Jean-François Nicolas

Dissociation of Allergenic and Immunogenic Functions in Contact Sensitivity to Para-Phenylenediamine

Contact sensitivity to para-phenylenediamine (PPD) is a frequent delayed-type hypersensitivity resulting in contact dermatitis. The aim of the present study, conducted in 16 patients allergic to PPD (as assessed by a positive patch test), was to get better insight into the mechanism of T-cell activation in PPD contact sensitivity. PPD was unable to induce significant proliferation of T cells from a first set of 9 patients. In 7 further patients, lymphocyte proliferation was assessed using PPD and 2 PPD metabolites, namely Brandrowskis base (BB) and benzoquinone (BQ). BB specifically stimulated T-cell proliferation in a dose-dependent fashion in all 7 patients whereas BQ, like PPD, was ineffective. The peripheral blood mononuclear cells (PBMC) of 8 PPD nonallergic individuals did not respond to either PPD, BB or BQ. We concluded from this study that: (1) the immunogenic hapten in PPD hypersensitivity is not PPD itself, and (2) BB might be the oxidative derivative of PPD endowed with T-cell-activating properties. Further support to this statement was provided by the observation that a T cell line derived from PBMC of a PPD-allergic patient in the presence of PPD responded to BB but not to PPD. Our in vitro results suggest that PPD is a prohapten which when applied on the skin is metabolized and converted into products (such as BB) which are the immunogenic haptens able to activate specific T cells.

Effet de l’arrêt des corticoïdes au cours de l’urticaire chronique (étude prospective de 17 malades)

BACKGROUNDnAlthough two reports have indicated benefits of oral steroids in acute urticaria, the 2003 French guidelines emphasized their inefficacy in the treatment of idiopathic chronic urticaria, and the lack of studies. We present the results of a prospective study in 17 patients presenting severe chronic urticaria who agreed to stop taking oral steroids over a one-year period.nnnPATIENTS AND METHODSnThis single-centre prospective study included adults (1) presenting chronic urticaria as defined by the French consensus conference committee on chronic urticaria (2003), (2) exhibiting at least two of the following three criteria: sleep disturbance due to itching, repeated angioedema, general symptoms; (3) unresponsive or mildly improved by antihistaminic (anti-H1) therapy; (4) receiving oral steroids at least three days per month. After inclusion in the study, oral steroids were stopped either immediately or gradually, on a case-by-case basis. Two different anti-H1 agents were prescribed at inclusion with follow-up visits two, four and 12 months after complete withdrawal of oral steroids.nnnRESULTSnSeventeen patients were included (M/F sex-ratio: 0.54; mean age: 40 years). General signs (fever, arthralgia, various pains), delayed pressure urticaria, and idiopathic cutaneous vasculitis were noted respectively, in seven, nine and three cases. Oral steroids had been taken for three to 30 days per month before inclusion. Three patients had received prior treatment (e.g., immunosuppressants), with no improvement. After withdrawal of oral steroids, (1) 47% of patients presented a short relapse and/or worsening of chronic urticaria, (2) three patients dropped out of the study at four months (persistence of chronic urticaria unacceptable to patients, despite a clinical score showing mild response), (3) six (35%) had complete remission of chronic urticaria at 12 months, with delayed pressure urticaria in three of these cases, (4) eight (47%) had partial remission, five of whom had delayed pressure urticaria, (5) lasting remission of general symptoms.nnnDISCUSSIONnOur study shows that most cases of chronic urticaria are managed without oral steroids since inefficacy of anti-H1 drugs is generally only temporary. After withdrawal of oral steroids, a short increase in chronic urticaria was frequently observed with constant remission from extracutaneous signs and/or histological evidence of vasculitis. We suggest an active role of oral steroids in the failure of anti-H1 therapy. Moreover, oral steroids do not seem to confer any benefits in delayed pressure urticaria, and pending further prospective controlled studies, we recommend that these drugs be prescribed sparingly in chronic urticaria.

Nine μg intradermal influenza vaccine and 15 μg intramuscular influenza vaccine induce similar cellular and humoral immune responses in adults

Intanza® 9 μg (Sanofi Pasteur), a trivalent split-virion vaccine administered by intradermal (ID) injection, was approved in Europe in 2009 for the prevention of seasonal influenza in adults 18 to 59 years. Here, we examined the immune responses induced in adults by the ID 9 μg vaccine and the standard trivalent intramuscular (IM) vaccine (Vaxigrip® 15 μg, Sanofi Pasteur). This trial was a randomized, controlled, single-center, open-label study in healthy adults 18 to 40 years of age during the 2007/8 influenza season. Subjects received a single vaccination with the ID 9 μg (n = 38) or IM 15 μg (n = 42) vaccine. Serum, saliva, and peripheral blood mononuclear cells were collected up to 180 days post-vaccination. Geometric mean hemagglutination inhibition titers, seroprotection rates, seroconversion rates, and pre-vaccination-to-post-vaccination ratios of geometric mean hemagglutination inhibition titers did not differ between the two vaccines. Compared with pre-vaccination, the vaccines induced similar increases in vaccine-specific circulating B cells at day 7 but did not induce significant increases in vaccine-specific memory B cells at day 180. Cell-mediated immunity to all three vaccine strains, measured in peripheral blood mononuclear cells, was high at baseline and not increased by either vaccine. Neither vaccine induced a mucosal immune response. These results show that the humoral and cellular immune responses to the ID 9 μg vaccine are similar to those to the standard IM 15 μg vaccine.

Severe hypocalcemia and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome under deferasirox therapy for myelodysplasic syndrome

To the editor: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare life-threatening adverse drug reaction. The culprit drugs are dominated by Allopurinol and anticonvulsants [1]. The efficiency of deferasirox (DFX) has been reported in the treatment of iron overload secondary to myelodysplastic syndrome (MS) management [2]. We report the first case of DRESS during DFX treatment, associated with severe hypocalcemia. In 2010, a 75-year-old woman, followed for MS since 2004, was admitted in ICU, for exanthema associated with skin necrosis aeras, facial edema, and fever, 15 days after starting DFX therapy. Blood tests revealed no eosinophilia, leukocytosis (13,5 3 10 L (N < 10)), atypical lymphocytes, increased liver enzymes (ALAT until 10 N), prothrombin time at 30% (N > 70%), disseminated intravascular coagulation (DIC) signs (low fibrinogen 0.5 g L (N > 1.8), thrombopenia until 17 3 10 L), and severe hypocalcemia (ionized calcemia at 0.92 mmol L (N > 1.4 mmol L). Ferritin level was high (12,546 lg L (n < 322)), and triglycerides were normal. Serum calcium concentration before DFX therapy was normal. Bone marrow biopsy revealed eosinophils infiltrate (20%) and iron overload. without any sign of hemophagocytic syndrome, leukemia, or MS. VIH,VHB, VHC, HHV6, CMV, and EBV serology and blood polymerase chain reaction were negative. Repeated blood cultures and mycoplasma pneumoniae serology were negative. The evolution was complicated rapidly by cardiac arrest without any etiology except severe hypocalcemia. The vitamin D level (1.25OH D3) was low (<10 ng mL (N > 50)). Parathormone level was normal. Histologic analysis of skin and necrosis areas biopsy revealed perivascular lymphocytes infiltrates with eosinophils, compatible with DRESS and intracapillary thrombosis, compatible with cutaneous lesions of DIC. The diagnosis score, according to criteria published by Kardaun et al. [3], was calculated at 6 and confirm the diagnosis of probable DRESS. At admission, DFX was immediately stopped and systemic intravenous corticosteroid treatment by methylprednisolone 60 mg day and calcium supplementation, without antibiotics, were started. Under this therapy, the cutaneous rash, necrosis, and visceral involvement slowly improved. Nevertheless, electroencephalogram assay revealed the diagnosis of definitive chronic vegetative state probably secondary to cardiac arrest. DRESS is characterized by clinical criterias such as later onset, skin rash, multiorgan involvement, atypical lymphocytes, and eosinophilia [1]. DRESS is a lethal disease with an estimated mortality of 10%. Nevertheless, eosinophilia is often absent or delayed for 1 to 2 weeks, as reported by Chen et al. [4] with only 50% of eosinophilia or atypical lymphocytes in 60 DRESS cases. In our case, corticosteroids were started immediately before admission, which could also rapidly decrease or hide blood anomalies. Furthermore, even if eosinophils level were not high in blood, they could infiltrate other organs, such as the skin or bone marrow, as in our case. Only two cases of DFX allergic reactions have been reported including acute renal failure and delayed hypersensitivity syndrome [5]. DRESS is not well known as being responsible for profound hypocalcemia. Furthermore, hypocalcemia under DFX therapy with recurrence after re-exposure have been reported and suggest that DFX could be a risk factor of hypocalcemia in this case [6]. The suspected pathophysiology is an ‘‘hungry bone syndrome.’’ Under DFX, iron chelation in bone’s patient lead to an increase of bones calcium uptake and in consequence to serum calcium anomalies. In conclusion, clinicians should be aware of the risk of (i) severe hypocalcemia during DFX therapy and (ii) potentially lethal DRESS under DFX therapy, which is being more and more prescribed.

Severe sporotrichoid fishtank granuloma following infliximab therapy for Crohn's disease

To the Editor: Cutaneous adverse reactions of anti-TNFa biotherapies are varied and present frequently as eczematiform reactions, paradoxical psoriasis, or more rarely, infections. We report here a rare form of severe sporotrichoid fishtank granuloma following infliximab therapy that developed in a patient whose hobby was aquariophilia. A 63-year-old man with an otherwise unremarkable past medical history had been treated for Crohn’s disease since 2005 with infliximab, administered intravenously every other month. Steroid treatment was initially administered concomitantly but was discontinued in 2006. In June 2008 the patient presented with 3 nodules of 2 months’ duration that showed a linear arrangement; 2 of them were located on the right thumb (bulb and base of the first metatarsal) and the third one on the inner face of the forearm (Fig. 1). Laboratory work-up revealed raised C-reactive protein (CRP) titers (34 mg/L, N <5 mg/L). Neither lymphopenia nor kidney or liver dysfunctions were found. The diagnosis of sporotrichoid fishtank granuloma was considered clinically and was supported by the patient’s history, as he owned an aquarium and had cleaned it out around the time of the appearance of the nodules. Histological examination showed a moderately dense, diffuse dermal infiltrate made of lymphocytes and occasional histiocytes. Histochemical stains (PAS, Ziehl-Neelsen) failed to show microorganisms. The diagnosis of Mycobacterium marinum infection was confirmed by positive cultures of the microorganism. Infliximab was discontinued and the patient was given minocyclin (20 g/d). After 2 months the lesions had considerably regressed, leaving a residual hyperpigmentation; they healed completely after an additional 2 month’s treatment that was well tolerated. Infliximab was reintroduced in August because of worsening of Crohn’s disease, with no adverse effects to date. The patient mentioned that the skin disease was unknown to his aquariophilic friends and did not seem to be mentioned in specialized magazines. The risk of mycobacterial infections, especially tuberculosis, seems to be higher under TNFa inhibitors. Nevertheless, few atypical mycobacterium infections have been reported affecting the lungs, liver, or the skin. As a matter of fact, TNFa plays an essential role in the defense against infectious agents, namely, mycobacteria, by favoring the recruitment of inflammatory cells participating in the formation of tuberculous granulomas. However, it does not seem involved in granuloma formation but rather in its persistence, by preventing the necrosis of macrophages. To the best of our knowledge, only 3 cases of M. marinum infections have been so far reported under antiTNFa treatment. Confirmation of the diagnosis, which may initially be difficult in the absence of granuloma histologically, was only possible thanks to bacteriological examination in 2 cases, of which ours is the first occurring in an aquarium enthusiast. Remarkably, multiplicity of lesions and a sporotrichoid arrangement were noted in all cases, probably because of the iatrogenic immunosuppression. The treatment of M. marinum infections is a challenge. Single lesions can be excised surgically. First-line treatment for limited forms includes monotherapy with clarithromycin, trimethoprim sulfamethoxazole, minocyclin, or doxycyclin. The treatment must be continued for 2 months after clinical healing. In disseminated forms bitherapy is recommended, with various combinations of clarithromycin (1 g/d), rifampicin (10 mg/kg), minocyclin, and doxycyclin (200 mg/d). In vitro resistance, however, is frequent with ethambutol. When this fails, photodynamic therapy seems to be an interesting option. The choice of treatment, however, remains empirical since no randomized studies have been carried out.