Drug-induced hypersensitivity syndrome in internal medicine: diagnostic and therapeutic traps. Eight observations

PURPOSE: Drug-induced hypersensitivity syndrome (DIHS) is an acute and severe drug reaction. Manifestations include severe skin lesions, fever, nodal enlargement, blood eosinophilia and multisystemic involvement. The severe systemic manifestations of DIHS are responsible for a 10% mortality rate. The pertinence of corticosteroid therapy is discussed. METHODS: The authors report eight retrospective cases of DIHS obtained from the PMSI (Programme de Médicalisatiopn des Systèmes d'Information) between November 1991 and November 1998. RESULTS: The series consisted of five male and three female patients (mean age: 52.6 years; range: 23-83 years). The interval between the introduction of the drug and the onset of the reaction varied from two to eight weeks. Due to severe systemic manifestations, three patients were given corticosteroid therapy. Healing of skin and systemic disorders resolved with a mean delay of 4.4 weeks (range: 1 to 56 weeks). CONCLUSION: DIHS can be a diagnostic trap, as there are no diagnostic criteria for DIHS. Only the association of multiple arguments such as the time to the occurrence of symptoms, clinical similarity to many infectious illnesses, hypereosinophilia, atypical lymphocytosis, etc. may help guide diagnosis. DIHS can also be a therapeutic trap, as prompt withdrawal of the offending drug is essential to minimize morbidity. Although still controversial in the literature, the pertinence of corticosteroid therapy may be discussed in case of severe systemic effects. Patch testing can be a valuable tool to determine the responsibility of a drug; however it proves to be useful only when positive.     

Sarcoïdose au cours du traitement de l’hépatite C par interféron alpha et ribavirine : deux casSarcoidosis during the treatment of hepatitis C by interferon-alpha and ribavirin: two cases.

Introduction. – Interferon-alpha (IFNα) used to treat chronic hepatitis C can be responsible for some side effects. We report two cases of sarcoidosis which appeared in patients treated with IFNα and ribavirin for chronic hepatitis C.Exegesis. – A first patient, treated for 5 months with IFNα and ribavirin because of chronic hepatitis C, after the failure of a first treatment with IFNα alone, was hospitalized for dyspnea. The chest X-ray and scanner revealed an interstitial syndrome and mediastinal adenopathies. Biopsies of bronchial spurs revealed epithelioid and giganto-cellular granuloma. After discontinuation of antiviral treatment and starting corticosteroid therapy, the evolution was favourable but viremia reappeared. A second patient with IFNα and ribavirin for 4 months because of chronic hepatitis C (after the failure of a first treatment with IFNα alone) was hospitalized for fever, arthralgias, erythema nodosa and modification of previous skin scars. The biopsy of a scar showed an epithelioid and giganto-cellular granuloma. After discontinuation of antiviral therapy and starting corticosteroid treatment, the evolution was favourable.Conclusion. – Some publications mention occurrence of sarcoidosis during IFNα therapy, occasionally associated with ribavirin, disappearing after discontinuation of the treatment, though sometimes corticotherapy is necessary. The roles of IFNα and ribavirin are discussed.     

Un cas « historique » de saturnisme hydrique : difficultés diagnostiques et thérapeutiquesA historical case report of lead poisoning via drinking water: diagnostic and therapeutic issues.

Introduction. – It is likely that lead poisoning via drinking water is often overlooked because of its supposed rarity and nonspecific early symptoms, which result in delayed management.Exegesis. – One case of severe lead poisoning via drinking water is reported. The diagnosis was long missed and a particularly long chelating treatment was required. The clinical features included lead colic, a Burton’s lead line, anemia, polyneuritis and arterial hypertension. Eighteen courses of calcium EDTA were required to obtain ‘biological recovery’. The poisoning was linked to a very long water supply lead pipe and potomania secondary to alcohol withdrawal.Conclusion. – This case report illustrates how difficult the early recognition of lead poisoning can be, and underlines the need to inquire about a toxic aetiology, particularly via the environment, of otherwise unexplained pathological conditions.     

« Sclérose en plaques plus » :les leucoencéphalopathies aux frontièresde la médecine interne“Multiple sclerosis plus”: frontiers between multiple sclerosis and a new nosological entity.

Introduction. – Multiple sclerosis (MS) is an inflammatory, demyelinating and probably autoimmune disease affecting the white matter of the central nervous system (CNS). Due to the absence of specific clinical and laboratory markers, diagnosis remains difficult.Current knowledge and key points. – In particular, no clinical or paraclinical investigation is satisfactory to distinguish definite MS from other autoimmune or inflammatory diseases, especially when they predominantly affect  the CNS. Moreover, previous studies have reported that patients with definite MS could present clinical systemic signs suggestive of other inflammatory or autoimmune diseases, and that MS could be associated with other autoimmune diseases. On the other hand, the presence of biological autoimmune abnormalities, including antinuclear antibodies and antiphospholipid antibodies, has been observed, with a high frequency in patients with MS in comparison to control populations. These clinical and laboratory features could therefore represent a new nosological entity characterized by a systemic immune dysregulation more extensive than the CSN target, or a distinct subgroup of MS patients with a classical course of the disease. Because of the impact of the new therapeutic approach to MS, an important issue concerning this aspect that should be addressed is the use of immunomodulatory therapy, especially with interferon beta. It appears necessary to consider these abnormalities before treating MS patients with preventive therapy, in particular in the perspective of new strategies, such as treatment at an early stage of the disease or combination therapies.     

Artérite de Takayasu: explorations vasculaires et prise en charge thérapeutique. Expérience à propos de 16 patients

Purpose. -- There is no consensus in regard to vascular explorations and therapeutical management of Takayasu's arteritis. The objective of this study was therefore to establish the most appropriate vascular explorations and to analyze current treatments.Methods. -- Clinical, biological and morphological findings related to either diagnosis or treatment were retrospectively evaluated in sixteen patients diagnosed with Takayasu's arteritis according to the American College of Rheumatology criteria.Results. -- Median delay between the occurrence of the first symptoms and the diagnosis was 9 months. Aortic lesions and aortic valvular incompetence were more frequent. Statistical analysis showed the existence of a correlation between the lack of relapse and corticosteroid therapy (Fisher exact test, P = 0,021). Percutaneous transluminal angioplasty led to stabilization of vascular lesions. Surgical management led to satisfactory results, except for patients with aortic lesions, as survival was then less than 1 year.Conclusion. -- Early diagnosis is mandatory in patients with Takayasu's arteritis in order to propose appropriate therapy, particularly corticosteroid therapy. Surgery and angioplasty prove to be useful in occlusive forms. Late diagnosis is accompanied by severe aortic lesions and fatal outcome.

Résumé

Propos. -- Dans le cadre de l'artérite de Takayasu, il n'existe pas de consensus concernant les explorations vasculaires et la prise en charge thérapeutique. L'objectif de notre étude était d'analyser chez 16 malades souffrant d'artérite de Takayasu les méthodes d'exploration les plus adaptées et les traitements employés.Méthodes. -- Seize patients atteints d'artérite de Takayasu selon les critères de l'American College of Rheumatology ont été évalués de façon rétrospective de 1975 à 1997, cliniquement, biologiquement, morphologiquement, sur le plan diagnostic et thérapeutique.Résultats. -- Dans notre série, la médiane de retard diagnostique était de 9 mois. L'atteinte aortique et valvulaire aortique était plus fréquente. Les résultats ont montré l'existence d'une corrélation statistiquement significative entre l'absence de rechute et l'emploi des corticoïdes (test exact de Fisher, p = 0,021). L'utilisation de l'angioplastie a entraîné une stabilisation des lésions. La prise en charge chirurgicale s'est montrée satisfaisante, en dehors des patients ayant une atteinte aortique pour lesquels la survie était inférieure à 1 an.Conclusion. -- L'analyse de notre série montre la nécessité d'un diagnostic précoce afin de proposer une thérapeutique adéquate, en particulier la corticothérapie. La chirurgie et l'angioplastie sont des recours efficaces en cas de forme occlusive. Les formes diagnostiquées tardivement comportent une atteinte aortique sévère dont l'évolution est le plus souvent fatale.     

Amylose laryngée : une cause rare de dysphonieLaryngeal amyloidosis: a rare cause of hoarseness.

Introduction. – The larynx is a rare site of deposition for amyloidosis. Diagnosis may be delayed and evoked in patients with prolonged hoarseness. We have reported two cases of laryngeal amyloidosis.Exegesis. – One man and one woman suffered from  hoarseness during one and three years, respectively. Laryngoscopic examination showed diffuse infiltration of the larynx. Amyloidosis was confirmed by the characteristic Congo-red staining of laryngeal biopsies. The search for other localizations of amyloidosis was negative. No monoclonal plasma cell proliferation was detected. Both patients received endoscopic CO₂ laser excision. In one case, chemotherapy was initially associated due to dystrophic plasma cells in bone marrow aspiration and then withdrawn because of clinical failure. With a 6-month follow-up, hoarseness remained stable.Conclusion. – Laryngeal amyloidosis is an essentially localized disease revealed by hoarseness. Treatment is endoscopic by laser excision. In nearly half of the cases in the literature, it had to be repeated due to localized recurrent lesions. Long-term prognosis of localized laryngeal amyloidosis is better than systemic AL amyloidosis.     

Durée du traitement anticoagulant oral dans la maladie thromboembolique veineuse Duration of oral anticoagulant therapy for venous thromboembolism.

Purpose. – The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism is still a matter of debate. It is essential to balance the desired effect of the anticoagulants in reducing recurrences against the risk of major bleeding. The aims of this paper are to describe the current concepts in this field.Current knowledge and key points. – Recent data, based on randomised controlled trials, suggest that it is necessary to tailor the duration of anticoagulation individually according to the topography of venous thromboembolism and the presence of risk factors. A 6-week treatment for patients with isolated calf vein thrombosis is sufficient. For proximal thrombosis and/or pulmonary embolism, a short anticoagulant course seems sufficient in patients with temporary risk factors (3 months) and a longer anticoagulant course (6 months at least) is recommended for cases with permanent risk factors or idiopathic venous thromboembolism. The inherited or acquired hypercoagulable states can be divided into those that are common and associated with a modest risk of recurrence (i.e., isolated factor V Leiden or G20210A prothrombin gene) and those that are uncommon but associated with a high risk of recurrence (i.e., antithrombin, protein C or S deficiencies and anticardiolipin antibodies). Thus, the presence of one of these last abnormalities favours more prolonged anticoagulant therapy.Future prospects and projects. – 1) For patients at high risk of recurrence, there is a paucity of evidence-based medicine, particularly for patients with biological thrombophilia, and randomised controlled trials in this population are required. An assessment of low- or fixed-dose oral anticoagulation is also necessary in order to reduce the bleeding risk. 2) It is not always possible to precisely determine the optimal duration with the available data. We have performed a meta-analysis on summary data which suggests that a long course of oral anticoagulant therapy is superior to a short course. An individual meta-analytic approach is needed to draw more precise conclusions on an interesting and important clinical topic and we propose to perform this analysis in a international collaborative group.     

Les gammapathies monoclonales de signification indéterminéeMonoclonal gammopathy of undetermined significance.

Introduction. – Monoclonal gammopathy of undetermined significance is an asymptomatic disorder associated with serum monoclonal immunoglobulin spike. Its incidence is about 1% in patients of 50 years of age, and rapidly increases in elderly patients.Current knowledge and key points. – Within the 20 years following diagnosis, about 25% of patients will evolve towards either multiple myeloma (for patients with IgG or Ig A) or malignant lymphoproliferative disorder (for patients with IgM). Definition, circumstances associated with a transient monoclonal spike, and currently available parameters used for differential diagnosis with either multiple myeloma or malignant lymphoproliferative disorder are successively discussed. One part of the most usual biological parameters is of prognostic value, and is reviewed in more detail. Recent data concerning immunophenotype, cytogenetics and molecular biology of plasma cells reinforce the link between the asymptomatic condition and multiple myeloma. In monoclonal gammopathy of undetermined significance, some plasma cells resemble normal or reactive plasma cells, whereas others mimic those found in multiple myeloma.Future prospects and projects. – The most recent biological data are also discussed in order to evaluate whether some would help to discriminate those patients who will remain asymptomatic lifelong from those who will evolve towards multiple myeloma.     

Muscular haematoma in Henoch-Schönlein purpura

Introduction. – Henoch-Schönlein purpura is one of the most frequent systemic vasculitis in children. In adults, muscle involvement is extremely rare and not very well characterized. We report a case of Henoch-Schönlein purpura with severe skin and renal involvement in witch multiple intramuscular haematoma leaded to severe anaemia. Histological examination confirms the muscle localization of the disease.Exegesis. – A 68 years old man treated by oral anticoagulation for multiple venous thrombosis, was admitted with necrotic vasculitis of the skin, abdominal pain and segmental IgA glomerulopathy. The diagnosis of Henoch-Schönlein purpura was rapidly made and intensive steroid therapy started. After rapid improvement, a haemorrhagic shock due to voluminous intramuscular haematoma was diagnosed by MRI. Histological examination of the muscle, confirms the localization of the disease.Conclusion. – Intramuscular haematomas are very uncommon in Henoch-Schönlein purpura. There are usually a consequence of muscular immune complex vasculitis. In our patient, high dose corticosteroid was not unable to control the disease.     

Systemic lupus erythematosus: modern strategies for management – a moving target

In the past decade, advances in the area of lupus have led to a significant expansion in our armamentarium of therapeutics, although none is yet approved by the FDA for use in SLE. The use of mycophenolate mofetil has been a substantial advance. Recent clinical trials have shed light on optimizing usages and alternatives of more traditional therapies, such as antimalarials, cyclophosphamide, azathioprine, and mycophenolate mofetil. In addition, targeting components of the immune system has yielded promising new therapies in the arena of biologics, anticytokine therapy, and stem-cell transplantation, which are currently being tested. As data from ongoing trials evolve, our questions involving appropriate patient selection and disease indications will help bridge the gaps in our knowledge and understanding of administration of such potential therapies. Future innovative strategies might include further exploration of: (1) the body's inherent tolerance mechanisms, such as promoting T regulatory cells that help suppress self reactive immune cells; (2) targeting interferon pathways known to be dysregulated in patients with SLE; and (3) exploring interactions between the innate and adaptive immune system, such as studying toll-like receptors and dendritic cell activation.

• A greater understanding of immunopathogenesis has led to the development of biologics targeting individual components of the immune repertoire.

• Future studies are warranted for further investigation of the utility of biologics and promise of stem-cell transplantation in patients with SLE.

Vieillissement et régression de l’hypertrophie cardiaque chez l’hypertendu

Objective. -- This study was aimed at determining factors acting on the regression of left ventricular hypertrophy due to essential hypertension.Methods. -- It was a non-randomized, echocardiographic study of 60 previously untreated hypertensive subjects (20 to 75 years of age).Results. -- Following a 5-year therapy, the decrease in the left ventricular mass was 14%. Normalization of blood pressure and reversal of left ventricular hypertrophy were obtained in 50% and 58% of patients, respectively. Patients of the non-responder group (non-response being defined as a less than 10% decrease in the left ventricular mass) were older and had a longer history of high blood pressure. A positive correlation was observed between age and decrease in the left ventricular mass, the latter being less marked in older patients. Antihypertensive drugs classes had no influence on reversal of left ventricular hypertrophy.Conclusion. -- Ageing may be a factor of resistance to the decrease in left ventricular mass with therapy. These results suggest that early screening and management of hypertension are essential.

Résumé

Propos. -- Indépendent de l'élévation de la pression artérielle, le vieillissement est associé à un remodelage concentrique du ventricule gauche qui pourrait moduler avec le temps l'effet des traitements antihypertenseurs sur le cœur. L'objectif de la présente étude était de mettre en évidence les facteurs pouvant influencer la régression de l'hypertrophie ventriculaire gauche chez les hypertendus.Méthodes. -- Il s'agissait d'une étude de suivi, non randomisée, portant sur 60 patients hypertendus, âgés de 20 à 75 ans, jamais traités à l'inclusion et présentant une hypertrophie ventriculaire gauche.Résultats. -- Après 5 ans d'évolution sous traitement antihypertenseur, la diminution de la masse ventriculaire gauche de 14 % est largement significative. La pression artérielle s'était normalisée et l'hypertrophie avait régressé chez, respectivement, 50 et 58 % des patients. Le groupe de patients qui ne répondaient pas au traitement (44 % de la population), dont la diminution de la masse cardiaque, inférieure à 10 %, n'était pas significative, étaient plus âgés, la durée d'évolution de l'hypertension artérielle étant plus longue. Dans l'ensemble de la population, il a été montré l'existence d'une relation positive entre la diminution de la masse cardiaque et l'âge: c'est chez les patients les plus âgés que la diminution de la masse ventriculaire gauche est la moins importante. En revanche, il n'a pas été trouvé de relation avec la classe thérapeutique utilisée.Conclusions. -- La diminution de la masse cardiaque sous traitement antihypertenseur n'est pas seulement le résultat d'une diminution de la pression artérielle, mais fait intervenir d'autres facteurs. Parmi ceux-ci, le vieillissement pourrait être un facteur de résistance à l'action du traitement sur la diminution de la masse ventriculaire gauche. Ces résultats justifient un dépistage et une prise en charge précoce de la maladie hypertensive.     

Auto-anticorps anti-érythrocytaires et anémies hémolytiques auto-immunes. Étude de 80 observations. Aspects particuliers au sujet âgé

The following observations were drawn from the study of 80 patients with anti-erythrocyte auto antibodies (AEAA) :

- The average age was about 62 years with a maximal incidence in the 65–75 year range. There was a female predominance which increased after the age of 65 ;

- In 20 p. 100 cases, the majority being elderly patients, anti-erythrocytic auto immunisation seemed to be idiopathic. The aetiologies in the remaining cases comprised malignant haemoreticulopathies, connective tissue diseases, liver disorders, microorganism infection and treatment with alpha-methyldopa ;

- Anti-erythrocyte auto immunisation does not always cause haemolytic anaemia. In 66 p. 100 of patients with AEAA there were no clinical or biological signs of haemolysis ;

- The association of other immunological abnormalities (anti-organ antibodies, positive rheumatoid factor, hypergammaglobulinaemia…) and AEAA is common and seems to reflect a complex disorder of the immune system. This also applies in patients in whom the immunological type of AEAA changes during the course of the disease ;

- These observations lead to the discussion as to the possible relationship between auto immunity and the ageing process.