Further patch and intradermal testing to the insulin and m-cresol was planned, but she developed a nosocomial infection and died. We hypothesize that the adverse cutaneous reaction was a systemic manifestation of cresol sensitivity, given the rapid clinical resolution on changing insulins and the previously demonstrated sensitivity to chlorocresol, particularly as cross-reactivity between different low molecular weight methyl phenols is documented. Local injection site reactions and systemic side-effects including nausea, diarrhoea and vomiting have previously been reported with cresol-containing insulins, although to our knowledge, this is the first reported case of a severe cutaneous reaction. It is important to be aware of m-cresol as a potential allergen, as it is contained in most commercially available insulins.     

Delayed-type skin reaction to 2,4-dinitrophenylated epidermal cells in guinea pigs with contact sensitivity to 2,4-dinitrochlorobenzene

Summary Contact sensitivity (CS) induced by hapten has been thought to be analogous to delayed-type hypersensitivity, such as the Mantoux reaction, because of outstanding similarities between the two phenomena. It can be suggested that animals with CS respond also to intradermal injection of the conjugate of hapten and protein as well as to epicutaneous application of hapten. However, evidence against this has been reported. In the present experiments, delayed-type skin reaction (DSR) was successfully obtained in JY1 strain guinea pigs sensitized by painting the skin with 2,4-dinitrochlorobenzene using in vitro dinitrophenylated epidermal cell suspension (DNP-EC) as antigen for a delayed intradermal test. The experiment using anti-Ia alloantiserum and complement showed that the elicitation of DSR is due to the presence of Ia-positive cells (presumably Langerhans cells) among DNP-ECs. The delayed intradermal test with the conjugates such as haptenated ECs in the animals with CS is considered to be an experimentally useful way of analysing the antigen in the sensitivity.     

Is there any relation between serum insulin and insulin‐like growth factor‐I in non‐diabetic patients with skin tag?

Background Skin tags are common benign lesion occurring mainly on the neck and major flexures as a small soft pedunculated protrusion. This study evaluate insulin and insulin‐like growth factor‐I (IGF‐I) in non‐diabetic ones. Methods and materials A case–control study was conducted in non‐diabetic persons. Comparing insulin and IGF‐I between matched cases (n = 40) and controls (n = 40) by radioimmunoassay test. Cases and controls were recruited from patients consecutively seen at an academic outpatient dermatology clinic. Results The insulin level in patients with skin tags was significantly higher than controls (P = 0.00) but IGF‐I level was not significantly different (P = 0.43). Conclusion These results show an increased insulin level in non‐diabetics ones and overall importance of insulin effect in pathogenesis of skin tags.     

A newly described cutaneous reaction at sites of insulin pump use in a child with Type 1 diabetes

Continuous subcutaneous insulin infusion (CSII), or insulin pumps, with or without continuous glucose monitoring (CGM) devices have become the standard of care for patients with type 1 diabetes. While increasingly popular, a wide range of reported skin reactions to CSII and CGM devices was found. We present this case of a pyogenic granuloma‐like neutrophilic and granulomatous response to an insulin pump to increase awareness of a previously uncharacterized cutaneous adverse reaction at insulin pump infusion sites.     

Negative predictive value of drug skin tests in investigating cutaneous adverse drug reactions

Summary Background Drug skin tests are useful in aetiological analyses of cutaneous adverse drug reactions to determine if the drug can be rechallenged, or to avoid a cross‐reaction with a substitute drug. Objectives To evaluate the negative predictive value of drug skin tests. Methods We retrospectively analysed the files of patients referred for drug reactions. We have enrolled those having strictly determined drug reactions with clinical features, delayed onset after drug intake, drug causality assessment, and negative drug skin tests followed by drug administration. Oral provocation tests or substitution tests with a drug of the same class as that suspected of causing the drug reactions were performed. Results From 1957 files analysed, 200 patients were included. After 403 patch tests, 403 prick tests and 304 intradermal tests, which were all negative, 260 oral provocation tests and 143 substitution tests were done; 307 different drugs were rechallenged. There were 42 positive drug re‐administrations in 27 oral provocation tests and 15 substitution tests. The negative predictive value of our drug skin tests was 89·6%. The negative predictive value for beta‐lactams was 87% for oral provocation tests and 96% for substitution tests, and for corticosteroids it was 100% and 74%, respectively. Conclusions  Negative drug skin tests do not eliminate the responsibility of a drug in drug reactions, and must be followed by drug re‐administration under hospital surveillance.     

Permanent make‐up colorants may cause severe skin reactions

Background: In recent years, cosmetic tattoos [permanent make‐up (PMU)] on eyelids, eyebrows and lips have become increasingly popular. However, most colorants are manufactured for non‐medical purposes, without any established history of safe use in humans. Objectives: To investigate severe adverse reactions, such as swelling, burning, and the development of papules, of the lips and the surrounding area in 4 patients who had had at least two PMU procedures on their lips. Patients, Materials and Methods: Adverse skin reactions were examined with patch and prick testing of the colorants. In addition, skin biopsies were taken in the centre of the prick test for histology. One patient declined prick testing. Results: Beauticians tended to use various PMU products, but all contained Pigment Red 181 (CI 73360). All patients tested showed a clear delayed reaction to Pigment Red 181 or the tattoo ink, or both, after prick testing. Histology indicated an allergic reaction. Each lip lesion slowly abated after several months of topical or systemic therapy with steroids in combination with tacrolimus, but none has yet completely resolved. Conclusions: In light of the severe and often therapy‐resistant skin reactions, we strongly recommend the regulation and control of the substances used in PMU colorants.     

Evaluation of the skin test reactions in patients with delayed type rash induced by penicillins and cephalosporins

Skin test reactions were evaluated in 39 patients with delayed type generalized drug eruptions in which penicillins (PCs) or cephalosporins (CSs) were proved to be the causative drugs by intradermal testing and provocation. They were also compared with the experimental PC/CS rash of guinea pigs reported previously. The skin test was positive in 37 (95%) of 39 patients tested and in 13 (87%) of 15 patients, in whom the causative drugs were identified by provocation, in which intradermal testing with 2 to 10% PC/CS in saline solution was employed and the skin test reaction was observed not only 24 hours later but also 6 to 9 hours later. It is considered that the skin test is a valuable in vivo test for the diagnosis of drug allergy. From the skin test reaction, it appears that the PC/CS rash is classified into at least two different reactions, the Jones-Mote type reaction and the tuberculin type reaction. No cross reactions between PC and CS derivatives were observed in either the skin testing or the provocation in man, which is the same pattern seen in the animal model. Cross reactions among the PC derivatives in man were not found as frequently as expected from the results in animals.     

Effects of antihistamines on cutaneous reactions and influx of eosinophils after local injection of PAF, kallikrein, compound 48/80 and histamine in patients with chronic urticaria and healthy subjects.

The effects of one week's daily treatment with dexchlorpheniramine (3 + 3 mg x 2) and loratadine (10 mg x 2) on the cutaneous reactions to putative mediators of urticarial reactions were studied in healthy subjects and in patients with chronic urticaria. Biopsy specimens were taken from skin with delayed reactions and studied immunohistochemically for the presence of eosinophilic cationic protein (ECP). In healthy subjects both antihistamines significantly decreased the weal and flare induced by histamine and the histamine releaser compound 48/80. They also reduced the flare seen after injection of PAF (platelet activating factor) and kallikrein. In patients with chronic urticaria the delayed reactions to PAF and kallikrein were larger than in healthy subjects. The immediate flare seen after injection of histamine, 48/80 and PAF, and the delayed reaction to 48/80, were significantly decreased by treatment with loratadine. No correlation was found between the clinical response and test reactions. In the group of healthy subjects, eosinophils were increased in the skin of all subjects after intradermal injection of 100 micrograms of PAF and in 50% after 1 microgram of PAF, but no eosinophils were seen after injection of 1 ng of PAF. In patients with chronic urticaria the eosinophils were increased at all sites where 1 ng of PAF had been injected and also at a limited number of sites of injection of histamine, 48/80, kallikrein and saline. Treatment with the antihistamines had no effect on the influx of eosinophils in the skin.     

Insulin allergy

Insulin reactions occur rarely but are of tremendous clinical importance. The first was reported in 1922 as a callus reaction at the injection site of insufficiently purified bovine insulin. Porcine insulin was subsequently found to be less allergenic than bovine insulin. Increasingly pure insulins have decreased the risk of adverse reactions, and the production of recombinant insulin with the same amino sequence as human insulin saw a large decrease in adverse reactions. Currently, the prevalence of allergic reactions to insulin products appears to be approximately 2%, and less than one-third of these events have been considered related to the insulin itself. Other reactions occur due to the preservatives added to insulin, including zinc, protamine, and meta-cresol. Allergic reactions can be type I or immunoglobulin E-mediated, type III or Arthus, and type IV or delayed-type hypersensitivity reactions. Type I reactions are the most common and can, rarely, cause anaphylaxis. In contrast, type IV reactions can occur after a delay of several days. Investigations include skin prick testing, patch testing, intradermal testing, and occasionally, skin biopsy.     

Allergy to local anesthetics: Comparison of patch test with prick and intradermal test results

The interrelation between immediate and delayed hypersensitivity reactions to local anesthetics is poorly understood. Especially, the relevance of positive patch test reactions to local anesthetics with regard to the compatibility of injected local anesthetics is unclear. We therefore subjected 104 patch test-positive probands to prick and intradermal tests with seven local anesthetic agents. All prick tests were negative. Only 14 patients showed positive reactions in intradermal tests: 11 with the ester local anesthetic procaine, one with the amide local anesthetic butanilicaine, and two with both. Procaine yielded both immediate and delayed reactions; butanilicaine, only immediate reactions. All other local anesthetics showed negative reactions. It is concluded that in patients with positive patch test reactions to local anesthetics and negative history of anaphylactoid reactions, positive skin test reactions to intradermal application are rare and that, therefore, the risk of anaphylactic reactions to injection anesthesia with amide local anesthetics, except butanilicaine, appears low in these patients.     

Late phase allergic reaction to a CT contrast medium (iotrolan).

A 46-year-old male developed wide-spread erythema and edema after intravenous injection of a CT contrast medium (iotrolan). The skin eruption appeared at 6 h, reached a maximum at 9 to 12 h, and faded within 36 h after injection. A challenge with an intradermal injection of the agent provoked the same reaction where the eruption had originally appeared, but had no effect on previously unaffected regions. Histopathologic examination revealed a perivascular infiltration of small round cells, and a few neutrophils, and eosinophils in the dermis and focal spongiosis in the epidermis. This is the first report of a late phase allergic skin reaction induced by iotrolan.     

Delayed eczematous skin reaction as an adverse drug reaction to immunoglobulin infusions: A case series

BackgroundPompholyx and eczematous reactions are known adverse reactions to intravenous immunoglobulins (IVIg) infusion, but little is known about their clinical characteristics, associated outcomes and management.ObjectiveTo describe IVIg-induced eczematous skin reactions.MethodsWe conducted a retrospective study on cases of delayed skin reactions post-IVIg infusion notified to the French Regional Pharmacovigilance Centre from 1985 to 2020.ResultsA total of 27 patients were identified, of whom 85% were male. IVIg infusions were given in a neurological indication in 82% of cases. Eczematous skin reactions occurred in two-thirds of cases after the first infusion, with a median time to onset of 11 days. Palmoplantar pompholyx was the most common presentation, being seen in 63% of patients. Other eruptions were erythemato-squamous or maculopapular. Eight patients were classified as severely affected and developed extensive lesions (> 50% BSA). One third of the 27 patients required hospitalization. All of the severe eczematous reactions involved males receiving high doses of IVIg for neurological diseases. Biopsies of severe cases revealed a common non-specific eczematous pattern. Relapses were frequent and more severe than the initial reaction. Reintroduction of the same IVIg product consistently resulted in relapse, whereas switching IVIg type produced relapse in only 53% of patients.ConclusionWe present the largest retrospective study of delayed skin reactions after IVIg infusions. This side-effect may be severe and have a polymorphic presentation. Relapse occurs frequently but less consistently after IVIg switch.     

Reactions to resin‐based dental materials in patients–type,time to onset,duration, and consequence of the reaction

Objective: The aim of the present study was to determine the types of side‐effects occurring and for how long they lasted in a group of patients with side‐effects assessed to be caused by resin‐based materials. Methods: A total of 618 reports were received by the Swedish National Register of Side‐Effects to Dental Materials, among which 36 were on patients with reactions assessed to be caused by resin‐based restorative materials. The group examined consisted of 25 women and 11 men, with a mean age of 47.8 ± 15.6 years. A follow‐up was done through a structured telephone interview. Results: The majority of symptoms were intra‐oral or a combination of intra‐oral and extra‐oral symptoms that appeared within the first 24 hr after treatment. The most common adverse effects reported were skin problems, oral ulcers, and burning mouth. Within less than a week, the reactions had disappeared in 50% of the patients. Conclusion: Immediate reactions to resin‐based materials were more prevalent than delayed allergic reactions, and the mechanism of the immediate reactions is probably non‐allergic in most cases. There is a need for developing provocation tests to verify the association between the reaction and the material, and also to identify the offending component.     

Delayed hypersensitivity to a corticosteroid suspension containing methylprednisolone. Two cases of conjunctival inflammation after retrobulbar injection

Two patients with chronic iridocyclitis had a delayed hypersensitivity reaction, characterized by severe conjunctival inflammation, after retrobulbar injections with a commercial suspension of methylprednisolone acetate. Although patch test reactions to methylprednisolone at enhanced concentrations were negative, delayed hypersensitivity could be easily demonstrated by intradermal testing with this corticosteroid. Both patients also had concomitant delayed hypersensitivity to a proprietary preservative (myristyl gamma-picolinium chloride) in the commercial corticosteroid suspension, which was confirmed by intradermal testing. These observations (negative patch test reactions, positive intradermal test reactions) suggest that the route of administration may be an important determinant of antigenic hapten-protein complex formation and subsequent delayed hypersensitivity responses involving cutaneous or mucocutaneous tissue.     

Inflammatory properties of human C5a and C5a des Arg/ in mast cell-depleted human skin

C5a and its degradation product, C5a des Arg, elicit immediate cutaneous inflammatory reactions after intradermal injection. Histologically, these reactions are characterized by neutrophil-rich leukocytic infiltrates, leukocytoclasis, edema, and dermal mast cell degranulation. It has not been possible to assess in vivo the relative contributions of resident mast cells and circulating leukocytes to this reaction because the accumulation of leukocytes and degranulation of mast cells occur simultaneously after injection of these anaphylatoxins. To assess the role of mast cells in these inflammatory reactions, we have examined the reactivity of human skin selectively depleted of dermal mast cells by local corticosteroid treatment. Corticosteroid-treated skin became virtually devoid of dermal mast cells within 4-6 wk as assessed by light microscopy, immunofluorescence with fluorescein-conjugated avidin, or electron microscopy. Mast cell-depleted skin demonstrated normal vasopermeability and vasodilatory responsiveness to intradermal injection of histamine, but the reactivity of these sites to the mast cell secretagogue, morphine, was absent. Moreover, no clinical reactions were detectable in mast cell-depleted human skin after intradermal challenge with 50 ng of either C5a or C5a des Arg, despite the fact that biopsies of these sites revealed substantial, neutrophil-rich infiltrates. These infiltrates were qualitatively and quantitatively identical to C5a or C5a des Arg-induced infiltrates in mast cell replete skin. This experimental approach in vivo has allowed the independent analysis of the anaphylactogenic and chemoattractant activities of human C5a and C5a des Arg in human skin, demonstrated the importance of dermal mast cells in these clinical responses, and shown that leukocytes can accumulate at these injection sites directly in response to these mediators.     

Effect of intradermal injection of methionine-enkephalin on human skin

Methionine-enkephalin (met-enk) detected in monocytes in psoriatic skin can modulate inflammatory processes and keratinocyte differentiation/proliferation in vitro. The purpose of the present study was to determine the effect of intradermal injection of met-enk on normal human skin and on the development of a delayed type skin hypersensitivity reaction. In 6 healthy volunteers, 50 microl of met-enk (16, 30, and 45 nmol) was injected once in the forearm and the reaction was evaluated clinically and by video-optical recording for 120 min. Compared to vehicle (0.9% saline), met-enk induced a time- and dose-dependent flare reaction, but no significant stimulation of a weal reaction. The flare reaction was maximal after 1 min and disappeared within 45 min. Pre-treatment with the antihistamine cetirizine reduced the flare reaction. Furthermore, the effect of met-enk on lymphocyte/monocyte infiltration and epidermal proliferation in normal skin and on a delayed type skin hypersensitivity reaction was assessed. Met-enk (45 nmol/ 50 microl) was injected at 0, 24 and 48 h. In normal skin, met-enk increased the number of dermal lymphocytes/monocytes (CD3/CD68 positive cells) and the degree of epidermal proliferation (MIBI-Ki67). In a delayed type hypersensitivity reaction induced by tuberculin (PPD), the degree of epidermal proliferation and the number of infiltrating lymphocytes/monocytes were reduced compared to PPD alone. Our study suggests that intradermal injection of met-enk in normal human skin induces an inflammatory reaction that may involve the release of histamine. In contrast, met-enk seems to down-regulate the development of a delayed type skin hypersensitivity reaction. These results may indicate that the direction of the effect of the opioid peptide met-enk on human skin depends on the rate of epidermal proliferation and the activity of immunocompetent cells.     

Cutaneous delayed hypersensitivity reactions to heparins and heparinoids

INTRODUCTION: Due to cross-reactions between unfractionated heparins, low-molecular-weight heparins and sometimes heparinoids, cutaneous delayed hypersensitivity reactions might be a problem for the choice of therapeutic alternative. We report on two cases of sensitization to heparins and heparinoids. OBSERVATIONS: One woman developed localized skin reaction to a low-molecular-weight heparin, then a generalized maculopapular rash when an intravenous injection of unfractionated heparins was performed. The second patient had a localized then extended reaction to a low-molecular-weight heparin and was referred for the choice of a well tolerated method to obtain anticoagulation during a pulmonary surgery. METHODS: Patch tests, prick tests, intradermal and subcutaneous tests were performed with several unfractionated heparins, low-molecular-weight heparins, danaparoid and lepirudin in both cases. RESULTS: In the first case, tests performed with both heparins and heparinoid were positive and the use of lepirudin was proposed if anticoagulation was necessary. In the second case the subcutaneous danaparoid injection induced a localized reaction on the injection site. Danaparoid injections were continued associated with localized applications of dermocorticoids without any side effect. DISCUSSION: Cutaneous delayed hypersensitivity reactions occur on the injection site but can also be generalised. Cross reactions might be unexpected therefore skin-tests are necessary to guide the choice of a therapeutic alternative. In case of intolerance to both heparins and heparinoids various solutions may be proposed such as the application of topical corticosteroids on the injection site or the administration of hirudins. There is no cross sensitization between heparins and hirudins, but the use of hirudins is restricted and requires specific monitoring.     

Granulomatous reaction to Belotero Balance: A case study

Objective: The most commonly used dermal fillers are hyaluronic acids (HAs), and in general, are well tolerated with mild to moderate risk of adverse events. The most frequently reported side effects are injection site erythema and bruising. We present the first case of a patient who developed a severe granulomatous foreign body reaction to the HA filler, Belotero Balance. In our review of the literature, a granulomatous reaction has never before been reported as a side effect of this particular HA filler (1). Case: On exam, the patient had firm erythematous, granulomatous plaques on her bilateral cheeks, with a tender, fluctuant nodule on her right cheek. Complete resolution of this delayed reaction was achieved after several injections of intralesional Kenalog (IL-K) 2.5 mg/cc, and further fine-tuning was achieved through laser resurfacing. Conclusion: Granulomatous reactions can occur with any HAs, though such incidents are not commonly reported. These delayed reactions are generally localized immunological reactions, though biofilm infections should be excluded where appropriate. It is only with long-term (5-year) longitudinal studies that accurate numbers of such reactions will be known.     

Delayed pressure urticaria inhibition of induced lesions by adrenaline

Two patients with delayed pressure urticaria were studied to define some of the physical and pharmaceutical parameters related to the lesions. Skin tests were performed with a pressure testing; device. Graded pressures were applied from 175 g/cm² upward for several periods of time to the forearm and back. Induced lesions were clinically identical to spontaneous lesions. The threshold response was related to the amount of pressure, the duration of application and the body site tested. Induced lesions were followed by a refractory period of at least 2 h and up to 48 h. During this period, repeated challenges to an area that reacted previously did not produce any lesion, and, on the contrary, prolonged the refractory period. Any type of intradermal injection (NaCl, lidocaine, compound 48/80, histamine) induced a delayed reaction. But induced delayed lesions were inhibited by intradermal injection of adrenaline before, or after, the pressure stimulus. It is suggested that some intracutaneous targets react to external or intradermal pressure and release chemotactic factors, the effects of which are prevented by vasoconstriction.     

Allergic reaction to hyaluronidase use after hyaluronic acid filler injection

Hyaluronic acid (HA) is biocompatible, easy to use and reversible. HA fillers are considered to be safe, although some complications can occur. At this time, hyaluronidase is used off-label for correction. A 41-year-old woman presented to our clinic for focal erythematous plaque on hyaluronidase injection site. She got the injection for correction of HA filler excess. The skin lesion continued for 7 days. Histopathologic findings were nonspecific. On intradermal skin test, allergic reaction to hyaluronidase were confirmed. Adverse effects of this hyaluronidase are uncommon with local injection site reactions most frequently reported. Allergy to hyaluronidase should be included in the differential diagnosis when focal erythema and swelling occur after hyaluronidase injection.