Drug allergy passport and other documentation for patients with drug hypersensitivity - An ENDA/EAACI Drug Allergy Interest Group Position Paper.

The strongest and best-documented risk factor for drug hypersensitivity (DH) is the history of a previous reaction. Accidental exposures to drugs may lead to severe or even fatal reactions in sensitized patients. Preventable prescription errors are common. They are often due to inadequate medical history or poor risk assessment of recurrence of drug reaction. Proper documentation is essential information for the doctor to make sound therapeutic decision. The European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology have formed a task force and developed a drug allergy passport as well as general guidelines of drug allergy documentation. A drug allergy passport, a drug allergy alert card, a certificate, and a discharge letter after medical evaluation are adequate means to document DH in a patient. They are to be handed to the patient who is advised to carry the documentation at all times especially when away from home. A drug allergy passport should at least contain information on the culprit drug(s) including international nonproprietary name, clinical manifestations including severity, diagnostic measures, potential cross-reactivity, alternative drugs to prescribe, and where more detailed information can be obtained from the issuer. It should be given to patients only after full allergy workup. In the future, electronic prescription systems with alert functions will become more common and should include the same information as in paper-based documentation.

The Victorian Lung Cancer Registry pilot: improving the quality of lung cancer care through the use of a disease quality registry.

BACKGROUND: Lung cancer remains a major disease burden in Victoria (Australia) and requires a complex and multidisciplinary approach to ensure optimal care and outcomes. To date, no uniform mechanism is available to capture standardized population-based outcomes and thereby provide benchmarking. The establishment of such a data platform is, therefore, a primary requisite to enable description of process and outcome in lung cancer care and to drive improvement in the quality of care provided to individuals with lung cancer. MATERIALS AND METHODS: A disease quality registry pilot has been established to capture prospective data on all adult patients with clinical or tissue diagnoses of small cell and non-small cell lung cancer. Steering and management committees provide clinical governance and supervise quality indicator selection. Quality indicators were selected following extensive literature review and evaluation of established clinical practice guidelines. A minimum dataset has been established and training and data capture by data collectors is facilitated using a web-based portal. Case ascertainment is established by regular institutional reporting of ICD-10 discharge coding. Recruitment is optimized by provision of opt-out consent. RESULTS: The collection of a standardized minimum data set optimizes capacity for harmonized population-based data capture. Data collection has commenced in a variety of settings reflecting metropolitan and rural, and public, and private health care institutions. The data set provides scope for the construction of a risk-adjusted model for outcomes. A data access policy and a mechanism for escalation policy for outcome outliers has been established. CONCLUSIONS: The Victorian Lung Cancer Registry provides a unique capacity to provide and confirm quality assessment in lung cancer and to drive improvement in quality of care across multidisciplinary stakeholders.

Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group.

Drug hypersensitivity may deprive patients of drug therapy, and occasionally no effective alternative treatment is available. Successful desensitization has been well documented in delayed drug hypersensitivity reactions. In certain situations, such as sulfonamide hypersensitivity in HIV-positive patients or hypersensitivity to antibiotics in patients with cystic fibrosis, published success rates reach 80%, and this procedure appears helpful for the patient management. A state of clinical tolerance may be achieved by the administration of increasing doses of the previously offending drug. However, in most cases, a pre-existent sensitization has not been proven by positive skin tests. Successful re-administration may have occurred in nonsensitized patients. A better understanding of the underlying mechanisms of desensitization is needed. Currently, desensitization in delayed hypersensitivity reactions is restricted to mild, uncomplicated exanthems and fixed drug eruptions. The published success rates vary depending on clinical manifestations, drugs, and applied protocols. Slower protocols tend to be more effective than rush protocols; however, underreporting of unsuccessful procedures is very probable. The decision to desensitize a patient must always be made on an individual basis, balancing risks and benefits. This paper reviews the literature and presents the expert experience of the Drug Hypersensitivity Interest Group of the European Academy of Allergy and Clinical Immunology.

Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper.

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity.

Communication between ephrinB2 and EphB4 within the osteoblast lineage.

Members of the ephrin and Eph family are local mediators of cell function through largely contact-dependent processes in development and in maturity. Production of ephrinB2 mRNA and protein are increased by PTH and PTHrP in osteoblasts. Both a synthetic peptide antagonist of ephrinB2/EphB4 receptor interaction and recombinant soluble extracellular domain of EphB4 (sEphB4), which is an antagonist of both forward and reverse EphB4 signaling, were able to inhibit mineralization and the expression of several osteoblast genes involved late in osteoblast differentiation. The findings are consistent with ephrinB2/EphB4 signaling within the osteoblast lineage having a paracrine role in osteoblast differentiation, in addition to the proposed role of osteoclast-derived ephrinB2 in coupling of bone formation to resorption. This local regulation might contribute to control of osteoblast differentiation and bone formation at remodeling sites, and perhaps also in modeling.

Invasive Scedosporium sternal osteomyelitis following lung transplant: Cured.

Scedosporium is an important pathogen in cystic fibrosis (CF) and post-transplant but rarely causes invasive infection. Treatment remains challenging, particularly due to inherent resistance to multiple antifungal agents. We present a young man with CF who developed invasive sternal and rib infection 10-months following lung transplant. The infection has been clinically and radiologically cured with extensive surgery and triazole therapy. This case highlights the importance of adjunctive surgery in addition to prolonged triazole treatment to manage invasive Scedosporium infections in immunosuppressed patients.

Hairy-cell leukaemia: an immunoperoxidase study of paraffin-embedded tissues.

Paraffin sections of a variety of tissues from 12 patients with typical hairy-cell leukaemia (HCL) were stained for immunoglobulin heavy and light chains by the peroxidase-antiperoxidase (PAP) technique. Plasma cells were frequent, particularly in a lymph node from a severely infected patient. The reactive nature of the plasma cells of HCL was suggested by the fact that there was no restriction of light-chain expression, although viable hairy cells were shown to express monoclonal surface immunoglobulin. This, together with the absence by both light and electron microscopy of forms intermediate between hairy cells and plasma cells and the lack of ribosome-lamella complexes in the plasma cells, suggested that hairy cells do not differentiate into plasma cells. Although hairy cells are known to contain immunoglobulin, this was not demonstrable in hairy cells in the paraffin-embedded tissue. The PAP technique was also useful for demonstrating abundant splenic macrophages in HCL.

Recall phenomenon following epirubicin.

The case history is presented of a 46-year-old lady who was treated postoperatively for breast cancer with combination chemotherapy containing the antitumour agent epirubicin. The second cycle was complicated by a mild extravasation injury in the antecubital fossa, which settled with conservative management. Two weeks after a subsequent infusion into a different extremity she developed inflammation at the original site of injury, which rapidly led to tissue breakdown requiring surgical debridement and microvascular free flap reconstruction. To our knowledge, epirubicin has never been previously associated with 'recall reactions'. Histological evaluation of the debrided tissue has revealed a possible underlying mechanism for the cell damage.

Rapid desensitization for non-immediate reactions in patients with cystic fibrosis.

Non-immediate hypersensitivity reactions to antibiotics in patients with CF represent a real-life challenge for clinicians. Desensitization is often performed in patients who have exhausted all therapeutic options. Whilst desensitization is an established procedure for immediate reactions we assessed the outcomes and safety of desensitization for non-immediate reactions. We retrospectively reviewed 275 desensitization procedures in 42 patients with a range of non-immediate reactions to six commonly used antibiotics. Desensitization was performed using a 7-step rapid intravenous protocol on a normal medical ward. 250 (91%) of overall desensitization procedures were successful; however, this figure incorporates certain individuals having multiple successful procedures. Individual patient success ranged from 55% with tazocin through to 88% with tobramycin. In the 25 patients who failed desensitization the reactions were mild and the majority occurred within 48 h of starting treatment. Prophylactic anti-histamines and steroids did not reduce the risk of reaction. Whilst the mechanisms remain uncertain we can confirm that rapid desensitization is a safe and effective way of re-introducing an antibiotic to a patient with a non-immediate reaction.

Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes.

The therapeutic goal of increasing bone mass by co-treatment of parathyroid hormone (PTH) and an osteoclast inhibitor has been complicated by the undefined contribution of osteoclasts to the anabolic activity of PTH. To determine whether active osteoclasts are required at the time of PTH administration, we administered a low dose of the transient osteoclast inhibitor salmon calcitonin (sCT) to young rats receiving an anabolic PTH regimen. Co-administration of sCT significantly blunted the anabolic effect of PTH as measured by peripheral quantitative computer tomography (pQCT) and histomorphometry in the femur and tibia, respectively. To determine gene targets of sCT, we carried out quantitative real time PCR and microarray analysis of metaphyseal samples 1.5, 4 and 6.5h after administration of a single injection of PTH, sCT or PTH+sCT. Known targets of PTH action, IL-6, ephrinB2 and RANKL, were not modified by co-administration with sCT. Surprisingly, at all time points, we noted a significant upregulation of sclerostin mRNA by sCT treatment, as well as down-regulation of two other osteocyte gene products, MEPE and DMP1. Immunohistochemistry confirmed that sCT administration increased the percentage of osteocytes expressing sclerostin, suggesting a mechanism by which sCT reduced the anabolic effect of PTH. Neither mRNA for CT receptor (Calcr) nor labeled CT binding could be detected in sclerostin-enriched cells differentiated from primary calvarial osteoblasts. In contrast, osteocytes freshly isolated from calvariae expressed a high level of Calcr mRNA. Furthermore immunohistochemistry revealed co-localization of CT receptor (CTR) and sclerostin in some osteocytes in calvarial sections. Taken together these data indicate that co-treatment with sCT can blunt the anabolic effect of PTH and this may involve direct stimulation of sclerostin production by osteocytes. These data directly implicate calcitonin as a negative regulator of bone formation through a previously unsuspected mechanism.

A child with laryngo-onychocutaneous syndrome partially responsive to treatment with thalidomide.

Laryngo-onychocutaneous syndrome (LOCS) is a condition characterized by erosive or ulcerative skin lesions associated with excessive granulation tissue, at sites of trauma such as the digits, elbows and knees. Similar lesions can occur within the conjunctival mucosa, leading to corneal scarring and blindness. The main complications, however, occur in the respiratory tract, where a similar process of erosions and subsequent formation of granulation tissue causes airway obstruction which may lead to premature death. LOCS is now believed to be a nonblistering variant of junctional epidermolysis bullosa and to date there are no efficacious treatments available. We report a 16-year-old girl with LOCS who failed to respond to methylprednisolone and cyclophosphamide, but had a partial response to oral thalidomide with marked decrease in granulation tissue and tracheal secretions. Interruption of treatment resulted in prompt resurgence of the granulation tissue which was again controlled by reintroduction of thalidomide. We propose that in the absence of effective therapies for LOCS, a trial of thalidomide in these patients should be considered.

Cutaneous granulomas associated with primary immunodeficiency disorders.

Cutaneous granulomas are uncommon in primary immunodeficiency disorders. We report cutaneous granulomas in a child with ataxia telangiectasia (AT) and compare the clinical course with similar lesions in an adult with common variable immunodeficiency (CVI). A 4-year-old female with AT developed cutaneous granulomas as erythematous plaques. The largest lesion appeared on her left cheek and continued to progress despite treatment with topical and intralesional steroids. Disease control was obtained initially with oral antibiotics and low-dose oral steroids. On cessation of oral steroids, significant relapse of the facial granuloma occurred. Pulsed and then oral steroids were required to stop the disease process leaving significant scarring. The second case is of cutaneous granulomas in a 66-year-old man, with CVI, who presented with an erythematous reticulate rash on the legs. We consider it useful to report this patient here as disease control was obtained in a similar way with systemic immunosuppression. In this patient a combination of oral steroids and azathioprine was used. These cutaneous granulomas are thought to be a manifestation of immune dysregulation. No infectious cause has been found so far. We recommend the use of broad-spectrum antibiotics in conjunction with systemic steroids for progressive granulomas, as these patients are immunosuppressed and infection with an unidentified organism cannot be excluded.

Persistence of mild, early inflammatory arthritis: the importance of disease duration, rheumatoid factor, and the shared epitope.

OBJECTIVE: To determine the factors that predict clinical outcome at 6 months for patients with mild, early inflammatory arthritis. METHODS: Sixty-three patients with mild, untreated, early arthritis were given a single dose of corticosteroids at presentation. Administration was intramuscular if disease was polyarticular (n = 53) or intraarticular if patients had <5 synovitic joints (n = 10). The primary outcome measure was clinical disease remission or persistence of arthritis at 6 months following injection. RESULTS: At 6 months following injection, 49 of the 63 patients (78%) had persistent inflammatory joint disease. The other 14 (22%) had clinical disease remission. Regression analysis showed that only disease duration was significantly associated with persistent arthritis (P < 0.05). The other significant factor (by chi-square test) was the presence of the shared epitope (SE). Of the patients fulfilling the American College of Rheumatology (ACR) criteria at presentation (51% of the total), 53% with disease duration of < or = 12 weeks at presentation had persistent disease 6 months later, compared with 94% of those who presented with disease duration of >12 weeks. CONCLUSION: The strongest predictor of persistent disease was a disease duration of >12 weeks. Rheumatoid factor and SE were also predictors to a lesser extent. Patients who both fulfilled the ACR classification criteria for rheumatoid arthritis (RA) and had a short disease duration included some with an excellent prognosis. Therefore, 12 weeks may be a more appropriate disease duration to use for the RA classification criteria. Administering a bolus of corticosteroids may be a useful diagnostic/therapeutic approach.