Increased Basal Blood Histamine Levels in Patients with Self-Reported Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most prevalent causes of drug hypersensitivity reactions (DHRs), yet the underlying processes are far from clear. Despite the established role of histamine in allergic reactions, its precise implication in DHRs is elusive. OBJECTIVES: This study aimed to explore the connection of basal blood histamine levels to the reported NSAID hypersensitivity. METHODS: Sixteen patients reporting hypersensitivity reactions to a single or multiple NSAIDs and/or paracetamol and 18 healthy volunteers serving as the normal control group enrolled in the study. The medical history was recorded and histamine was quantified spectrophotofluorometrically in whole peripheral blood and plasma. RESULTS: Compared to the normal group, plasma but not whole blood histamine levels were significantly higher in patients (p < 0.001), mainly in the subgroup reporting hypersensitivity to a single agent (p < 0.001). Plasma histamine levels were significantly correlated with the culprit drug selectivity for cyclooxygenase (COX) isozymes (p < 0.001), with higher levels being obtained in patients reporting reactions to COX-1 than to COX-2 selective inhibitors (p < 0.05). CONCLUSIONS: The findings provide first evidence connecting basal blood histamine levels to the reported NSAID-triggered DHRs. Prospective studies are expected to decipher the contribution of histamine-associated parameters to the mechanisms underlying DHRs.

Flare-Up Phenomenon of Intradermal Test with Anaphylactic Reaction to Paracetamol (Acetaminophen).

BACKGROUND: Paracetamol is a Non-Steroidal Anti-Inflammatory Drug (NSAID) that can produce hypersensitive reactions mediated by specific immunological mechanisms (IgE or T celldependent) or by a non-immunological mechanism (inhibition of cyclooxygenase COX-1). OBJECTIVE: An 80-year-old man with a history of allergy to pyrazolones, with good tolerance to other NSAIDs was referred to our allergy department because he presented a generalized urticaria after the administration of Intravenous (IV) paracetamol. METHODS: We performed an Intradermal Test (IDT) with paracetamol (0.02mg/ml) and later a Single Blind Oral Challenge Test (SBOCT) with oral paracetamol. RESULTS: IDT reading at 15min showed negative result so an SBOCT was performed with oral paracetamol. With an accumulative dose of 250mg, after 20min, he developed discomfort, nausea and dizziness, urticarial, hypotension (BP 80/40) as well as flare-up phenomenon was observed in the site of the IDT with paracetamol. Tryptase levels during the reaction and 2hrs later were increased. CONCLUSION: We present an anaphylactic shock due to sensitization to paracetamol because of a type I hypersensitivity mechanism, diagnosed by SBOCT and a positive IDT because of flare-up phenomenon, in a patient with previous pyrazolones allergy and with tolerance to other NSAIDs. Some relevant patents are also summarized in this paper.

Acetaminophen hepatotoxicity and sterile inflammation: The mechanism of protection of Chlorogenic acid.

Acetaminophen hepatotoxicity is characterized by extensive necrotic cell death and a sterile inflammatory response. A recent report suggested that a therapeutic intervention with chlorogenic acid, a dietary polyphenolic compound, protects against acetaminophen-induced liver injury by inhibiting the inflammatory injury. The purpose of this letter is to discuss a number of reasons why the protective mechanism of chlorogenic acid against acetaminophen hepatotoxicity does not involve an anti-inflammatory effect and provides an alternative explanation for the observed protection.

Mechanisms of drug-induced liver injury.

PURPOSE OF REVIEW: Idiosyncratic drug-induced liver injury (iDILI) is a relatively rare condition, but can have serious consequences for the individual patient, public health, regulatory agencies and the pharmaceutical industry. Despite increased awareness of iDILI, its underlying mechanism is still not fully understood. This review summarizes the current understanding of the molecular mechanism behind iDILI. RECENT FINDINGS: Genetic variations in drug metabolizing genes are in line with proposed mechanisms based on acetaminophen hepatotoxicity, whereby reactive metabolites covalently bind to cellular proteins and disturb the redox balance. In addition, immune-mediated effects have been reported for flucloxacillin hepatotoxicity, demonstrating both haptenization and direct binding between the drug and immune receptors. SUMMARY: Idiosyncratic DILI development is believed to be orchestrated by multiple events, such as reactive metabolite formations, oxidative stress and signalling pathway inductions, with the mitochondria taking centre stage. Evidence also points towards the immune system (innate and adaptive responses) as important components in iDILI. Interindividual differences in one or more of these events, due to genetic variations and environmental factors, are likely to contribute to the idiosyncratic nature of this condition and subsequently distinguish between patient susceptibility and tolerance.

Environment and primary biliary cirrhosis: electrophilic drugs and the induction of AMA.

Environmental stimulation is a major factor in the initiation and perpetuation of autoimmune diseases. We have addressed this issue and focused on primary biliary cirrhosis (PBC), an autoimmune disease of the liver. Immunologically, PBC is distinguished by immune mediated destruction of the intra hepatic bile ducts and the presence of high titer antimitochondrial autoantibodies (AMA) directed against a highly specific epitope within the lipoic acid binding domain of the pyruvate dehydrogenase E2 subunit (PDC-E2). We submit that the uniqueness of AMA epitope specificity and the conformational changes of the PDC-E2 lipoyl domain during physiological acyl transfer could be the lynchpin to the etiology of PBC and postulate that chemical xenobiotics modification of the lipoyl domain of PDC-E2 is sufficient to break self-tolerance, with subsequent production of AMA in patients with PBC. Indeed, using quantitative structure activity relationship (QSAR) analysis on a peptide-xenobiotic conjugate microarray platform, we have demonstrated that when the lipoyl domain of PDC-E2 was modified with specific synthetic small molecule lipoyl mimics, the ensuing structures displayed highly specific reactivity to PBC sera, at levels often higher than the native PDC-E2 molecule. Hereby, we discuss our recent QSAR analysis data on specific AMA reactivity against a focused panel of lipoic acid mimic in which the lipoyl di-sulfide bond are modified. Furthermore, data on the immunological characterization of antigen and Ig isotype specificities against one such lipoic acid mimic; 6,8-bis(acetylthio)octanoic acid (SAc), when compared with rPDC-E2, strongly support a xenobiotic etiology in PBC. This observation is of particular significance in that approximately one third of patients who have taken excessive acetaminophen (APAP) developed AMA with same specificity as patients with PBC, suggesting that the lipoic domain are a target of APAP electrophilic metabolites such as NAPQI. We submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate loss of tolerance and lead to the development of PBC.

Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?

The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antimitochondrial autoantibodies (AMAs) directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Furthermore, approximately one-third of patients who have ingested excessive amounts of acetaminophen (paracetamol) develop AMA of the same specificity as patients with PBC. Quantitative structure-activity relationship (QSAR) data indicates that acetaminophen metabolites are particularly immunoreactive with AMA, and we submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate a loss of tolerance and lead to the development of PBC.

Virus infection and allergy in the development of asthma: what is the connection?

PURPOSE OF REVIEW: Information is accumulating which implicates airway inflammation resulting from respiratory viral infections, acting against a background of atopy, in both the cause and pathogenesis of atopic asthma. This review brings together the most recent publications relevant to this rapidly evolving area, particularly those focusing on underlying pathogenic mechanisms. RECENT FINDINGS: Salient findings from the recent literature include increased respiratory infection-associated symptom severity/duration and loss of asthma control in atopic relative to nonatopic children; up-regulation of FcεR1 expression on circulating monocytes/dendritic cells occurs during virus-associated atopic asthma exacerbations, providing a mechanism for transient amplification of underlying allergic airways inflammation; high potency of hRV-type C in induction of infection-associated wheeze; Th2-polarized immunity to mucosal dwelling bacteria and protection against asthma; a role for IL-15 in viral-associated airways inflammation; vitamin D and protection against infection-associated asthma exacerbations; strategies for reduction of infection-associated wheezing severity by boosting mucosal Treg cell activity via immunostimulation of the gut mucosa. SUMMARY: Research in this area is pointing towards new rationales for development of early intervention strategies for prevention of asthma initiation and progression in childhood, based on control of respiratory infections and/or sensitization to aeroallergens.

Highly specific, sensitive and rapid enzyme immunoassays for the measurement of acetaminophen in serum.

Acetaminophen antibodies were purified using affinity chromatography and labelled with horseradish peroxidase (HRP). The antibody-HRP conjugate and a new acetaminophen derivative were used in the construction of two immunoassay methods facilitating the direct quantitative measurement of acetaminophen in serum: a 96-well microtitre plate and coated-tube ELISAs. A minimum detection limit of 0.2 µg mL(-1) and a dynamic range of 0.2 to 1 µg mL(-1) in serum were achieved using the 96-well microtitre plate ELISA. The tube assay was optimised for the measurement of the clinically critical acetaminophen concentration of 50 to 250 µg mL(-1) of serum. The quantitative and specific tests could be completed within less than an hour. Common drugs including aspirin showed less than 0.1% cross-reactivity.

Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity.

Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.

[Acute eosinophilic pneumonia caused by several drugs including ibuprofen].

A 41-year-old woman took an EVE-A tablet, which contained ibuprofen, because of pyrexia over 39 degrees C. Due to continued pyrexia, she visited a physician and received cefcapene and acetaminophen under a diagnosis of cold. However, next day, she was admitted to our hospital with severe hypoxemia and pulmonary infiltrates on chest radiograph. Analysis of bronchoalveolar lavage fluid disclosed an increased proportion of 66% eosinophils. All of the lymphocyte stimulation tests for EVE-A tablet, cefcapene and acetaminophen showed positive. After the cessation of these drugs, she was successfully treated with steroids. This case was diagnosed as eosinophilic pneumonia caused by several drugs, and to our knowledge, this is the first report in Japan of ibuprofen (EVE-A tablet)-induced pneumonia.

Hypersensitivity to paracetamol in Asian children with early onset of nonsteroidal anti-inflammatory drug allergy.

BACKGROUND: The published incidence of paracetamol cross-reactivity in adults and adolescents with nonsteroidal anti-inflammatory drug (NSAID) reactions is low and all data on such reactions in young children is sparse. The study aim was to characterize the clinical presentation and cross-reactivity with paracetamol in patients with a reported onset of NSAID hypersensitivity before 6 years of age. METHODS: A retrospective case review was done of patients with cross-reactive hypersensitivity reactions to antipyretic/analgesic medications from the pediatric allergy clinic of the Kendang Kerbau Hospital, Singapore. Included patients reported the onset of such reactions before 6 years of age. Hypersensitivity was established through a detailed history of recurrent reactions to NSAIDs or an oral provocation test. RESULTS: Eighteen patients fulfilled the diagnostic criteria within the study period. Eighty-three percent had cross-reactive reactions with paracetamol. When compared to the group of children with later onset of NSAID hypersensitivity, children with onset before 6 years of age had a significantly increased likelihood of reacting to paracetamol (odds ratio 9.6, 95% confidence interval 1.6-58.0, p < 0.05). CONCLUSION: Paracetamol seems to be a major eliciting drug in this group of children.

Factors associated with allergic rhinitis in children from northern Mexico City.

BACKGROUND: The International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire allows users to find factors associated with allergic diseases, but thus far most of the studies on risk factors for allergic diseases have been devoted to asthma and not to rhinitis. OBJECTIVE: To determine the main factors associated with symptoms of allergic rhinitis and rhinoconjunctivitis in school children and adolescents in northern Mexico City. PATIENTS AND METHODS: A cross sectional, multicenter survey was conducted in northern Mexico City, in children aged 6-7 and 13-14 years. The survey instrument was the Phase Three B ISAAC questionnaire, which was validated and standardized in Spanish. RESULTS: There were 4106 6-7-year-olds and 6576 13-14-year-olds. The total prevalence of diagnosis of allergic rhinitis was 4.6%. The prevalence of cumulative and current symptoms of rhinitis was considered high (>29%), but the prevalence of the diagnosis of allergic rhinitis was considered low (ranging from 3.4% to 5.6%). The prevalence of symptoms of rhinitis with conjunctivitis had intermediate values (ranging from 20.3% to 30.2%). Cumulative symptoms of allergic rhinitis, current symptoms of allergic rhinitis, and rhinoconjunctivitis were related to symptoms of current or cumulative asthma, symptoms of current or cumulative atopic eczema, and current use of paracetamol (odds ratio > 1, P < .05). CONCLUSION: The present results support the concept of rhinitis and asthma as common chronic respiratory diseases, and this study also found a relation between paracetamol use and rhinitis in children.

Prenatal paracetamol exposure and risk of asthma and elevated immunoglobulin E in childhood.

BACKGROUND: We recently found that paracetamol (acetaminophen) use in late pregnancy was associated with an increased risk of early wheezing in the offspring. OBJECTIVE: To see whether use of paracetamol in late pregnancy is associated with an increased risk of asthma, wheezing and other atopic outcomes in the child at school age. METHODS: In the population-based Avon Longitudinal Study of Parents and Children, we measured associations of paracetamol and aspirin use in late pregnancy (20-32 weeks) with asthma, hayfever, eczema (n = 8511) and wheezing (8381) in the offspring at 69-81 months, and with atopy (positive skin prick test to Dermatophagoides pteronyssinus, cat or grass, n = 6527) and blood total IgE (n = 5148) at 7 years. We used logistic and linear regression to analyse binary outcomes and log-transformed IgE, respectively, controlling for potential confounders. RESULTS: Use of paracetamol, but not aspirin, in late pregnancy was positively associated with asthma (odds ratios (ORs), comparing children whose mothers took paracetamol 'sometimes' and 'most days/daily' with those whose mothers never took it, 1.22 (95% confidence interval (CI): 1.06-1.41) and 1.62 (95% CI: 0.86-3.04), respectively; P trend = 0.0037), wheezing (ORs 1.20 (95% CI: 1.02-1.40) and 1.86 (95% CI: 0.98-3.55), respectively; P trend = 0.011), and total IgE (geometric mean ratios 1.14 (95% CI: 1.03-1.26) and 1.52 (95% CI: 0.98-2.38), respectively; P trend = 0.0034), but not hayfever, eczema or skin test positivity. The proportion of asthma attributable to paracetamol use in late pregnancy, assuming a causal relation, was 7%. CONCLUSION: Paracetamol exposure in late gestation may cause asthma, wheezing and elevated IgE in children of school age.

The flow-cytometric determination of basophil activation induced by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is useful for in vitro diagnosis of the NSAID hypersensitivity syndrome.

BACKGROUND: Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs), manifested by cutaneous symptoms and/or airway manifestations represent 20-25% of all hypersensitivity reactions to drugs. Today, it is still claimed that no in vitro diagnostic tests exist for that condition and that the only way to confirm the diagnosis is a provocation challenge. OBJECTIVE: The objective of this study was to assess whether NSAIDs may provoke blood basophil activation in vitro in such patients, as detected by a flowcytometric technique. METHODS: Sixty NSAID hypersensitive patients (38 with cutaneous, 20 with airway and two with cutaneous and airway symptoms) and 30 control patients (15 asthmatics) were selected. Their hypersensitivity was confirmed by documented history indicating at least two clinical episodes to two or more different NSAIDs or by positive oral provocation challenge. Isolated buffy coat leukocytes were stimulated in vitro with aspirin, paracetamol, metamizol, diclofenac, and naproxen. The percentage of activated basophils was evaluated by an anti-CD63. RESULTS: Aspirin showed a sensitivity of 43.3%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 99.4%. For the other NSAIDs, the sensitivity and specificity values were: for paracetamol 11.7% and 100%, for metamizol 15% and 100%, for diclofenac 43.3% and 93.3% and for naproxen 54.8% and 74.1%. When considering the first four NSAIDs, the global sensitivity raised to 63.3% and specificity to 93.3%. If the number of tests is to be limited for practical reasons, the combination of acetylsalicylic acid and diclofenac at two concentrations yields a sensitivity of 58.3% and a specificity of 93.3%. CONCLUSIONS: Flowcytometric determinations of basophil activation following stimulation with NSAIDs show a high sensitivity (60-70%) with specificity above 90%. So this test may help avoiding some cumbersome and dangerous provocation challenges.