Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome.

BACKGROUND: A multidrug regimen including isoniazid, rifampicin, pyrazinamide and ethambutol is commonly used as first-line treatment for tuberculosis. However, this regimen can occasionally result in severe adverse drug reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and drug-induced liver injury. The culprit drug and mechanistic basis for the hypersensitive reaction are unknown. OBJECTIVES: To investigate drug-specific T-cell responses in patients with antituberculosis drug (ATD)-induced cutaneous hypersensitivity and its underlying mechanism. METHODS: We enrolled eight patients with ATD-induced maculopapular exanthema and DRESS and performed a lymphocyte transformation test. Subsequently, drug-specific T-cell clones were generated from four of the patients who showed proliferation in response to ATDs. We measured the drug-specific proliferative responses and counted the drug-specific interferon (IFN)-γ/granzyme B-producing cells after drug stimulation. Antihuman leukocyte antigen (HLA) class I and class II blocking antibodies were used to analyse human leukocyte antigen-restricted T-cell responses. RESULTS: Positive proliferative responses to ATDs were mostly found in patients with cutaneous hypersensitivity. Furthermore, we isolated isoniazid/rifampicin-specific T cells from patients, which consisted primarily of CD4+ T cells. Drug-specific CD4+ T cells proliferated and secreted IFN-γ/granzyme B when stimulated with isoniazid or rifampicin, respectively. Isoniazid-responsive T-cell clones did not proliferate in the presence of rifampicin and vice versa. Drug-specific T-cell responses were blocked in the presence of anti-HLA class II antibodies. CONCLUSIONS: This study identifies the presence of isoniazid/rifampicin-specific T cells in patients with ATD-induced maculopapular exanthema and DRESS. Furthermore, it highlights the important role of drug-specific T-cell immune responses in the pathogenesis of these reactions.

Desensitization to antibiotics in children.

Drug hypersensitivity reactions can occur to almost all drugs and antibiotics are among the most common cause for this kind of reactions. Drug hypersensitivity may affect any organ or system, and manifestations range widely in clinical severity from mild pruritus to anaphylaxis. In most cases, the suspected drug is avoided in the future. In case of infection, there is usually a safe antibiotic alternative. Nonetheless, in some cases, no alternative treatment exists for optimal therapy. Under these circumstances, desensitization may be performed. Drug desensitization is defined as the induction of a temporary state of tolerance to a drug which can only be maintained by continuous administration of the medication responsible for the hypersensitivity reaction. Desensitization is mainly performed in IgE-mediated reactions. Increasing doses of the implicated drug are administered over a short period of time, until the therapeutic dose is achieved and tolerated. Very few studies confined to children are found in literature. Most of them are case reports. In general, the proposed desensitization schemes are similar to those used in adults differing only in the final dose administered. The purpose of this study is to review desensitization to antibiotics in children presenting and discussing three clinical practical cases of desensitization in this age group.

Nonirritant intradermal skin test concentrations of ciprofloxacin, clarithromycin, and rifampicin.

BACKGROUND: Intradermal skin testing of the clinically important antibiotics ciprofloxacin, clarithromycin, and rifampicin in the case of suspected allergies to antibiotics is poorly standardized. For clinical practice, standardized procedures and protocols are desired. METHODS: Fifteen healthy volunteers were tested with different concentrations of the antibiotics as well as with appropriate controls. Test readings included wheal area measured by digital image analysis and blood flow increase measured by laser Doppler flowmetry (LDF). To reduce interpersonal variability, test results were normalized with the individual controls using a novel protocol. RESULTS: Nonirritating concentrations of the three antibiotics (ciprofloxacin ~0.0067 mg/ml, clarithromycin ~0.05 mg/ml, rifampicin ~0.002 mg/ml) could be defined for healthy volunteers. Laser Doppler flowmetry generates comparable results to wheal area measurement. Normalization of the test results is necessary and can be applied in a practical algorithm. CONCLUSIONS: Standardized skin testing to detect sensitization to broadly used nonbetalactam antibiotics was presented and should be applied in truly sensitized patients. This approach should help to minimize the inter- and intraindividual differences in reactivity.

Incidence, Clinical Manifestation, Treatment Outcome, and Drug Susceptibility Pattern of Nontuberculous Mycobacteria in HIV Patients in Tehran, Iran.

BACKGROUND: Nontuberculous mycobacterial (NTM) infections have radically increased worldwide due to the increase in HIV infections. The disease activity increases with progressive immunodeficiency. METHODS: A total of 216 HIV seropositive patients suspected of having mycobacterial infection were recruited for this study. Clinical samples were collected from each patient and cultured on Lowenstein-Jensen media. Detection and species identification were simultaneously done using Reverse Blot Hybridization Assay System. Also, the minimum inhibitory concentrations (MIC) for each isolate were determined in 7H9 broth media for 10 antibiotics. RESULTS: In this study, 4 rapid and 4 slow-growing NTM species were isolated and identified. Mycobacterium fortuitum was the most common NTM species, 3/8 (37.5%), followed by Mycobacterium kansasii, 2/8 (25%). The cases were identified as pulmonary disease, 5/8 (62.5 %), disseminated infection, 2/8 (25%), and skin abscess, 1/8 (12.5%). M. chelonae and Mycobacterium avium were isolated from patients diagnosed with disseminated infection with treatment failure. The skin abscess was caused by infection with M. simiae. The results of the MIC testing were as follows: M. kansasii and M. fortuitum were susceptible to amikacin (AMK); M. avium to clarithromycin (CLA); M. fortuitum 2/3 (67%) to ciprofloxacin (CIP); 1/2 (50%) of M. kansasii isolates to CLA, and M. chelonae to rifampin (RIF), linezolid (LIN), AMK, and CIP at medium and high concentrations. CONCLUSION: AMK showed incredible in vitro activity against M. kansasii and M. fortuitum. Also, M. avium was susceptible to CLA, whereas M. simiae and M. chelonae were resistant to the tested drugs in this study.

Efficacy and tolerability of desensitization in the treatment of delayed drug hypersensitivities to anti-tuberculosis medications.

BACKGROUND: Delayed drug hypersensitivity to first-line anti-tuberculosis medication is a major challenge in tuberculosis treatment. OBJECTIVE: This study was performed to investigate the efficacy/tolerability of desensitization therapy in treatment of first-line anti-tuberculosis medication hypersensitivity and the usefulness of immunologic evaluation therein. METHODS: This study was conducted as a prospective, observational cohort study. Subjects who experienced hypersensitivity reactions, including maculopapular exanthema (MPE) and drug reaction with eosinophilia and systemic symptoms (DRESS), to first-line anti-tuberculosis medications (isoniazid [INH], ethambutol [EMB], rifampin [RFP], and pyrazinamide [PZA]) were enrolled. Patch, intradermal, lymphocyte transformation, and oral provocation tests were performed to determine culprit drugs, which were desensitized with rapid and graded challenge protocols. Breakthrough reactions (BTRs) during or after desensitization were assessed. RESULTS: In total, 31 desensitization treatments (INH, 8; EMB, 8; RFP, 11; PZA, 4) to 12 patients (8 with MPE and 4 with DRESS) were performed. The overall success rate of desensitization was 80.7%. All the study subjects except one completed the full course of anti-tuberculosis treatment. The overall BTR free rate was 64.5%. Sixteen (80%) treatments for MPE and four (36.4%) for DRESS were BTR free (P = 0.023). Drugs that were positive on any two of three immunologic studies showed significantly high BTR rates (P = 0.014), although this was not correlated with desensitization failure rate. CONCLUSION: Rapid desensitization therapy to multiple anti-tuberculosis medications for delayed drug hypersensitivity was safe and successful. Combination of multiple immunologic evaluations may predict BTR although it needs validation in larger studies.

Flow cytometry in the diagnosis of drug-induced thrombocytopenia: two illustrative cases.

Drug-induced thrombocytopenia is a challenging diagnosis in the clinical practice because of the many drugs or alternative causes that may be implicated. Exact identification of such drug(s) is required to guide future management and avoid re-exposure. We describe two cases of isolated thrombocytopenia in which cytometric analysis, a readily available technique, allowed the identification of the causative drug in the context of complex therapies (rifampicin and abciximab causing late onset thrombocytopenia).

[Desensitization to cotrimoxazole, rifampicin and penicillin G in nine patients with prior hypersensitivity]. / Original Breve Desensibilización de cotrimoxazol, rifampicina y penicilina G en nueve pacientes con hipersensibilidad previa.

OBJECTIVE: To present a protocol for the administration and development technique of the desensitization regimens for cotrimoxazole, rifampicin and penicillin G hypersensibility. METHOD: A review of the available desensitization protocols for these antibiotics and a retrospective study of desensitization processes undertaken in the center from 1998. A development technique of the antibiotic dosages was designed. RESULTS: Desensitization regimens for cotrimoxazole, rifampicin and penicillin G undertaken in the center in 9 patients came from a protocol by Glucksteins et al., Holland et al. and Wendal et al., respectively. After the literature review and the satisfactory results that allowed subsequent antibiotic administration in the 9 cases, these regimens were established as protocols of the center. CONCLUSIONS: Dosage development and patient administration have a practical application and can help to decrease the potential mistakes related to the complexity of the process.

'Flu' syndrome on once monthly rifampicin: a case report.

'Flu' syndrome as a complication of intermittent weekly administration of rifampicin is well documented. The rare occurrence of 'flu' syndrome on once monthly rifampicin is reported in this paper.

Lymphocyte transformation test for the evaluation of adverse effects of antituberculous drugs.

The usefulness of the lymphocyte transformation test (LTT) for the analysis of adverse reactions to antituberculous drugs was evaluated. - The LTT was performed with isoniazid and rifampicin in 15 tuberculosis and 2 MOTT (Mycobacteria other than tuberculosis)-infection patients who suffered drug reactions, in 23 patients without any adverse reactions, in 7 controls previously exposed to antituberculous drugs, and in 14 controls who had never been exposed. 4/15 of the hepatotoxic reactions only showed a positive LTT with rifampicin, 3/15 only with isoniazid, and in 8/15 the LTT was negative. In an anaphylactoid shock reaction the LTT was extremely exaggerated for both rifampicin and isoniazid. In patients without any side effects only one slightly increased LTT due to isoniazid was observed. Two healthy controls with previous contact to these drugs showed a positive LTT for isoniazid, one of those with both rifampicin and isoniazid. The LTT was negative in all control persons without any former contact to antituberculous medications. In most cases hepatotoxicity seems to be a pure toxic reaction without the participation of cellular immune mechanisms. LTT can be useful for identifying the drug responsible for immunological side effects.

[The usefulness of the desensitization to rifampin in the treatment of mycobacterial disease in patients with AIDS]. / Utilidad de la desensibilización a rifampicina en el tratamiento de enfermedades producidas por micobacterias en pacientes con SIDA.

BACKGROUND: Hypersensitivity reactions to rifampin are relatively uncommon, but they may result in cessation of therapeutic medications. PATIENTS AND METHODS: We report our experience with oral desensitization protocol to rifampin in a group of 35 HIV-positive patients with mycobacterial disease who had some hypersensitivity reaction to this drug. RESULTS: Adverse reactions with this protocol were few and easily treated. CONCLUSIONS: Oral desensitization to rifampin is safe and effective, allowing some of these patients (60%) to reintroduce the drug and to reduce the time of treatment.

Flu like syndrome with rifampicin pulse therapy.

Flu like syndrome was found in a patient of BT leprosy taking Rifampicin in pulse therapy. This side effect was absent when the dose of Rifampicin was decreased. Details of this case is given with a review of literature.

[Immunoallergic complication induced by rifampicin with disseminated intravascular coagulation]. / Accident immunoallergique à la rifampicine avec coagulation intravasculaire disséminée.

In a 48-years old woman, intermittent rifampicin treatment induced an immunoallergic reaction with digestive disorders, haemolysis, acute renal failure and prolonged prothrombin time. The reintroduction of rifampicin, 17 days later, resulted in a similar, though more severe, reaction associated with diffuse haemorrhages from disseminated intravascular coagulation, this association being exceptional. The responsibility of rifampicin was demonstrated by the chronological relationship between clinical symptoms and administration of the drug, and by the presence in the patient's serum of anti-rifampicin antibodies. The antigen-antibody reaction with complement activation and haemolysis probably explains the disseminated intravascular coagulation.

[Severe immunoallergic reaction in a patient treated for two months continuously with rifampicin]. / Accident immunoallergique grave chez un patient traité quotidiennement depuis deux mois par rifampicine.

BACKGROUND: Rifampicin is a major drug used for the treatment of mycobacterial infections. It is usually well tolerated although cases of immunoallergic events have been reported in discontinuous regimens. CASE REPORT: We report the case of a 55-year-old man who developed a severe drug reaction after taking rifampicin daily for two months with no interruption. The clinical course was favorable after drug withdrawal. Challenge with other antituberculous drugs did not induce any adverse reaction. CONCLUSION: Despite the few cases reported, antituberculous regimens containing rifampicin can cause severe adverse reactions which subside progressively after drug withdrawal.

[Rifampicin: rabbits sensitization, two rifampicin-protein conjugates and detection of rifampicin specific IgG].

The presence of rifampicin (RFP) specific IgG in the sera of rabbits immunized with RFP or with two RFP-protein conjugates (RFP-bovine serum albumin, RFP-BSA and RFP-rabbit serum albumin RFP-RSA) was measured by ELISA. The way of conjugation and the molecular conjugation rate were different between RFP-BSA and RFP-RSA. The titre of RFP specific IgG was 1:10-1:100 in RFP immunized rabbits, 1:100-1:1,000 in RFP-RSA immunized rabbits, and over 1:1000 in RFP-BSA immunized rabbits. The binding properties of the sera to RFP were demonstrated by inhibition assay. These are the models of RFP sensitization first established by immunization animals with RFP itself or RFP-protein conjugates.

[Clinical evaluation on the detection of rifampicin specific IgG, IgM].

Using RFP-BSA as antigen, an ELISA was established to detect RFP specific IgG/IgM in the serum of 128 RFP treated patients. The results showed that RFP specific IgG/IgM could not be detected either in tuberculosis patients or healthy controls as long as the subjects were RFP free. A small number of positive results (8%) could be found in the RFP treated patients without reactions. In RFP treated patients with untoward reactions, RFP specific IgG/IgM had a high positive rate (39.3%, P < 0.05). The reactions of the positive serum could be inhibited significantly by the addition of RFP, RFP-RSA but not by RSA. In 7 patients that RFP rechallenge test was performed the result of RFP Specific-IgG/IgM was in concordance with clinical test. The results showed that this method was specific for the detection of RFP specific IgG/IgM and at least a part of RFP adverse reactions may have some relation with RFP specific IgG/IgM.

[Detection of antibody specific to rifampicin metabolite by ELISA--mechanism of sensitization by rifampicin].

A 46-year-old male tuberculosis patient developed acute renal failure and liver dysfunction following the oral administration of rifampicin (RFP). The mechanism of the reaction was examined by means of enzyme-linked immunosorbent assay (ELISA). 3-formylrifamycin-SV (Formylrifamycin), which is one of RFP metabolites, was conjugated to human serum albumin. ELISA was performed with this conjugate (Formylrifamycin-HSA) as an antigen. We also evaluated 100 tuberculosis patients receiving oral RFP and 45 healthy volunteers in order to determine the incidence of sensitization by RFP. IgG and IgM antibodies specific to Formylrifamycin-HSA were detected in serum from the patient with RFP-induced renal failure. Among the IgG subclasses, IgG1 antibody was detected. IgG and IgG1 antibodies specific to Formylrifamycin-HSA were detected in serum from only one of the 100 tuberculosis patients. Our results indicate that sensitization to RFP can occur on oral administration, and that acute renal failure was caused by IgG, IgM, and IgG1 antibodies specific to Formylrifamycin as a hapten.

Rare immediate hypersensitivity to rifampicin in a patient with tuberculosis requiring drug discontinuation.

A 47-year-old Turkish female patient was diagnosed with tuberculosis of the sacro-iliac joints and terminal ileum. She developed a severe adverse drug reaction while taking first-line tuberculosis therapy consisting of isoniazid, pyrazinamide and rifampicin as Rifater and ethambutol. Within 5 min of ingestion she developed pruritic rash, angioedema and breathing difficulties, resulting in an A&E admission. The tuberculosis therapy was discontinued. Intradermal and oral challenge tests for rifampicin were conducted but abandoned early on due to reactions which included audible wheeze, vomiting, throat pain and violent rigours. Clinical manifestations were swiftly treated with appropriate medications. This resulted in a change to the tuberculosis treatment regime, where streptomycin, isoniazid, ethambutol and pyrazinamide were given for 2 months and isoniazid and ethambutol for 12 months. Allergic reactions to rifampicin are rare and should be distinguished from flushing due to pyrazinamide. Prompt diagnosis and treatment by clinicians can be life saving.